ENTOURAGE EFFECT

Synergies of cannabinoids and terpene - the influence of RDTGH - Three cancers - Superstitions in the time of Smuts - pain and alcohol meet the entourage - blocking addiction to opioids - Twelve cancers - Sleep - ZPPPD is a testicle-limiting law - Glymphatic and hemifusome systems - To pharmocratic reductionism and back again

"Understanding the intricate interplay between cannabinoids, terpenes, and flavonoids is paramount for realizing the full therapeutic benefits of cannabis," say Al-Khazaleh et al (2024)

"Cannabinoids, pivotal in cannabis's bioactivity, exhibit well-documented analgesic, anti-inflammatory, and neuroprotective effects. Terpenes, aromatic compounds imbuing distinct flavours, not only contribute to cannabiss sensory profile but also modulate cannabinoid effects through diverse molecular mechanisms. Flavonoids, another cannabis component, demonstrate anti-inflammatory, antioxidant, and neuroprotective properties, particularly relevant to neuroinflammation. The entourage hypothesis posits that combined cannabinoid, terpene, and flavonoid action yields synergistic or additive effects, surpassing individual compound efficacy. Recognizing the nuanced interactions is crucial for unravelling cannabiss complete therapeutic potential. Tailoring treatments based on the holistic composition of cannabis strains allows optimization of therapeutic outcomes while minimizing potential side effects."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10821245 [4417]

To this end, Namdar et al of the Institute of Plant Sciences and the Israeli Gene Bank

"...found that in 'high THC' or 'high CBD' strains, phytocannabinoids are produced alongside certain sets of terpenoids. Only co-related terpenoids enhanced the cytotoxic activity of phytocannabinoids on MDA-MB-231 and HCT-116 cell lines. This was found to be most effective in natural ratios found in extracts of cannabis inflorescence. The correlation in a particular strain between THCA or CBDA and a certain set of terpenoids, and the partial specificity in interaction may have influenced the cultivation of cannabis and may have implications for therapeutic treatments."

The scientists discovered that for cytotoxicity in MDA-MB-231 and HCT-116 cell lines, ingredients that went together went together.

"In this paper we present a clear example of the inter-entourage effect on cytotoxic activity. We showed: (1) A significant correlation between certain terpenoids and the main phytocannabinoids in various C. sativa strains. (2) Terpenoids, present in relatively minute amounts in cannabis extracts and possessing no therapeutic effect by themselves at these concentrations, add to the cytotoxicity of the dominant phytocannabinoid. This demonstrates the inter-entourage effect in cannabis treatments. (3) The inter-entourage interaction is specific, in part, since THC activity was enhanced only by its co-related terpenoids, at terpenoid to phytocannabinoid ratios found naturally in the plant, while CBD was more tolerant. (4) The relative ratio of phytocannabinoid to terpenoids, demonstrating the enhanced biological activity, entitled entourage effect, showed nonlinear dose dependency, rather a dose-specificity mode of action."
https://www.mdpi.com/1420-3049/24/17/3031/pdf?version=1566384625 [4418]

The "top 25 cannabinoids" are mapped out and grouped and described:
https://www.higherlearninglv.co/post/cannabinoid-clinic-research-based-training [2178]

In 2006 Varvel et al

"investigated whether CBD may modulate the pharmacological effects of intravenously administered THC or inhaled marijuana smoke on hypoactivity, antinociception, catalepsy, and hypothermia, the well characterized models of cannabinoid activity."

They found

"Intravenously administered CBD possessed very little activity on its own and, at a dose equal to a maximally effective dose of THC (3 mg/kg), failed to alter THC's effects on any measure. However, higher doses of CBD (ED(50)=7.4 mg/kg) dose-dependently potentiated the antinociceptive effects of a low dose of THC (0.3 mg/kg). Pretreatment with 30 mg/kg CBD, but not 3 mg/kg, significantly elevated THC blood and brain levels."
https://pubmed.ncbi.nlm.nih.gov/16572263/ [1796]

A UK study by Imperial College looked at childhood epilepsy, again making the astonishing discovery that THC and CBD work better together.

"Twenty-three (65.7%) patients achieved a 50% reduction in seizure frequency. 94.1% (n = 16) of patients treated with CBD and 9 -THC observed a 50% reduction in seizure frequency compared to 31.6% (n 6) and 17.6% (n = 3) of patients treated with CBD isolates and broad-spectrum CBD products, respectively (p< 0.001)."
https://www.thieme-connect.de/products/ejournals/pdf/10.1055/a-2002-2119.pdf [2180]

It's almost as if it's part of some divine plan! In 2017 King et al, at something called the "Center for Substance Abuse Research" in Philadelphia discovered that THC and CBD go together! They work better together at treating the symptoms of anti-cancer drugs with lots of side effects.

"Both CBD and THC alone attenuated mechanical allodynia [touch-sensitive pain] in mice treated with paclitaxel. Very low ineffective doses of CBD and THC were synergistic when given in combination. CBD also attenuated oxaliplatin- but not vincristine-induced mechanical sensitivity, while THC significantly attenuated vincristine- but not oxaliplatin-induced mechanical sensitivity. The low dose combination significantly attenuated oxaliplatin- but not vincristine-induced mechanical sensitivity."
https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.13887 [1325]

Ozmen et al (2024) found CBD reduced the harm caused by another cancer drug.

"Methotrexate (MTX) is a widely used medication for various cancers, yet its use is associated with adverse effects on organs, notably the lungs. Cannabidiol (CBD), known for its antioxidant and anti-inflammatory properties, was investigated for its potential protective effects against MTX-induced lung injury. Thirty-two female Wistar Albino rats were divided into four groups: control, MTX (single 20 mg/kg intraperitoneal dose), MTX + CBD (single 20 mg/kg MTX with 0.1 ml of 5 mg/kg CBD for 7 days intraperitoneally) and CBD only (for 7 days). Lung tissues were analysed using histopathological, immunohistochemical and PCR methods after the study. Histopathological assessment of the MTX group revealed lung lesions like hyperemia, edema, inflammatory cell infiltration and epithelial cell loss. Immunohistochemical examination showed significant increases in Cas-3, tumour necrosis factor-alpha (TNF-α) and nuclear factor-kappa B (NF-κB) expressions. PCR analysis indicated elevated expressions of apoptotic peptidase activating factor 1 (Apaf 1), glucose-regulated protein 78 (GRP 78), CCAAT-enhancer-binding protein homologous protein (CHOP) and cytochrome C (Cyt C), along with reduced B-cell lymphoma-2 (BCL 2) expressions in the MTX group, though not statistically significant. Remarkably, CBD treatment reversed these findings."
https://onlinelibrary.wiley.com/doi/10.1111/bcpt.13992 [3845]

In "Cannabidiol Increases Psychotropic Effects and Plasma Concentrations of Δ9-Tetrahydrocannabinol Without Improving Its Analgesic Properties" Gorbenko et al (2024) found the influence of CBD on THC to be rather different to what most would expect:

"Cannabidiol (CBD), the main non-intoxicating compound in cannabis, has been hypothesized to reduce the adverse effects of Δ9-tetrahydrocannabinol (THC), the main psychoactive and analgesic component of cannabis. This clinical trial investigated the hypothesis that CBD counteracts the adverse effects of THC and thereby potentially improves the tolerability of cannabis as an analgesic. A randomized, double-blind, placebo-controlled, five-way cross-over trial was performed in 37 healthy volunteers. On each visit, a double-placebo, THC 9 mg with placebo CBD, or THC 9 mg with 10, 30, or 450 mg CBD was administered orally. Psychoactive and analgesic effects were quantified using standardized test batteries. Pharmacokinetic sampling was performed. Data were analyzed using mixed-effects model. Co-administration of 450 mg CBD did not reduce, but instead significantly increased subjective, psychomotor, cognitive, and autonomous effects of THC (e.g., VAS 'Feeling High' by 60.5% (95% CI: 12.7%, 128.5%, P < 0.01)), whereas THC effects with 10 and 30 mg CBD were not significantly different from THC alone. CBD did not significantly enhance THC analgesia at any dose level. Administration of 450 mg CBD significantly increased AUClast of THC (AUClast ratio: 2.18, 95% CI: 1.54, 3.08, P < 0.0001) and 11-OH-THC (AUClast ratio: 6.24, 95% CI: 4.27, 9.12, P < 0.0001) compared with THC alone, and 30 mg CBD significantly increased AUClast of 11-OH-THC (AUClast ratio: 1.89, 95% CI: 1.30, 2.77, P = 0.0013), and of THC (AUClast ratio: 1.44, 95% CI: 1.01, 2.04, P = 0.0446). Present findings do not support the use of CBD to reduce adverse effects of oral THC or enhance THC analgesia."
https://ascpt.onlinelibrary.wiley.com/doi/10.1002/cpt.3381 [3498]

Summarising the benefits of cannabis in "Cannabis and cancer: unveiling the potential of a green ally in breast, colorectal, and prostate cancer" AlSalamat et al (2024) add to data on the synergy of cannabinoids and oxaliplatin:

"Oxaliplatin is a chemotherapeutic medication that is used to treat cancer. It is a platinum medication with alkylating properties (O'Dowd et al. 2023). Oxaliplatin, like other alkylating drugs, operates by interfering with the development of DNA in a cell. It kills cells by preventing them from growing and replicating (O'Dowd et al. 2023). This aids in the treatment of cancer, which is characterized by uncontrollable cell growth and division (O'Dowd et al. 2023). Exploring novel techniques to improve the efficacy of CRC treatment by identifying molecules and mechanisms linked with oxaliplatin resistance is necessary (Jeong et al. 2019). CBD has the potential to assist human CRC cells overcome Oxaliplatin resistance. Jeong et al. conducted a study to demonstrate the effect of CBD on inducing autophagy in Oxaliplatin resistance colorectal cancer cell (CRC), they generated oxaliplatin-resistant cell lines, which didnt respond to oxaliplatin treatment (Jeong et al. 2019). When the cell lines were treated with a combination of CBD and oxaliplatin, the death of oxaliplatin-resistant CRC was considerably raised (Jeong et al. 2019). The authors also performed an in-vivo study on mice. They injected a group of mice with oxaliplatin-resistant cell lines subcutaneously, then they measured the tumor size and weight every 2 days. They found that both size and weight of tumor were lower in mice that were treated with both oxaliplatin and CBD than in the non-treated control group and mice that were treated with either drug. The mechanism behind this is that CBD decreases NOS3 phosphorylation-which is essential for Oxaliplatin resistance development- and superoxide dismutase-2 (which is an intracellular antioxidant) increasing Reactive Oxygen Species (ROS) through mitochondrial dysfunction leading to induce autophagy (Jeong et al. 2019)."

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-024-00233-z [4655]

Summarising the anti-cancer activities of cannabis, Nigro et al (2021) say:

"Both THC and non-psychoactive cannabinoids have been reported to possess peripheral anti-inflammatory properties in a plethora of in vitro and in vivo models. In human peripheral blood cells, CB1 is expressed by B cells, NK cells, neutrophils, CD8+ T cells, monocytes, and CD4+ T cells, whereas CB2 mRNA is expressed by human B cells, NK cells, monocytes, neutrophils, and T cells. Typically, CB2 inhibits the production of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-𝛼), interleukin (IL)-2, IL-6, IL-8, and IFN-𝛾 by immune cells. CBD decreases peripheral inflammation through reduction of prostaglandin E2 (PGE2), nitric oxide (NO), and malondialdehyde production. In addition, CBD, in combination with minor phytocannabinoids of Cannabis sativa L. extracts, can induce a greater pharmacological anti-inflammatory activity. Indeed, a standardized cannabis extract enriched with CBD exerts a more powerful anti-inflammatory activity than CBD alone. Besides CBD, THC also possesses potent anti-inflammatory properties both in vivo and in vitro. Recently, in a mouse model of acute respiratory distress syndrome, THC leads to the suppression of the cytokine storm. The molecular mechanisms at the basis of THC down-regulation of the inflammatory processes are various and tissue-dependent. Indeed, regarding gastrointestinal and systemic inflammatory reactions, THC suppresses both lymphocytes and neutrophils activity; in epithelial and skin cells, THC inhibits the release of inflammatory mediators through impairment of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway. It is of note that there is clear evidence of the synergistic action of THC and CBD in terms of down-regulation of the inflammatory processes.

"Regarding other combination extracts, Shebabya et al. demonstrated that Cannabis sativa L. oil extract markedly suppresses the release of TNF-α in LPS-stimulated rat monocytes with inhibition of LPS-induced COX-2 and i-NOS protein expression and blockage of MAPKs phosphorylation. Additionally, the presence of phenols, terpenes, or other phytocannabinoids enhance the therapeutic activity of CBD, defined as entourage effects. In addition, cannabis extract inhibits the production of IL-8, matrix metallopeptidase (MMP)-9, and vascular endothelial growth factor (VEGF), an effect not detected with CBD alone, in skin cells. Other non-psychoactive cannabinoids, including CBC and CBN, also showed substantial in vivo anti-inflammatory responses. On the other hand, monoterpenes such as α- and β-pinene, myrcene, and limonene have been also reported to possess substantial anti-inflammatory properties.

"Regarding neuroinflammation, both CBD and THC have protective effects through the activation of NF-𝜅B as well as the inhibition of Toll like receptor (TLR4). Indeed, in a vitro model of LPS-stimulated neuroinflammation, CBD suppresses the release of TNF-α, IL-1β, and IL-6 through the inhibition of NF-𝜅B phosphorylation and the concomitant activation of COX and iNOS. In addition, THC treatment selectively reduces CD8+ T cell response accompanied by inhibition of IL-6 release. The combination of THC and CBD seems to be the most potent anti-inflammatory drug able to inhibit the T helper response as well as CD4+ T response in a mouse model of multiple sclerosis (MS).

"Beyond the regulation of inflammation, phytocannabinoids can prevent proliferation, metastasis, and angiogenesis, as well as induce apoptosis in a variety of cancer cell types. Treatments with CBC and THC or CBD led to cell cycle arrest and cell apoptosis. Additionally, CBC and THC or CBD treatments inhibit bladder urothelial carcinoma cell migration and affected F-actin integrity.

"Beyond the actions of CBC, THC, and CBD on different pathways involved into development of cancer cell types, also cannabigerol (CBG), cannabidivarin (CBDV), cannabinol (CBN), cannabivarin (CBV), and tetrahydrocannabivarin (THCV) have showed a role as anti-cancer for different cells line."
https://pmc.ncbi.nlm.nih.gov/articles/PMC8124362/ [5796]

For Anis et al (2025) "Targeting bladder cancer: Potent anti-cancer effects of cannabichromene and delta-9-tetrahydrocannabinol-rich Cannabis sativa strains"

"A large retrospective epidemiological study revealed that cannabis use among the general population may be associated with a reduced incidence of bladder cancer. This association remained unexplained. We have previously shown that cannabis-derived compounds have cytotoxic synergistic activity against UC cell lines. Our work demonstrated a consistent inhibitory effect of cannabichromene (CBC) and delta-9-tetrahydrocannabinol (THC) at well-defined concentrations and ratios on UC cell proliferation, migration, cell cycle arrest, and treatment-induced apoptosis of UC cells."
https://www.sciencedirect.com/science/article/pii/S2214388225000335?via%3Dihub#bib2 [5797]

Apparently the worst thing that can happen to you if cannabinoids make you better is that you will actually feel that you are better. Having such feelings is very much against the trend of modern western pharmaceutical interventions.

"One of the major challenges for future research is designing synthetic cannabinoids that elicit positive effects of CB1 activation in peripheral neurons and in specific brain regions, but without significant cognitive effects."

...say Scott et al in an otherwise enthusiastic article loaded heavily in favour of synthetic cannabinoids. But it remains inescapable that a plant got there first. [4027]

And how or why these "positive effects of CB1 activation" must take place without cognitive effects is not explained. An analogy:

"Alcohol free pubs allow people to gather, and you can laugh, spill things, or fall over, leading to neuronal stimulation, without the significant cognitive effects caused by alcohol."

Indeed no pro-alcohol researchers claiming red wine has health benefits have ever claimed that it ought to be alcohol-free red wine. So the feelgood benefits of wine and those of cannabis are strangely set apart for no discernable reason. Except of course, the reason that you won't get any money for supporting cannabis euphoria. Thus Doboviek et al are able to state in "Cannabinoids and triple-negative breast cancer treatment" (2024):

"Cannabinoids show antitumor activity in most preclinical studies in TNBC models and do not appear to have adverse effects on chemotherapy."

and

"The antitumor effect of THC on breast cancer cell lines was documented. Among the tumor cells, those with a more aggressive phenotype, including the MDA-MB-231 cell line, were more sensitive to THC."

and

"The antitumor efficacy of pure THC was compared with that of an herbal drug preparation of fresh cannabis flowers containing a variety of cannabinoids and terpenes. The herbal drug preparation contained THC and CBG, but no CBD, and was more effective than pure THC in producing antitumor responses in cell cultures and animal models of various breast cancer subtypes, including the TNBC subtype (MDA-MB-231 and SUM159 cell lines)."

and

" The herbal drug preparation was significantly more potent than pure cannabinoid (the same dose of THC was administered)."

As for reducing the harms of the official cures:

"Importantly, the major cannabinoids (THC, CBD, and cannabinol) and their metabolites found in the plasma of cannabis users can inhibit several P450 enzymes, including CYP2B6, CYP2C9, and CYP2D6, and cause pharmacokinetic interactions between these cannabinoids and xenobiotics that are extensively metabolized by these enzymes. There is evidence that cannabinoids alleviate peripheral neuropathic pain caused by chemotherapy and prevent doxorubicin-induced cardiomyopathy. Both are side effects of taxane and anthracycline chemotherapy, which is frequently used in TNBC."

While it may seem important that

"Cannabis use correlated with a significant reduction in time to tumor progression and OS [overall survival]. Cannabis users were associated with a lower number of immune-related adverse events (iAEs)."

The researchers do not seem to think much of the placebo effect or belief:

"Many patients take cannabinoids in the belief that this will help cure their disease, although there is currently no clinical data to support this claim in breast cancer patients, including TNBC. A survey of breast cancer patients found that 42% of survey participants used cannabis to treat symptoms and about half of these participants believed that cannabis could treat the cancer itself."

But it is as all this never existed when we learn that, for some reason, CBD

"...is a non-psychoactive substance and therefore a potential therapeutic agent."
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1386548/pdf [3427]

Many researchers have plodded on obediently with this "rather die than get high" mentality (RDTGH). Thus, in a study of phytocannabinoids' effects upon calcium fluxes dependent on transient vanilloid receptor type 1 only

"Cannabinoids other than the highly psychoactive tetrahydrocannabinol (THC) that rank order in abundance directly below THC in Cannabis chemotypes were selected for analysis. Cannabidiol (CBD), Cannabinol (CBN) and the minor cannabinoids Cannabidiolic Acid (CBDA), Cannabidivarin (CBDV), Cannabichromene (CBC), Cannabigerol (CBG), Cannabigerolic Acid (CBGA) were selected."

They writhe around in a twisted mess of self-interest and legality:

"Cannabinoids are of significant interest in the context of 'medicinal' [note the sarcastic quotes] Cannabis use. Pain is one of the most common indications for which medical marijuana is legally allowed to be prescribed and is demanded by patients."

According to their thinking, which is apparently anti-euphoria:

"The psychoactive nature of THC-containing whole chemovars of Cannabis, which is typically the available form of the drug in dispensaries, leads to regulatory issues and adverse side-effects."

A key assumption is that a pain-free existence and happiness are mututally exclusive - it sounds like a religious idea. You can see what they are trying to do is like alcohol-free beer or decaf. We could go on to take vitamin pills instead of eating vegetables. We have meat-free protein, but perhaps what we really need is a scientist to design protein-free meat.

"The distinct response profiles of the different cannabinoids that we observe also provide the possibility of fine-tuning or shaping desirable responses using cannabinoid mixtures. At the level of the sensory neuron bundles, the fact that cannabinoids appear to discriminate between TRP receptors and that the receptors in turn respond distinctively to the compounds, again offers the potential for rational design of therapeutic mixtures."

Their 2019 ideas for the future are not much use if you wanted pain relief in 2012 or 1991, are they?

While they continue to tinker around, there's this plant, isn't there?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557596/ [1639]

Other researchers are more understanding to THC and other CCx. Consider Reva et al (2025) who examined "Comparative Effects of THC and CBD on Chemotherapy-Induced Peripheral Neuropathy: Insights from a Large Real-World Self-Reported Dataset":

"Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting adverse effect of various chemotherapeutic agents. Previous work demonstrated that cannabis alleviates symptoms of oxaliplatin-induced CIPN. To evaluate the effects of cannabis components, cannabidiol (CBD) and tetrahydrocannabinol (THC), on CIPN-related symptoms. Methods: We reviewed a patient-reported outcomes dataset from 'Tikun Olam,' a major medical cannabis provider. Of 1493 patients, 802 reported at least one CIPN symptom at baseline, including a burning sensation, cold sensation, paresthesia (prickling) and numbness, and 751 of them met the study inclusion criteria. Patients were categorized into THC-high/CBD-low and CBD-high/THC-low groups. Symptom changes after six months of cannabis use were analyzed using K-means clustering and logistic regression, incorporating interactions between baseline symptoms and THC and CBD doses. Linear regression assessed changes in activities of daily living (ADL) and quality of life (QOL). Results: Both groups reported symptom improvement. The THC-high group showed significantly greater improvement in burning sensation and cold sensation (p = 0.024 and p = 0.008). Improvements in ADL and QOL were also significantly higher in the THC group (p = 0.029 and p = 0.006). A significant interaction between THC and CBD was observed for symptom improvement (p < 0.0001). Conclusions: Cannabis effectively reduces CIPN symptoms and improves QOL and ADL. Higher THC doses were more effective than lower doses, with combined CBD and THC doses yielding greater symptom relief."
https://www.mdpi.com/2227-9059/13/8/1921 [5352]

Is there any evidence Jan Smuts knew anything about insulin in 1924? Here's an ngram.



Smuts was a keen reader, so he might have come across it. Would he have associated it in his mind with dagga? This proposition is impossible to prove. Smuts' contributions to the field of physiology are more of a philosophical nature:

"Also at that time, biological science was evolving away from materialism as the pure physiology model of nineteenth century. So, while psychologys original aim was to explain all mental activity by mechanical principles with its failure on the physiological level biochemistry as the familiar partner of mechanistic physiology began pointing in another, relativistic-biologic direction. Escaping this irrelevance, biochemistry better and better differentiated living from dead matter and, as a result, scientific interest turned to investigating living material. These investigations produced questions more fundamental to human life; those about organic material and about its biological phenomena, for example the process of regeneration in nature (e.g., tapeworm survival after vivisection) and the healing process in general. What grew to be a revolution in biology joined phenomenology in conceptualizing organisms as unities. As Smuts (1926) had conjectured philosophically and Goldstein (1934/1963) contended neurologically, maintenance of the integrity of the whole cannot be deduced biochemically. Each tissue and every organ seem to follow a law of the total organism."

Though he was probably interested in battle wounds, the Defendant could find no evidence Smuts dug deeply into the small stuff, like insulin. In the Boer War, if you got shot in a limb, they chopped it off. If you were shot anywhere else, you died.

In fact the idea of lipid cell membranes began in December 1925, with a paper by Gortel and Grendel at the University of Leiden.

"It is clear that all our results fit in well with the supposition that the chromocytes are covered by a layer of fatty substances that is two
molecules thick."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2130960/pdf/439.pdf [2539]

Theories of cell membrane structure continued through the prohibition era and various iterations of the cannabis legislation:

"Then in the 1950s, Robertson proposed a three-layer structure, where two layers of proteins were attached to a lipid layer in the middle. A few years later Lenard and Singer suggested a revised model, where the proteins were now allowed to span a lipid bilayer structure. This picture was yet considered incomplete, and in 1972 Singer and Nicolson proposed the famous 'fluid mosaic' model that is nowadays generally known also as the SingerNicolson model."

But even by 2019, many mysteries were unresolved:

"Biological membranes are everywhere. All our cells are surrounded by a biological membrane. So also are the tiny organelles such as the nucleus that contains our genetic code and the endoplasmic reticulum that synthesizes most of our proteins. Biological membranes keep us alive when they transfer oxygen from our lungs to our bloodstream. Biomembranes also control our mood, because they host the receptors of signaling molecules such as dopamine in our brain.

"It is quite intriguing that membranes can play such crucial roles in maintaining life, yet these membranes are basically just soft, few nanometers thick lipid interfaces. However, the more closely one looks at them, the more complex they turn out to be. It is quite justified to note that despite about 100 years of research, we still do not understand exactly what biological membranes really look like."
https://pubs.acs.org/doi/10.1021/acs.chemrev.8b00538 [2531]

So obviously Smuts did not know anything about that?

Smuts was already 55 by 1925. Germ layer theory was wiped out in 1926. Endosymbiosis in evolutionary theory was proposed in 1927. Penicillin arrived in 1928. ATP was discovered in 1929. Vitalism had died by the end of the 20s. Essential fatty acids arrived in 1929/1930. Human metabolism was far removed from anything going on in Smuts' head about cannabis.
https://www.researchgate.net/publication/367444844_Psychopathology/link/63d94b8dc465a873a271f667/download [2129]

Here's another example of woo woo in the way.

Jan Smuts or the League of Nations could not have known in 1924 that

"The endocannabinoid system has emerged as a key regulatory signaling pathway in the pathophysiology of alcohol-associated liver disease (ALD). More than 30 years of research have established different roles of endocannabinoids and their receptors in various aspects of liver diseases, such as steatosis, inflammation, and fibrosis."

But what is curious is how the introduction goes on. For, they warn

"However, pharmacological applications of the endocannabinoid system for the treatment of ALD have not been successful because of psychoactive side effects, despite some beneficial effects."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496755/ [2048]

Two things should strike the Court as curious about this.

Firstly, nowhere do they query the role of alcohol in alcohol-associated liver disease. For these authors these liver diseases are alcohol-associated because it says so in the name. It is incontrovertibly true that alcohol has gotten the ALD patients into this disease spectrum.

Secondly, their complaint about euphoria is entirely directed towards the putative medicaments for ALD.

Why is no one suggesting making alcohol non-euphoric?

Rather than trying to cure liver disease after you have drunk the legal drugs, why not make them ineffective? You could limit the alcohol content to 0.2%. You could make it no crime to buy but illegal to sell. Or you could make a complicated medical model concentrating the supply into the hands of a coterie of doctors or therapists, thickening Slovenia's starchy rentier economy. Why not do that?

Why, given the euphoria potential for alcohol, is that not reason enough alone to stop people being attracted to it in the first place?

And yet for someone who doesn't want to be a fat alcoholic diabetic with cancer, these kind of measures are in effect?

The euphoria of alcohol is brief, and associated with a low BAC. Why are the scientists closing the barn door after the horse has bolted?

So we have, essentially a "good euphoria" in the past which has made all these people ill, and a "bad euphoria" which - like most anxiety - concerns the future, specifically the future for patentable pharmaceuticals that can target the endocannabinoid system without the alcohol victim losing his shit. The Defence fears this is much more of a concern around the former reason than the latter. "Bad euphoria" may be added to the list of Prohibition's friends.

Later they come back to this "limitation" of drugs that make you happy while fixing your alcohol-ravaged liver:

"The endocannabinoid system has been observed in both the hepatocytes and various nonparenchymal cells in the liver, in which the endocannabinoid production and its receptor activation may contribute to the development of a spectrum of ALD, ranging from simple alcoholic steatosis to more severe forms such as steatohepatitis and fibrosis. Therefore, understanding the precise physiology of the endocannabinoid system in the liver and unveiling the mechanism underlying the association between ALD progression and hepatic endocannabinoid signaling seem to bear a paramount significance for the advancement of ALD treatment, as well as for the treatment of other chronic liver diseases (e.g., NAFLD, viral hepatitis). Moreover, developing efficacious and highly selective cannabinoid receptormodulating drugs could be a major breakthrough in the treatment of ALD.

"However, efforts to develop second- and third-generation CB1R antagonists must overcome the complications caused by the first generation of CB1R antagonists, which were able to penetrate the blood-brain barrier and produced critical psychiatric side effects."

and

"However, pharmacological applications of the endocannabinoid system for the treatment of ALD have not been successful because of psychoactive side effects, despite some beneficial effects."

Meanwhile findings continue to demonstrate the relative uselessness in many pathways of legally-available CBD products and point towards whole-plant effectiveness due to the so-called entourage effect.

University of Michigan researchers with the company Gb Sciences Inc. evaluated the effect of selected terpenes and cannabinoids on human primary leukocytes.

The terpenes evaluated included α-pinene, trans-nerolidol, D-limonene, linalool and phytol. The three immune cell types were chosen based on their important roles in modulating the inflammatory cascade.

The study found that the most efficient cannabinoid was THC, followed by CBDV (Cannabidivarin), CBG (Cannabigerol), CBC (Cannabichromene), CBN (Cannabinol) and finally, CBD.

The terpene α-Pinene showed the greatest immune modulating activity from the group followed by linalool, phytol and trans-nerolidol. Limonene had no effect which was attributed to some terpenes being highly selective or targeting a single cell type.

Peripheral Blood Mononuclear Cells are any peripheral blood cell having a round nucleus, and include lymphocytes (T cells, B cells, and NK cells), monocytes, and dendritic cells. In humans, the frequencies of these populations vary across individuals, but typically, lymphocytes are in the range of 7090 %, monocytes from 10 to 20 %, while dendritic cells are rare, accounting for only 12 %.

"Human PBMC were pretreated with each compound, individually, at concentrations extending from 0.001 to 10 μM and then stimulated with CpG (plasmacytoid dendritic cell), LPS (monocytes), or anti-CD3/CD28 (T cells). Proliferation, activation marker expression, cytokine production and phagocytosis, were quantified. Of the 21 responses assayed for each compound, cannabinoids showed the greatest immune modulating activity compared to their vehicle control. Delta-9-tetrahydrocannabinol possessed the greatest activity affecting 11 immune parameters followed by cannabidivarin, cannabigerol, cannabichromene, cannabinol and cannabidiol. α-Pinene showed the greatest immune modulating activity from the selected group of terpenes, followed by linalool, phytol, trans-nerolidol. Limonene had no effect on any of the parameters tested. Overall, these studies suggest that selected cannabis-derived terpenes displayed minimal immunological activity, while cannabinoids exhibited a broader range of activity."
https://www.sciencedirect.com/science/article/abs/pii/S0278691522006561 [1726]



Some consider the effect to be additive, rather than synergistic or multiplicative in nature. Discussing D9-THC and terpene interactions in 2021, Liktor-Busa et al at the Department of Pharmacology of the University of Arizona summarise:

"These studies suggest that although terpenes may have significant antinociceptive properties (discussed above), it is likely that these properties are not modulated through direct interactions at cannabinoid receptors, nor does it appear they will modify antinociception induced by cannabinoids such as D9 -THC. However, these studies are limited and do not rule out an interaction definitively."

As for CBD, evidence is "limited":

"An in vivo study observing the difference between CBD, D9 -THC, or a C. sativa high-CBD extract (containing other phytocompounds) demonstrated that the antinociceptive properties of the CBD extract were greater than CBD or D9 -THC alone in a chronic constriction injury model of neuropathic pain (Comelli et al., 2008). Furthermore, combining pure CBD and pure D9 -THC in a similar ratio to the high-CBD extract could not recapitulate the greater effect of the extract, suggesting other noncannabinoid contributions. They also state that although a single dose of CBD could not alleviate the neuropathic pain, a single dose of the CBD extract could reduce thermal hyperalgesia comparable to D9 -THC, but data were not provided. The antinociceptive effects of the CBD extract could be blocked with a TRPV1 antagonist but not a CB1 or CB2 antagonist."
https://pharmrev.aspetjournals.org/content/pharmrev/73/4/1269.full.pdf [2937]

Tomko et al at Dalhousie University in Halifax, Canada found "Anti-cancer properties of cannflavin A and potential synergistic efects with gemcitabine, cisplatin, and cannabinoids in bladder cancer" (2022):

"Cell viability of bladder cancer cell lines was affected in a concentration-dependent fashion in response to cannflavin A, and its combination with gemcitabine or cisplatin induced differential responses-from antagonistic to additive-and synergism was also observed in some instances, depending on the concentrations and drugs used. Cannflavin A also activated apoptosis via caspase 3 cleavage and was able to reduce invasion by 50%. Interestingly, cannflavin A displayed synergistic properties with other cannabinoids like Δ9-tetrahydrocannabinol, cannabidiol, cannabichromene, and cannabivarin in the bladder cancer cell lines."
https://jcannabisresearch.biomedcentral.com/counter/pdf/10.1186/s42238-022-00151-y.pdf [2941] and see [3007]

Cannabis components such as the cannflavins may be manipulable using different artificial light and cultivars:

"Increased solar UV radiation results in higher CBDA, terpene, and cannaflavin [sic] content in the hemp variety Kompolti (Giupponi et al., 2020). Notably, UV radiation sources used in both studies had relatively broad spectra, compared to electrical UV radiation sources, such UV-discharge lamps and light-emitting diodes (LEDs). It is unknown if there is was an interactive effect between UV-A (315380 nm) and UV-B radiation, as a high percentage of UV-A radiation was present in both the UV-B and control light treatments (Mirecki and Teramura, 1984; Lydon et al., 1987; Giupponi et al., 2020). A subsequent study examined the impact of UV-A radiation on cannabinoid accumulation, and reported increased cannabinoid levels other than Δ9-THC (Magagnini et al., 2018). Low percentages of UV-A radiation (2%) from full-spectrum LED arrays induced an increase of several cannabinoids, including CBD, CBG, Δ9-THC, and tetrahydrocannabivarin (THCV), compared to a high pressure sodium (HPS) lamp that contained 1% of UV-A radiation (Magagnini et al., 2018)."

Yet by 2021, according to "Cannabinoids and Terpenes: How Production of Photo-Protectants Can Be Manipulated to Enhance Cannabis sativa L. Phytochemistry" the pathway(s) by which cannflavins are produced in the plant was still a matter of debate.



Brousseau et al also offer a "simplified overview" of the effect of spectra on synthesis of the cannabis components:



"FIGURE 1. A simplified overview of cannabinoid and terpene biosynthesis pathways in cannabis (Cannabis sativa L.), derived from recent reviews (Hazekamp, 2007; Degenhardt et al., 2017; Sirikantaramas and Taura, 2017; Jin et al., 2019). Enzymes are in dashed line box. Enzymes in shaded blue boxes are upregulated by UV radiation and blue light in Lamiaceae [a family that includes mint. basil, oregano and lavender]. Cannabis precursor (shade blue): CBDA, cannabidiolic acid; DMAPP, dimethylallyl pyrophosphate; G3P, glyceraldehyde 3-phosphate; GPP, geranyl pyrophosphate; GPPS, geranyl pyrophosphate synthase; MEP, methylerythritol phosphate; PT4, geranylpyrophosphate: olivetolate geranyltransferase 4; IPP, isopentenyl diphosphate; IPPi, isopentenyl-diphosphate delta-isomerase; OA, olivetolic acid; OAC, olivetolic acid cyclase; TK, tetraketide; TKS, tetraketide synthase. Cannabinoid (shade red): CBC, cannabichromene; CBCA, cannabichromentic acid; CBCAS, cannabichromentic acid synthase; CBDAS, cannabidiolic acid synthase; CBD, cannabidiol; CBG, cannabigerol; CBGA, cannabigerolic acid; CBL, cannabicyclol; CBLA, cannabicyclolic acid; CBN, cannabinol; CBNA: cannabinolic acid; Δ8-THC, Δ8-tetrahydrocannabinol; Δ9-THC (or THC), Δ9-tetrahydrocannabinol; THCA, tetrahydrocannabinolic acid. Terpene precursor (shade orange): FPP, farnesyl diphosphate; FPPS, farnesyl diphosphate synthase; MEV, mevalonate; TPS, terpene synthase."
https://www.frontiersin.org/articles/10.3389/fpls.2021.620021/full [3038]

de Christo Scherer et al found a dose-dependent effect in the "Wound healing activity of terpinolene and α-phellandrene by attenuating inflammation and oxidative stress in vitro" (2019). As they explain:

"Terpenoids represent the oldest and most diverse class of secondary metabolites formed from five-carbon isoprene units called isoprenoids. They represent a highly diversified group of naturally occurring organic compounds, and more than 30,000 different natural terpene metabolites were identified. In plants, terpenoids have a multitude of ecological and physiological functions. They chemically defend against insects and environmental stress and are involved in the repair mechanism of wounds and injuries."

and

"In summary, the results of the present study showed that terpinolene and α-phellandrene, which share similar chemical characteristics, exhibited similar wound healing properties. Using cell-based assays, both compounds effectively stimulated proliferation and migration of fibroblasts, protected macrophages against cellular oxidative damage, and suppressed the production of pro-inflammatory cytokines (IL-6 and TNF-α) and NF-κB activity."
https://www.sciencedirect.com/science/article/abs/pii/S0965206X18301311 [2494]

According to Susanto et al (2024) phellandrene, found in several herbs, has a synergestic antiproliferative effect on cancer cells with 5-fluorouracil. HT-29 is a human colorectal adenocarcinoma cell line with epithelial morphology, sensitive to 5-FU.

"The combination of 5-FU and α-PA had a synergistic inhibitory effect on cell viability, as determined by assessing the combination index value. Bax protein expression levels were higher in the 50, 100 or 250 M α-PA combined with 5-FU groups compared with those in the 5-FU alone group (P<0.05). By contrast, Bcl-2 protein expression levels and mitochondrial membrane potential (MMP, ΔΨm) were lower in the 100 or 250 M α-PA combined with 5-FU groups than those in the 5-FU alone group (P<0.05). In addition, hexokinase-2 (HK-2) protein expression levels were lower in the 50, 100 or 250 M α-PA combined with 5-FU groups than those in the 5-FU alone group (P<0.05). Compared with 5-FU alone, after HT-29 cells were treated with 50, 100 or 250 M α-PA combined with 5-FU, the mRNA expression levels of extrinsic-induced apoptotic molecules, including caspase-8 and Bid, were higher (P<0.05). Treatment with 50, 100 or 250 M α-PA combined with 5-FU also increased the mRNA expression levels of cytochrome c, caspase-9 and caspase-3, regulating intrinsic apoptosis (P<0.05). These results showed that α-PA and 5-FU had a synergistic effect on reducing the viability of human colon cancer HT-29 cells by inducing extrinsic and intrinsic apoptosis pathways."
https://pmc.ncbi.nlm.nih.gov/articles/PMC10940876/ [3649]

Ten years earlier, Slovenia's alcohol-worshippers could have learned from Hsieh et al (2014) about "Induction of necrosis in human liver tumor cells by α-phellandrene":

"Human liver tumor (J5) cells were incubated with α-PA and analyzed for cell cycle distribution, expression of Bax, Bcl-2, poly (ADP-ribose) polymerase (PARP) protein, and caspase-3 activity of J5 cells, and levels of nitric oxide (NO) production, lactate dehydrogenase (LDH) leakage, and ATP depletion were also analyzed in this study. Results found that α-PA significantly (P < 0.05) decreased the cell viability of J5 cells after 24-h treatment. The cell cycle distribution, Bax, Bcl-2, PARP protein levels, and caspase-3 activity of J5 cells did not change for 24 h after treatment with 30 μM α-PA. Reactive oxygen species levels significantly increased, mitochondrial membrane potential levels significantly decreased when J5 cells were treated with 30 μM α-PA for 24 h (P < 0.05). Thirty μM α-PA significantly (P < 0.05) increased the necrotic cell number, NO production, LDH leakage, and ATP depletion after 24 h of incubation. These results suggest that α-PA induced J5 cell necrosis but not apoptosis, and α-PA-induced necrosis possibly involved ATP depletion."
https://pubmed.ncbi.nlm.nih.gov/25077527/ [3650]

Aydin et al (2013) investigated "Anticancer and antioxidant properties of terpinolene in rat brain cells":

"Terpinolene (TPO) is a natural monoterpene present in essential oils of many aromatic plant species. Although various biological activities of TPO have been demonstrated, its neurotoxicity has never been explored. In this in vitro study we investigated TPO's antiproliferative and/or cytotoxic properties using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) test, genotoxic damage potential using the single-cell gel electrophoresis (SCGE), and oxidative effects through total antioxidant capacity (TAC) and total oxidative stress (TOS) in cultured primary rat neurons and N2a neuroblastoma cells. Dose-dependent effects of TPO (at 10 mg L(-1), 25 mg L(-1), 50 mg L(-1), 100 mg L(-1), 200 mg L(-1), and 400 mg L(-1)) were tested in both cell types. Significant (P<0.05) decrease in cell proliferation were observed in cultured primary rat neurons starting with the dose of 100 mg L(-1) and in N2a neuroblastoma cells starting with 50 mg L(-1). TPO was not genotoxic in either cell type. In addition, TPO treatment at 10 mg L(-1), 25 mg L(-1), and 50 mg L(-1) increased TAC in primary rat neurons, but not in N2a cells. However, at concentrations above 50 mg L(-1) it increased TOS in both cell types. Our findings clearly demonstrate that TPO is a potent antiproliferative agent for brain tumour cells and may have potential as an anticancer agent, which needs to be further studied."

As for genotoxicity:

"In vitro exposure to TPO of either cell type did not result in comet formation, regardless of the dose, indicating the non-genotoxic nature of TPO (Figure 2)."

For total antioxidant capacity (in Trolox Equivalent / mmol L-1)...

"TPO at the concentrations of 100 mg L-1 and 200 mg L-1 did not affect TAC in primary rat neuron cells, increased it signifi cantly at the concentrations of (10, 25, and 50) mg L-1, and decreased it signifi cantly at the highest concentration (400 mg L-1) compared to control (Table 1). Similarly, in N2a neuroblastoma cells TPO (at 10 mg L-1 and 25 mg L-1) did not change TAC levels, but decreased them signifi cantly at ((50, 100, 200, and 400) mg L-1, compared to control."
https://sciendo.com/pdf/10.2478/10004-1254-64-2013-2365 [3562]

Reminding us that "Cannabis sativa has been utilized for medical purposes for thousands of years. It continues to be recognized as a plant with an extensive variety of medicinal and nutraceutical uses today," a paper on the discovery of "New Cannabinoids and Chlorin-Type Metabolites from the Flowers of Cannabis sativa L.: A Study on Their Neuroblastoma Activity" by Nguyen et al from Korea reported in April 2025:

"Eleven compounds were isolated from the flowers of C. sativa, including two new compounds, namely cannabielsoxa (1), 132-hydroxypheophorbide c ethyl ester (2), and six known cannabinoids (611), together with the first isolation of chlorin-type compounds: pyropheophorbide A (3), 132-hydroxypheophorbide b ethyl ester (4), and ligulariaphytin A (5) from this plant. The results also demonstrated that cannabinoid compounds had stronger inhibitory effects on neuroblastoma cells than chlorin-type compounds. Conclusions: The evaluation of the biological activities of compounds showed that compounds 410 could be considered as the potential compounds for antitumor effects against neuroblastomas. This is also highlighted by using docking analysis. Additionally, the results of this study also suggest that these compounds have the potential to be developed into antineuroblastoma products."
https://www.mdpi.com/1424-8247/18/4/521 [4978]

Further discoveries ensued, including "New Cannabinoids and Chlorin-Type Metabolites from the Flowers of Cannabis sativa L.: A Study on Their Neuroblastoma Activity" by Nguyen et al (2025).

"These purified compounds were evaluated for antitumor activity against SK-N-SH neuroblastoma cells."

Since for reasons of professional and not patient safety they can't just say "try some weed", a reductive and more patentable strategy is proposed:

"Eleven compounds were isolated from the flowers of C. sativa, including two new compounds, namely cannabielsoxa (1), 132-hydroxypheophorbide c ethyl ester (2), and six known cannabinoids (6–11), together with the first isolation of chlorin-type compounds: pyropheophorbide A (3), 132-hydroxypheophorbide b ethyl ester (4), and ligulariaphytin A (5) from this plant. The results also demonstrated that cannabinoid compounds had stronger inhibitory effects on neuroblastoma cells than chlorin-type compounds. Conclusions: The evaluation of the biological activities of compounds showed that compounds 4–10 could be considered as the potential compounds for antitumor effects against neuroblastomas. This is also highlighted by using docking analysis. Additionally, the results of this study also suggest that these compounds have the potential to be developed into antineuroblastoma products."
https://pmc.ncbi.nlm.nih.gov/articles/PMC12030031/ [6061]

Sztolsztener et al (2023) describe the "Concentration-Dependent Attenuation of Pro-Fibrotic Responses after Cannabigerol Exposure in Primary Rat Hepatocytes Cultured in Palmitate and Fructose Media":

"Hepatic fibrosis is a consequence of liver injuries, in which the overproduction and progressive accumulation of extracellular matrix (ECM) components with the simultaneous failure of matrix turnover mechanisms are observed. The aim of this study was to investigate the concentration dependent influence of cannabigerol (CBG, Cannabis sativa L. component) on ECM composition with respect to transforming growth factor beta 1 (TGF-β1) changes in primary hepatocytes with fibrotic changes induced by palmitate and fructose media. Cells were isolated from male Wistar rats livers in accordance with the two-step collagenase perfusion technique. This was followed by hepatocytes incubation with the presence or absence of palmitate with fructose and/or cannabigerol (at concentrations of 1, 5, 10, 15, 25, 30 M) for 48 h. The expression of ECM mRNA genes and proteins was determined using PCR and Western blot, respectively, whereas media ECM level was evaluated using ELISA. Our results indicated that selected low concentrations of CBG caused a reduction in TGF-β1 mRNA expression and secretion into media. Hepatocyte exposure to cannabigerol at low concentrations attenuated collagen 1 and 3 deposition. The protein and/or mRNA expressions and MMP-2 and MMP-9 secretion were augmented using CBG. Considering the mentioned results, low concentrations of cannabigerol treatment might expedite fibrosis regression and promote regeneration." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10526512/pdf/cells-12-02243.pdf [4045]

A reduction in cell viability in human pancreatic ductal adenocarcinoma (PDAC) cell lines was assisted by a "synergistic effect of CBG in combination with gemcitabine (GEM) and paclitaxel (PTX)" [3979]

Sativa terpenes on their own "mimic the effects of cannabinoids, including a reduction in pain sensation," notes a statement from the University of Arizona Health Sciences.

But when terpenes were combined with cannabinoids, "the pain-relieving effects were amplified without an increase in negative side effects," investigators report.
https://www.nature.com/articles/s41598-021-87740-8 [500]

Smith et al examined the chemical reality of THC-dominant, CBD-dominant and balanced THC:CBD strains and found the present labels inadequate. 2022's "The phytochemical diversity of commercial Cannabis in the United States" found that CBD-dominant and THC:CBD balanced products "displayed myrcene-dominant terpene profiles compared to THC-dominant samples."

"Mapping the chemical diversity of the Cannabis-derived products consumed by millions of people has important implications for consumer health and safety, such as identifying the number of chemically distinct types of Cannabis being consumed in legal markets. This may be consequential if distinct chemotypes are later determined to cause reliably different effects."

The researchers analyzed 89,923 different samples of loose-leaf cannabis from six certified testing laboratories in the U.S. states.

"84.5 percent of CBD-dominant samples had total THC levels above 0.3 percent, the threshold used to legally define hemp in the U.S.," noted the researchers. "This indicates that a substantial fraction of CBD-dominant cannabis would not meet the legal definition of hemp in the U.S.," indicating a collision between the biochemical reality of this plant species and the regulatory framework wrapped around it in the United States.

The most common terpenes present in the flower samples were beta-caryophyllene (BCP), limonene, and myrcene (the most common terpene in cannabis, according to other studies). "In most cases, individual terpenes were rarely present at more than 0.5 percent weight."

and the research found that THC-dominant cannabis products (Type I) "displayed significantly higher levels of [terpene] diversity than both balanced THC:CBD [Type II] and CBD-dominant products [Type III]."

The study found that the labels of indica, sativa, and hybrid did not correspond well to the terpene profiles of the samples. "It is likely that a sample with the label 'indica' will have an indistinguishable terpene composition as samples labelled 'sativa' or 'hybrid.'"

The scientists determined that a simple product labeling system "in which THC-dominant samples are labelled by their dominant terpene" would better serve both the industry and consumers and be "better at discriminating samples than the industry-standard labelling system" of indica, sativa, and hybrid.

The study found "a large amount of variability in mean consistency scores across all 'strain names.'" Sometimes, the chemical makeup of a strain featured relatively strong consistency across the data set. For example, 96 percent of flower samples labeled to be the strain Purple Punch feature strong levels of beta-caryophyllene and limonene, while only 62.5 percent of products labeled Tangie fell into a single cluster.

The study identified three cluster groups that each are dominated by a different terpene pair.

Cluster I: Relatively high levels of beta-caryophyllene and limonene

Cluster II: Relatively high levels of myrcene and pinene

Cluster III: Relatively high levels of myrcene and terpinolene

"Samples across these clusters display similar total THC distributions, while Cluster III is associated with modestly higher CBG levels," summarized the study's authors.

The scientists concluded that their study results "provide new possibilities for systematically categorizing commercial cannabis [products] based on chemistry, the design of preclinical and clinical research experiments, and the regulation of commercial cannabis marketing."

"The general approach we have used in this study can serve as a basic guide for cannabis product segmentation and classification rooted in product chemistry," they wrote. "Consumer-facing labelling systems should be grounded in such an approach so that consumers can be guided to products with reliably different sensory and psychoactive attributes."
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0267498 [2007]

I predict that Slovenian fun-reduction experts will want, for the first time ever, a ban on emotive, hyperbolic advertising, with only government-approved strain names like "Bureaucrat Grey" and "Reverend Brown" allowed.

For some researchers, the major cannabinoids are relatively uninteresting:

"In this study we provide the first comprehensive overview of the effects of whole-plant Cannabis extracts and various pure cannabinoids on store-operated calcium (Ca2+) entry (SOCE) in several different immune cell lines. Store-operated Ca2+ entry is one of the most significant Ca2+ influx mechanisms in immune cells, and it is critical for the activation of T lymphocytes, leading to the release of proinflammatory cytokines and mediating inflammation and T cell proliferation, key mechanisms for maintaining chronic pain. While the two major cannabinoids cannabidiol and trans-Δ9-tetrahydrocannabinol were largely ineffective in inhibiting SOCE, we report for the first time that several minor cannabinoids, mainly the carboxylic acid derivatives and particularly cannabigerolic acid, demonstrated high potency against SOCE by blocking calcium release-activated calcium currents. Moreover, we show that this inhibition of SOCE resulted in a decrease of nuclear factor of activated T-cells [NFAT] activation and Interleukin 2 production in human T lymphocytes. Taken together, these results indicate that cannabinoid-mediated inhibition of a proinflammatory target such as SOCE may at least partially explain the anti-inflammatory and analgesic effects of Cannabis."

You should know

"The release of proinflammatory mediators is regulated by calcium-dependent signaling mechanisms that activate several transcription factor pathways, including NFAT, nuclear factor kappa B (NF-KB), and cAMP response element-binding protein."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9334010/ [2005]

Musetti et al, discussing the anti-atherosclerotic effects of three cannabis extracts, point out that:

"...the effect of the extracts was greater than the addition of the inhibitory effect of the individual cannabinoid components. This synergy or more than additive effect could be explained by the entourage effect. The term was first coined by Ben-Shabat et al. to explain that non-active metabolites potentiated the effect of the endocannabinoid 2-arachidonoylglycerol. Individual components could exhibit additive effects, their combined impact is simply the sum of their individual effects; antagonistic interactions, or synergistic interactions when compounds produce an effect surpassing the sum of their individual contributions. Cannabinoid-cannabinoid interactions, cannabinoid-terpene, and terpene-terpene interactions could account for intra or inter entourage effects. Our observation that the extracts as a whole exhibit stronger inhibition than the sum of the effect of the component cannabinoids supports either an entourage effect or the additive effect of a low-abundance component with potent bioactivity.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0310777 [3817]

Despite insisting on looking only at CBD a review of 246 studies on lung cell cancer apoptosis reported, in 2022:

"The most common cell line used in all of the studies was A549; however, some studies included other cell lines, including H460 and H358. We concluded that CBD has direct antineoplastic effects on lung cancer cells by various mechanisms mediated by cannabinoid receptors or independent of them."
https://pubmed.ncbi.nlm.nih.gov/36437760/ [1756]

"Humulene Inhibits Acute Gastric Mucosal Injury by Enhancing Mucosal Integrity" by Yeo et al (2021) looks at the cannabis terpene humulene.

"In this study, a HCl/ethanol-induced gastritis or pylorus ligation-induced ulcer rat model was utilized to reveal the protective effect of α-humulene and its related mechanism for mucus secretion, gastric acid secretion, oxidant/antioxidant balance, and mucosal stabilizing factors such as MUC5AC and MUC6 in vivo. In addition, we used the phorbol 12-myristate 13-acetate (PMA)-induced human mast cell-1 (HMC-1) model. PMA, a potent activator of protein kinase C, stimulates HMC-1 cells to exhibit characteristis of tissue mast cells including degranulation, surface antigen profile, and cytokine activation pathways. Thus, we examined the inhibitory effect of α-humulene and its underlying molecular mechanism of histamine release, oxidative stress, and NF-κB-mediated inflammatory responses in the HMC-1 cell line stimulated with PMA."

finding that

"α-Humulene Attenuates Mucosal Lesions in an HCl/Ethanol-Induced Gastritis Model"

and

"α-Humulene Increases mRNA Expression Levels of Mucus-Stabilizing Factors in
HCl-Ethanol-Injured Stomach Tissues"

yet

"the protective action of α-humulene against HCl/ethanol-induced gastric injury was not driven by direct neutralization."

but

"α-Humulene Inhibits Histamine Release in HMC-1 Cells through Ca2+ and Cyclic Adenosine Monophosphate"

plus

"α-Humulene Inhibits Inflammation-Related Factors in PMA-Stimulated HMC-1 Cells"

and

"Under stress conditions such as alcohol abuse, the level of histamine is elevated, which increases acid production, thus inducing gastritis. Therefore, we investigated the inhibitory effect of α-humulene on histamine release using HMC-1 cells. When stimulated with compound 48/80 or PMA, HMC-1 cells release histamine. Here, we showed that α-humulene significantly decreased histamine secretion without cellular toxicity. Previous studies have shown that both intracellular calcium and cAMP act as important modulators during the degranulation of HMC-1 cells. When mast cells are stimulated, calcium channels rapidly open at the membrane, and a large amount of calcium enters the cytoplasm. Moreover, activated phospholipase C converts phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol 1,4,5-trisphosphate (IP3), which binds to the IP3-gated calcium channel of the mast cell endoplasmic reticulum (ER). Then, a large amount of calcium stored in the ER is released into the cytoplasm. To investigate the underlying molecular mechanism of the antihistamine effect of α-humulene, the following experiment was conducted. First, we examined the changes in calcium influx using the fluorescent dye, Fluro-2/AM. Compared to compound 48/80-treated cells, α-humulenetreated cells showed lower levels of intracellular calcium. Next, we investigated the changes in cAMP, because intracellular cAMP increases to inhibit the release of mediators in mast cell. Similar to curcumin (positive control), α-humulene increased intracellular cAMP levels, which resulted in the inhibition of histamine release. Taken together, α-humulene inhibits histamine secretion by regulating intracellular calcium and cAMP concentrations without any cytotoxicity."
https://www.mdpi.com/2076-3921/10/5/761/pdf?version=1620732119 [1932]

In "Terpenes from Cannabis sativa Induce Antinociception in Mouse Chronic Neuropathic Pain via Activation of Spinal Cord Adenosine A2A Receptors" by Schwarz et al (2024) five cannabis terpenes were tested on pain in mice using a Chemotherapy-Induced Peripheral Neuropathy, and lipopolysaccharide-induced Acute Inflammatory Models:

"Terpenes are small hydrocarbon compounds that impart aroma and taste to many plants, including Cannabis sativa. A number of studies have shown that terpenes can produce pain relief in various pain states in both humans and animals. However, these studies were methodologically limited and few established mechanisms of action. In our previous work, we showed that the terpenes geraniol, linalool, β-pinene, αhumulene, and β-caryophyllene produced cannabimimetic behavioral effects via multiple receptor targets. We thus expanded this work to explore the efficacy and mechanism of these Cannabis terpenes in relieving chronic pain. We first tested for antinociceptive efficacy by injecting terpenes (200 mg/kg, IP) into male and female CD1 mice with chemotherapy-induced peripheral neuropathy (CIPN) or lipopolysaccharide-induced inflammatory pain, finding that the terpenes produced roughly equal efficacy to 10 mg/kg morphine or 3.2 mg/kg WIN55,212. We further found that none of the terpenes produced reward as measured by conditioned place preference, while low doses of terpene (100 mg/kg) combined with morphine (3.2 mg/kg) produced enhanced antinociception vs. either alone. We then used the adenosine A2A receptor (A2AR) selective antagonist istradefylline (3.2 mg/kg, IP) and spinal cord-specific CRISPR knockdown of the A2AR to identify this receptor as the mechanism for terpene antinociception in CIPN. In vitro cAMP and binding studies and in silico modeling studies further suggested that the terpenes act as A2AR agonists. Together these studies identify Cannabis terpenes as potential therapeutics for chronic neuropathic pain, and identify a receptor mechanism in the spinal cord for this activity."

In the LPS arm

"Mechanical allodynia was produced by LPS in all mice (Figure 2A). Most terpenes (200 mg/kg, IP) produced significant time-dependent antinociception over vehicle control; the only exception was β-pinene, which produced a small, non-significant improvement in mechanical threshold (Figure 2A). AUC analysis backed up this conclusion, with geraniol and linalool both producing significant elevation in AUC over vehicle control (Figure 2B). Much like with CIPN above, while the other terpenes had non-significant AUC increases, the mean values were still elevated 5-7 fold over the vehicle mean (Figure 2B). Both data types together suggest that all terpenes except β-pinene are effective antinociceptive agents in this second, different pathological pain type."
https://journals.lww.com/pain/fulltext/2024/11000/terpenes_from_cannabis_sativa_induce.16.aspx [3100]

"'The terpenes were tested individually and compared with morphine. The research team found that each terpene was successful in reducing the sensation of pain at levels near to or above the peak effect of morphine. When the terpenes were combined with morphine, the pain-relieving effects of all five terpene/morphine combinations were significantly increased.

"'That was really striking to us, but just because something relieves pain doesnt necessarily mean its going to be a good therapy,' [lead researcher John] Streicher said.

"Comparing Terpenes and Opioids
Opioids are often used to treat many types of pain, but they can come with a host of unwanted side effects. Opioids activate the brains reward system, which is what can lead to addiction, and can cause tolerance, a condition that occurs when the body gets used to a medication and needs increasingly larger doses to have the same effect. Opioids also can cause respiratory depression, which can lead to death.

'We looked at other aspects of the terpenes, such as: Does this cause reward? Is this going to be addictive? Is it going to make you feel awful?' Streicher said. 'What we found was yes, terpenes do relieve pain, and they also have a pretty good side effect profile.'

"None of the terpenes had reward liability, making them a low risk for addiction. Some of the terpenes also did not cause aversive behaviors, which suggests they could be effective therapeutics without producing distressing side effects.

"Finally, researchers tested different routes of terpene administration: injection, oral dosing, and inhalation of vaporized pure terpenes. They found that when terpenes were given orally or inhaled, the effects were significantly reduced or absent.

"'A lot of people vape or smoke terpenes as part of cannabis extracts that are available commercially in states where cannabis use is legal,' Streicher said 'We were surprised to find that the inhalation route didnt have an impact in this study, because there are a lot of at least anecdotal reports saying that you can get the effects of terpenes whether taken orally or inhaled. Part of the confounding factor is that terpenes smell quite nice and its hard to disguise that aroma, so people could be kind of having the psychosomatic placebo-style effect.'"

Their future aims to exploit this supposedly placebo, anti-rewarding effect:

"...you could have a combination therapy, an opioid with a high level of terpene, that could actually make the pain relief better while blocking the addiction potential of opioids,' Streicher said. 'Thats what we are looking at now.'"
https://scitechdaily.com/natures-painkiller-natural-molecules-found-in-cannabis-rival-morphine-in-groundbreaking-study/ [3101]

2019's "The heterogeneity and complexity of Cannabis extracts as antitumor agents" from the University of Haifa, Israel concluded your chances against cancer are improved with a shotgun effect of natural cannabinoid combinations compared to single extracts. Nature got it right again.

"Dr. Baram et al. investigated the effect of various combinations of cannabis extracts and their effect on 12 different cancers. Results demonstrated a variable response depending upon the cancer type and content profile of the specific cannabis extract. Of the 12 cancer varieties tested, components of THC were found to be successful in inducing cell death. Apoptotic features and/or inhibition of proliferation were found to be the underlying mechanism. Interestingly, two extracts consisting of equal amounts of THC but varying levels of other cannabinoids (i.e., CBD, Cannabigerol [CBG], THCA, etc.) had different outcomes in terms of cell death. Such findings indicate the likelihood that the interplay of the combination of cannabinoids may be the true determining factor of the extract's effectiveness rather than the presence or amount of THC. Therefore, the authors recommend whole extract cannabinoid therapy as opposed to single-agent THC formulations that have higher anti-tumor properties."



"The 124 extracts segregate into five major clusters comprised of phytocannabinoids that associate with: (1) larger amounts of CBG-type; (2) larger amounts of CBD-type.; (3) larger amounts of CBDA-type; (4) larger amounts of Δ9-THC-type; (5) larger amounts of Δ9-THCA-type."

Twelve cannabinoids were selected and their effect on A549 lung cancer cell survival is shown in



"A549 cells were treated with three different Cannabis extracts: CAN5, a Δ9-THC-rich extract; CAN9, a CBD-rich extract; and CAN10, a CBG-rich extract. Treatment with each of these Cannabis extracts for 24 h led to apoptosis of A549 cells in a dose-dependent manner."

Again in A549,

"CAN5 and CAN9 extracts produced statistically significant reductions in cell proliferation."

Both CAN2 (a CBD-type extract) and CAN5 (high THC) were among the top scorers overall.

The colorectal adenocarcinoma HT29 cell line was the least sensitive to all the extracts studied of all the cell lines studied, but even so, increased apoptosis was observed with all 12 extracts in HT29.

The values in Supplementary Table I are IC50 (not LC50 as printed - the LC50 is an LD50 for substances in air) and IC50 is measured in g/ml. Values above 10 are lumped together as showing the action to be relatively useless: the lower the figure the more effective the extract.

The half maximal inhibitory concentration (IC50) is a measure of the potency of a substance in inhibiting a specific biological or biochemical function. IC50 is a quantitative measure that indicates how much of a particular inhibitory substance (e.g. drug) is needed to inhibit, in vitro, a given biological process or biological component by 50%.

The 144 cell line/extract combinations are CAN1 to CAN12 and

A549 (lung cancer)
NCIH460 (fast growing hypertriploid lung cancer)
PC3 (Caucasian prostate adenocarcinoma)
LNcAP (androgen-sensitive human prostate adenocarcinoma)
HT29 (colorectal adenocarcinoma)
SW480 (adenocarcinoma of the colon)
A431 (squamous carcinoma)
A375 (melanoma)
MDA231 (breast adenocarcinoma)
MCF7 (breast cancer)
U87MG (glioblastoma)
T98G (glioblastoma)

"CAN7, a Δ9-THC-rich extract, was the least discriminatory of the twelve extracts, as it significantly reduced the survival of both cancerous and non-cancer lung epithelial cell lines."

By my own count, pure THC beat extracts in 31 (19.9%) out of 156 pairings (Supplementary Table 1). This of course means that entourage effects were more proapoptotic in 125 (80.1%) of the cases. At the same time this doesn't mean THC did not contribute in the 19.9%.

The results are summarised in graphical form in Figure 3:



In their discussion the authors refer to some other reports of synergistic effects between THC and CBD and consider that

"...beyond the major phytocannabinoids present in these extracts, other Cannabis extract components may play a role in either increasing phytocannabinoid potency or phytocannabinoid affinity to respective cannabimimetic receptors, and therefore are important for the anti-tumor effects produced by Cannabis."

They are quite definite that

"Although we observed that specific Δ9-THC-rich Cannabis extracts were very potent in inducing cell death, their cytotoxic effects cannot be explained solely by the amount of Δ9-THC in the extracts. Nor can the potencies of these extracts be explained by other individual phytocannabinoids detected in them." (Supplementary Table 2)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609248/ [1164]

Rios et al (2025)

"...investigated the effect of combining a terpene, Beta-Caryophyllene (BCP), and cannabidiol (CBD) on neuropathic pain and associated depression. We employed a chronic constriction injury (CCI) neuropathic pain model and a series of behavioral tests to evaluate how oral administration of this combination influences neuropathic pain and depression-like behaviors in mice. We employed immunohistochemistry and proteomics approaches to explore the mechanism. Results: The analgesic effect of combining CBD and BCP is synergistic in neuropathic pain and also shows an antidepressant effect. Additionally, we found that this combination decreases neuroinflammation associated with CCI and affects specific genes involved in the inflammation."
https://www.mdpi.com/2227-9059/13/12/3103 [5802]

"Does cannabidiol make cannabis safer? A randomised, double-blind, cross-over trial of cannabis with four different CBD:THC ratios" examined various cognitive and physiological markers:

"This study aimed to determine if increasing the CBD content of cannabis can reduce its harmful effects. Forty-six healthy, infrequent cannabis users participated in a double-blind, within-subject, randomised trial of cannabis preparations varying in CBD content. There was an initial baseline visit followed by four drug administration visits, in which participants inhaled vaporised cannabis containing 10 mg THC and either 0 mg (0:1 CBD:THC), 10 mg (1:1), 20 mg (2:1), or 30 mg (3:1) CBD, in a randomised, counter-balanced order. The primary outcome was change in delayed verbal recall on the Hopkins Verbal Learning Task. Secondary outcomes included change in severity of psychotic symptoms (e.g., Positive and Negative Syndrome Scale [PANSS] positive subscale), plus further cognitive, subjective, pleasurable, pharmacological and physiological effects. Serial plasma concentrations of THC and CBD were measured. THC (0:1) was associated with impaired delayed verbal recall (t(45) = 3.399, d = 0.50, p = 0.001) and induced positive psychotic symptoms on the PANSS (t(45) = −4.709, d = 0.69, p = 2.41  105). These effects were not significantly modulated by any dose of CBD. Furthermore, there was no evidence of CBD modulating the effects of THC on other cognitive, psychotic, subjective, pleasurable, and physiological measures. There was a dose-response relationship between CBD dose and plasma CBD concentration, with no effect on plasma THC concentrations. At CBD:THC ratios most common in medicinal and recreational cannabis products, we found no evidence that CBD protects against the acute adverse effects of cannabis. This should be considered in health policy and safety decisions about medicinal and recreational cannabis."

and

"There were no significant differences in either peak plasma THC, OH-THC or COOH-THC, or their respective AUCs [areas under the curve] between the CBD:THC ratios (p > 0.008, Fig. 3A, Appendix pp612). In contrast, there was a significant, dose-dependent increase in peak plasma CBD, and in plasma CBD AUC, as CBD:THC ratio increased (p < 0.001, Fig. 3B, Appendix pp612). Peak plasma 7-OH-CBD was higher for the 3:1 ratio compared to 0:1 (EMM [estimated marginal mean] difference = 2.686, 95%CI: 1.888, 3.483, p = 1.25  10−9) and 1:1 (EMM difference = 2.206, 95% CI: 1.551, 2.861, p = 0.002), with AUC higher for 2:1 compared to 0:1 (EMM difference = 4.676, 95% CI: 3.287, 6.064, p = 0.003) and for 3:1 compared to 0:1 EMM difference = 8.898, 95%CI: 6.256, 11.540, p = 1.71  10−9) and 1:1 (EMM difference = 6.843, 95% CI: 4.811, 8.875, p = 3.57  10−6). Logarithmic concentrations of THC and CBD over time, with intercept and slope across ratios are presented in Appendix pp1314."

CBD and coughing...

"There was evidence of greater CBD:THC ratios increasing inhalation time and coughing in a dose responsive manner (Appendix pp4650). Greater inhalation time was correlated with lower peak and AUC concentrations of cannabinoids at higher CBD:THC ratios."

and as for the pleasure

"All CBD:THC ratios increased scores for both chocolate and music compared to baseline, but there were no significant differences between the CBD:THC ratios (p > 0.008, Appendix pp4345)."
https://www.nature.com/articles/s41386-022-01478-z [1876]

In another study Preet et al (2007) demonstrated that two different lung cancer cell lines as well as patient lung tumor samples express CB1 and CB2, and that non-toxic doses of THC inhibited growth and spread in the cell lines. When the cells are pretreated with THC, they have less EGFR stimulated invasion as measured by various in-vitro assays, Preet said.

"In this study we characterized the effects of THC on the EGF-induced growth and metastasis of human non-small cell lung cancer using the cell lines A549 and SW-1573 as in vitro models. We found that these cells express the cannabinoid receptors CB(1) and CB(2), known targets for THC action, and that THC inhibited EGF-induced growth, chemotaxis and chemoinvasion. Moreover, signaling studies indicated that THC may act by inhibiting the EGF-induced phosphorylation of ERK1/2, JNK1/2 and AKT. THC also induced the phosphorylation of focal adhesion kinase at tyrosine 397. Additionally, in in vivo studies in severe combined immunodeficient mice, there was significant inhibition of the subcutaneous tumor growth and lung metastasis of A549 cells in THC-treated animals as compared to vehicle-treated controls. Tumor samples from THC-treated animals revealed antiproliferative and antiangiogenic effects of THC."
https://www.researchgate.net/publication/6217199_D9-Tetrahydrocannabinol_inhibits_epithelial_growth_factor-induced_lung_cancer_cell_migration_in_vitro_as_well_as_its_growth_and_metastasis_in_vivo/link/0deec525c152d7388c000000/download [1734]

In 2010 Preet et al confirmed:

"Reduced proliferation and vascularization, along with increased apoptosis, were observed in tumors obtained from animals treated with JWH-133 and Win55,212-2. Upon further elucidation into the molecular mechanism, we observed that both CB1 and CB2 agonists inhibited phosphorylation of AKT, a key signaling molecule controlling cell survival, migration, and apoptosis, and reduced matrix metalloproteinase 9 expression and activity. These results suggest that CB1 and CB2 could be used as novel therapeutic targets against NSCLC."
https://pubmed.ncbi.nlm.nih.gov/21097714/ [3681]

According to Ramer et al (2011) "Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1":

"Cannabinoids inhibit cancer cell invasion via increasing tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). This study investigates the role of intercellular adhesion molecule-1 (ICAM-1) within this action. In the lung cancer cell lines A549, H358, and H460, cannabidiol (CBD; 0.001-3 μM) elicited concentration-dependent ICAM-1 up-regulation compared to vehicle via cannabinoid receptors, transient receptor potential vanilloid 1, and p42/44 mitogen-activated protein kinase. Up-regulation of ICAM-1 mRNA by CBD in A549 was 4-fold at 3 μM, with significant effects already evident at 0.01 μM. ICAM-1 induction became significant after 2 h, whereas significant TIMP-1 mRNA increases were observed only after 48 h. Inhibition of ICAM-1 by antibody or siRNA approaches reversed the anti-invasive and TIMP-1-upregulating action of CBD and the likewise ICAM-1-inducing cannabinoids Δ(9)-tetrahydrocannabinol and R(+)-methanandamide when compared to isotype or nonsilencing siRNA controls. ICAM-1-dependent anti-invasive cannabinoid effects were confirmed in primary tumor cells from a lung cancer patient. In athymic nude mice, CBD elicited a 2.6- and 3.0-fold increase of ICAM-1 and TIMP-1 protein in A549 xenografts, as compared to vehicle-treated animals, and an antimetastatic effect that was fully reversed by a neutralizing antibody against ICAM-1 [% metastatic lung nodules vs. isotype control (100%): 47.7% for CBD + isotype antibody and 106.6% for CBD + ICAM-1 antibody]. Overall, our data indicate that cannabinoids induce ICAM-1, thereby conferring TIMP-1 induction and subsequent decreased cancer cell invasiveness."
https://pubmed.ncbi.nlm.nih.gov/22198381/ [3680]

Meanwhile in real life:

"Conventional lung cancer treatments include surgery, chemotherapy and radiotherapy; however, these treatments are often poorly tolerated by patients. Cannabinoids have been studied for use as a primary cancer treatment. Cannabinoids, which are chemically similar to our own bodys endocannabinoids, can interact with signalling pathways to control the fate of cells, including cancer cells. We present a patient who declined conventional lung cancer treatment. Without the knowledge of her clinicians, she chose to self-administer cannabidiol (CBD) oil orally 23 times daily. Serial imaging shows that her cancer reduced in size progressively from 41 mm to 10 mm over a period of 2.5 years. Previous studies have failed to agree on the usefulness of cannabinoids as a cancer treatment. This case appears to demonstrate a possible benefit of CBD oil intake that may have resulted in the observed tumour regression. The use of cannabinoids as a potential cancer treatment justifies further research."
https://casereports.bmj.com/content/14/10/e244195.full [1761]

Research that began in 1975 with the discovery of the antineoplastic properties of Δ9-THC, Δ8-THC and CBN, which inhibited the growth of Lewis lung adenocarcinoma cells. More research was needed then and more research is still needed, now. Of course a lot of cannabis users have delayed or prevented their death and a lot of NECUD sufferers have not, in the intervening period.

According to "Antineoplastic activity of cannabinoids",

"Lewis lung adenocarcinoma growth was retarded by the oral administration of delta9-tetrahydrocannabinol (delta9-THC), delta8-tetrahydrocannabinol (delta8-THC), and cannabinol (CBN), but not cannabidiol (CBD). Animals treated for 10 consecutive days with delta9-THC, beginning the day after tumor implantation, demonstrated a dose-dependent action of retarded tumor growth. Mice treated for 20 consecutive days with delta8-THC and CBN had reduced primary tumor size. CBD showed no inhibitory effect on tumor growth at 14, 21, or 28 days. Delta9-THC, delta8-THC, and CBN increased the mean survival time (36% at 100 mg/kg, 25% at 200 mg/kg, and 27% at 50 mg/kg, respectively), whereas CBD did not. Delta9-THC administered orally daily until death in doses of 50, 100, or 200 mg/kg did not increase the life-spans of (C57BL/6 times DBA/2)F1 (BDF1) mice hosting the L1210 murine leukemia. However, delta9-THC administered daily for 10 days significantly inhibited Friend leukemia virus-induced splenomegaly by 71% at 200 mg/kg as compared to 90.2% for actinomycin D. Experiments with bone marrow and isolated Lewis lung cells incubated in vitro with delta9-THC and delta8-THC showed a dose-dependent (10(-4)-10(-7)) inhibition (80-20%, respectively) of tritiated thymidine and 14C-uridine uptake into these cells. CBD was active only in high concentrations (10(-4))."
https://pubmed.ncbi.nlm.nih.gov/1159836/ [1996]

Powells et al (2005) found that THC is cytotoxic to leukemic cell lines:

"Concentration-dependent decreases in cell viability were seen in all cell lines cultured with THC for 2 days".

However:

"Cytotoxic effect of THC is not mediated via the CB1-R and CB2-R."

And:

"THC does not increase p53 expression."

Moreover, THC decreases phosphorylated pERK protein expression:

"Genes in the MAPK signaling cascade that showed altered expression were DUSP6 (encoding dual specificity phosphatase 6/MAPK phosphatase 3 [MKP3]) and MAP2K2 (mitogenactivated protein kinase kinase 2/MEK2). Interestingly, MKP3 and MAP2K2 have the same intracellular target, the extracellular signal-regulated kinase 2 protein (ERK2/mitogen-activated protein kinase 1). They have, however, opposing functions: MEK2 phosphorylates, and thereby activates ERK2, whereas MKP3 dephosphorylates ERK2, taking it to an inactive state. Accordingly, the expression changes in response to THC observed were an increase in MKP3 expression in all 3 samples and a decrease in MAP2K2 expression (Table 2). Both changes are consistent with decreased MAPK signaling."
https://www.researchgate.net/profile/Robert-Te-Poele/publication/8261865_Cannabis-induced_cytotoxicity_in_leukemic_cell_lines_The_role_of_the_cannabinoid_receptors_and_the_MAPK_pathway/links/53e0abbf0cf24f90ff6091e2/Cannabis-induced-cytotoxicity-in-leukemic-cell-lines-The-role-of-the-cannabinoid-receptors-and-the-MAPK-pathway.pdf?_tp=eyJjb250ZXh0Ijp7ImZpcnN0UGFnZSI6Il9kaXJlY3QiLCJwYWdlIjoicHVibGljYXRpb24iLCJwcmV2aW91c1BhZ2UiOiJfZGlyZWN0In19 [4808]

Now the idea in practice is, you ignore alcohol causing cancer, food causing cancer, heavy metals causing cancer, plastics causing cancer and everything else causing cancer. After you have ignored those things for a while,...Oh! You have cancer. But the mechanisms involved in the progress of cancer did not suddenly appear with the diagnosis of the disease. They were there all the time, but in balance and under control.

Following the 1975 Munson et al paper on Lewis lung adenocarcinoma, according to Abrams:

"For unclear reasons, that line of research was not pursued further at the National Institutes of Health in the United States, but was subsequently picked up by investigators in Spain and Italy, who have made enormous contributions to the field.

"If cannabinoids are postulated to have a potential anticancer effect working through the cb1 receptor, it would follow that the brainwhere the cb1 receptor is the most densely populated seven-transmembrane domain G protein coupled receptor would be a good place to start the investigation. And, in fact, numerous studies in vitro and in animal models have suggested that cannabinoids can inhibit gliomas. Other tumour cell lines are also inhibited by cannabinoids in vitro, and cannabinoid administration to nude mice curbs the growth of various tumour xenografts representing multiple solid and hematologic malignancies, including adenocarcinomas of the lung, breast, colon, and pancreas, and also myeloma, lymphoma, and melanoma."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791148/ [1997]

Abrams, who can be found in the Hematology-Oncology department at San Francisco General Hospital; also at Integrative Oncology, UCSF Osher Center for Integrative Medicine; and also at the University of CaliforniaSan Francisco, San Francisco, CA, U.S.A., writing March 23 in Current Oncology, wrote:

"Much attention has been paid to the unearthing of the 2500-year-old mummy known as the 'Siberian Ice Maiden.' Discovered in 1993, her subterranean burial chamber included a pouch of cannabis among other archeologic findings. Magnetic resonance imaging revealed that the princess had a primary tumour in the right breast, with axial adenopathy and metastatic disease. It is hypothesized that the cannabis was used to manage her pain and perhaps other symptoms, or even possibly as a treatment for her malignant disease.

"Widely used as medicine during the ensuing millennia, cannabis disappeared from the pharmaceutical armamentarium in the 1940s as its prohibition took hold. Today, we are in the midst of what appears to be something of a medicinal cannabis renaissance, with patients across the globe gaining increased access to this potent botanical medicine. In a 2014 WebMD poll, 82% of oncologists indicated their belief that patients should have access to cannabis, ranking highest among medical subspecialists in their support. Regrettably, most oncologists trained during the era of cannabis prohibition and have no knowledge of how to use the plant as medicine. In these days of targeted therapies and nanotechnology, the modern oncologist might feel somewhat ill at ease recommending a herbal intervention, notwithstanding the number of potent cytotoxic chemotherapeutic agents derived from plants."

and

"...administration of anandamide (an endocannabinoid) together with an inhibitor of the fatty-acid amide hydrolase that metabolizes anandamide attenuated chemotherapy-induced peripheral neuropathy. Cannabidiol pretreatment stops paclitaxel-induced neuropathy in mice. To date, the only human study of a cannabis-based medicine in chemotherapy-induced peripheral neuropathy is a crossover placebo-controlled trial of nabiximols."

and in a suggestion for more research that might be needed...

"Even more exciting would be a study demonstrating the potential for cannabis to actually lower the risk for neuropathy or to prevent it from developing in the first place, as the animal models suggest."

Meanwhile we are reminded

"The cb receptors are not present to react with the phytocannabinoids from cannabis alone. They exist because, on demand, humans produce endogenous cannabinoidsendocannabinoidsthat react with the receptors, effecting changes in intracellular signalling. It has been suggested that the entire function of the system of cannabinoid receptors and endocannabinoids might be to assist in modulation of the response to pain. With that in mind, it is not surprising that an increasing body of knowledge is being developed about the effects on pain of cannabinoid medicines." [1997]

By 2022 the same author was reporting that

"THC and CBD may both impact the metabolism of other pharmaceuticals and botanicals by way of cytochrome p450 interactions. To date, very few pharmacokinetic interaction studies have been investigated to evaluate the effects of cannabis or isolated cannabinoids on blood levels of conventional cancer therapies."

and

"No studies of cannabis to promote weight gain in cancer patients have been reported likely due to the barriers to conducting research with the botanical. Cannabis, however, with both antiemetic and orexigenic effects, may be a useful therapeutic for cancer patients and should be further explored in future clinical investigations."
https://journals.sagepub.com/doi/full/10.1177/15347354221081772 [1998]

Tai, Wong and Wen (2015), recalling that

"Innate immunity is the first line of defense of the body in response to exogenous insults such as bacterial, viral and fungal infections and innate immunity acts through highly conserved pattern-recognition receptors, such as Toll-like receptors (TLR), to coordinate the innate inflammatory response to both endogenous and exogenous stimuli. After engaging with their ligands, the downstream inflammatory responses of most TLRs are mediated through the [Myeloid differentiation primary response 88] MyD88-dependent pathway, except TLR3, which is [TIR-domain-containing adapter-inducing interferon-β] TRIF dependent."

and they tell us a 2014

"...study by Alkanani and colleagues also showed that induction of diabetes in the RIP-B7.1 C57BL/6 mouse model was critically dependent on TLR3 and MyD88 pathways and an altered intestinal microbiome was responsible for the diabetes modulation. Experimental data from BB rats performed by Roesch and colleagues also showed the altered gut microbiota were linked to the onset of diabetes in BB-DP (diabetes-prone) compared to BB-DR (diabetes-resistant) rats. Moreover, Hara et al showed that antibiotic treatment could prevent Kilham rat virus-induced insulitis and T1D in the LEW1.WR1 rat model, suggesting that microbiota might also be involved in virus-induced diabetes. Transfer of gut microbiota from diabetes-protected MyD88-deficient [non-obese diabetic] NOD mice at an early age could stably alter the composition of the gut microbiota of recipient NOD mice, reduce insulitis and significantly delay the onset of diabetes. Taken together, these data indicate altered gut microbiota are strongly associated with T1D and modulation of the gut microbiota by transfer of so-called 'protective gut flora' could delay and/or prevent diabetes development. However, how gut microbiota are altered and what mechanisms are involved in the immune regulation by the commensal bacteria in diabetes development need to be further investigated."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348024/ [1546]

Can demyelination be prevented, slowed, or reversed? Some Google search results for these show you are allowed to believe in these things - by such treatments as lowering depression, preventing activation of innate immune mechanisms that provoke hypoxia, and superoxide and nitric oxide formation, increasing inspired oxygen, upregulation of miR-23, arsa-cel gene therapy, Sphingosine 1-phosphate receptor modulation with BAF312 (siponimod), astrocytic yes-associated protein, induction of heat shock protein 70, administration of interferon beta-1a, glatiramer acetate, the monoclonal antibody, BIIB033, agonists of PPAR-beta and RXR-alpha, Astragalus polysaccharides, nervonic acid, EHP-101, thrombin inhibitors, nerve growth factor or its analogues, transcranial electrical stimulation, a compound found in cashew nut shells, ginger, omega-3 fatty acids, vitamin D, vitamin B12, folate, vitamin C, glutathione, vitamin K, lithium, melatonin, lipoic acid, niacin, and cholesterol, curcumin, thyme, rosemary, quercetin, licorice, resveratrol, and black cumin seeds.
https://www.google.co.uk/search?q=%22preventing+demyelination%22&lr=&newwindow=1&safe=images&as_qdr=all&ei=CrypY5u2HqPosAfy6IOoDw&ved=0ahUKEwib45yMy5f8AhUjNOwKHXL0APUQ4dUDCA8&uact=5&oq=%22preventing+demyelination%22&gs_lcp=Cgxnd3Mtd2l6LXNlcnAQAzIECAAQHjIFCAAQhgMyBQgAEIYDMgUIABCGAzIFCAAQhgMyBQgAEIYDOgoIABBHENYEELADOgYIABAHEB46CggAEAgQBxAeEA86CAgAEAUQHhANOggIABAIEB4QDToKCAAQCBAeEA8QDUoECEEYAEoECEYYAFC3C1iXDmCnEWgBcAF4AIABqQGIAfMCkgEDMS4ymAEAoAEByAEIwAEB&sclient=gws-wiz-serp [3907]

In "CNS Demyelination Syndromes Following COVID-19 Vaccination: A Case Series" by Yasser et al (2024):

"The study was carried out on 18 patients who presented with different neurological disorders after the first or second dose of the COVID-19 vaccine. There were eight men (44.44%) and ten women (55.56%) with a mean age of 34.78 7.13 years, ranging from 23 to 44 years. The mean duration between the onset of symptoms and the date of the last dose of the COVID-19 vaccine was 7.67 3.83 days, ranging from 214 days. Regarding the type of vaccine, 12 patients (66.67%) received the Pfizer vaccine, and the remaining six (33.33%) received the AstraZeneca vaccine. Eight patients (44.44%) developed neurological manifestations after the first dose of the vaccine, and the remaining ten (55.56%) developed them after the second dose [Table 1].

"Four patients (22.22%) presented with optic neuritis, three (16.67%) with hemiparesis, three (16.67%) with paraparesis, three (16.67%) with seizures (GTC and myoclonic), two (11.11%) with ataxia, one (5.56%) with hemihypesthesia, one (5.56%) with headache, and one (5.56%) with tinnitus [Table 2]. Sixteen patients (88.89%) had brain MRI findings suggestive of a demyelinating disorder [Figures 1 and 2], and two (11.11%) had a normal brain MRI but with the spine MRI showing a picture of transverse myelitis [Figure 3]. In the results of the oligoclonal band in CSF and serum, ten patients (55.56%) had a positive oligoclonal band in the CSF only, and the remaining eight (44.44%) had negative results. VEP was performed for ten patients. The results showed that four (22.22%) had prolonged P 100 latency, and the remaining six had normal P 100 latency. AQP-4 was performed for three patients and was negative [Tables 3 and 4]."

As to the potential mechanisms of this they say:

"Although the precise mechanism of demyelination following COVID-19 vaccinations is still not fully known, a combination of vaccine-related variables and patient susceptibility plays a significant role. Some individuals may experience an unintended immune reaction as a result of the resemblance between the proteins of the viruses used for vaccination and self-antigens (such as myelin). Another factor is the use of immunologic adjuvants, which are substances that increase immune responses to certain antigens and can mimic evolutionarily conserved chemicals that activate both the innate and adaptive immune systems. TLR7 and TLR8 activation also results in the production of type I interferon, potent T and B cell responses, and the activation of bystander autoreactive cells. This bystander activation and cytokine secretion by macrophages might lead to local inflammation and the recruitment of more T-helper cells."
https://journals.lww.com/jpbs/fulltext/2024/16001/cns_demyelination_syndromes_following_covid_19.298.aspx [3127]

Demyelinating conditions are among those whose odds ratios increased after Covid-19 vaccination according to a VAERS analysis by Cosgrove et al, who compared adverse events from the mRNA shots with influenza vaccine recipients, finding increases in:

Rare Neurodegenerative & Demyelinating Conditions:

CreutzfeldtJakob disease (CJD) 847 more likely to be reported compared to flu shots
Myelitis (all types) 31 more likely
Transverse myelitis 21 more likely
Viral myelitis 115 more likely
Noninfectious myelitis 132 more likely
Prion disease (general) 62 more likely

CNS Infections:

Meningitis (all types) 34 more likely
Aseptic meningitis 53 more likely
Bacterial meningitis 36 more likely
Autoimmune encephalitis 79 more likely
Limbic encephalitis 146 more likely
Bickerstaffs encephalitis 68 more likely
Neuroborreliosis (Lyme CNS infection) 321 more likely
Toxic encephalopathy 157 more likely
Progressive multifocal leukoencephalopathy (PML) 45 more likely

Herpetic CNS Reactivations:

Herpes zoster meningitis over 1,200 more likely
Herpes zoster meningoencephalitis 339 more likely
Herpes zoster neurological disease 680 more likely
Herpes simplex meningitis 132 more likely
Herpetic meningoencephalitis 136 more likely
Varicella meningitis 168 more likely

Brain & Spinal Abscesses:

Brain abscess 120 more likely
Extradural abscess 169 more likely
Spinal cord abscess 89 more likely
Subdural abscess 36 more likely
https://www.researchgate.net/profile/Nicolas-Hulscher/publication/395581251_COVID-19_mRNA_Vaccination_Implications_for_the_Central_Nervous_System/links/68cb55840f14e901fcd12bbc/COVID-19-mRNA-Vaccination-Implications-for-the-Central-Nervous-System?_tp=eyJjb250ZXh0Ijp7ImZpcnN0UGFnZSI6InB1YmxpY2F0aW9uIiwicGFnZSI6InB1YmxpY2F0aW9uIn1 [5461]

Anything which could ameliorate these odds ought not to be banned.

In 2000, five months after the enactment of the ZPPPD, Derocq and colleagues investigated the "enigma" of the CB2 receptor, becoming the first to discover a role in immune cell differentiation and chemotaxis, as:

"...activation of the CB2 receptors induced an up-regulation of nine genes involved in cytokine synthesis, regulation of transcription, and cell differentiation. A majority of them are under the control of the transcription factor NF-kB, whose nuclear translocation was demonstrated. Many features of the transcriptional events, reported here for the first time, appeared to be related to an activation of a cell differentiation program, suggesting that CB2 receptors could play a role in the initialization of cell maturation. Moreover, we showed that CB2-activated wild-type HL-60 cells developed properties usually found in host defense effector cells such as an enhanced release of chemotactic cytokines and an increased motility, characteristic of more mature cells of the granulocytic-monocytic lineage."
https://www.jbc.org/article/S0021-9258(19)80340-X/pdf [3531]

In 2005 the CB2 receptor was shown to be essential for macrophage chemotaxis.
https://www.jbc.org/article/S0021-9258(19)46626-X/pdf [3530]

Low dose THC was found to reduce the progression of atherosclerosis in mice. According to Steffens et al (2005):

"Lymphoid cells isolated from THC-treated mice showed diminished proliferation capacity and decreased interferon-γ secretion. Macrophage chemotaxis, which is a crucial step for the development of atherosclerosis, was also inhibited in vitro by THC. All these effects were completely blocked by a specific CB2 receptor antagonist. Our data demonstrate that oral treatment with a low dose of THC inhibits atherosclerosis progression in the apolipoprotein E knockout mouse model, through pleiotropic immunomodulatory effects on lymphoid and myeloid cells."
https://www.jbc.org/article/S0021-9258(19)46626-X/pdf [3532]

This could turn out to be useful and adds to the risks of NECUD as SARS-CoV-2, the virus that causes COVID-19, can directly infect the arteries of the heart and cause the fatty plaque inside arteries to become highly inflamed, increasing the risk of heart attack and stroke, according to "SARS-CoV-2 infection triggers pro-atherogenic inflammatory responses in human coronary vessels" by Eberhardt et al (2023):

"Here we report that SARS-CoV-2 viral RNA is detectable and replicates in coronary lesions taken at autopsy from severe COVID-19 cases. SARS-CoV-2 targeted plaque macrophages and exhibited a stronger tropism for arterial lesions than adjacent perivascular fat, correlating with macrophage infiltration levels. SARS-CoV-2 entry was increased in cholesterol-loaded primary macrophages and dependent, in part, on neuropilin-1. SARS-CoV-2 induced a robust inflammatory response in cultured macrophages and human atherosclerotic vascular explants with secretion of cytokines known to trigger cardiovascular events. Our data establish that SARS-CoV-2 infects coronary vessels, inducing plaque inflammation that could trigger acute cardiovascular complications and increase the long-term cardiovascular risk."

Cholesterol-laden foam cells were the most susceptible to infection and unable to readily clear the virus. This suggested that foam cells might act as a reservoir of SARS-CoV-2 in the atherosclerotic plaque:

"The significantly higher accumulation of nucleoprotein (NP) in foam cells compared to macrophages infected with SARS-CoV-2 USA WA1/2020 isolate (Fig. 2b and Extended Data Fig. 3b) confirmed a higher susceptibility of foam cells to the virus."
https://www.nature.com/articles/s44161-023-00336-5 [3640]

In a 2015 study macrophage chemotaxis was found to be activated by CB2R agonists but independently of them. According to Taylor et al:

"Activation of CB2 has been demonstrated to induce directed immune cell migration. However, the ability of CB2 to act as a chemoattractant receptor in macrophages remains largely unexplored. Using a real-time chemotaxis assay and a panel of chemically diverse and widely used CB2 agonists, we set out to examine whether CB2 modulates primary murine macrophage chemotaxis. We report that of 12 agonists tested, only JWH133, HU308, L-759,656 and L-759,633 acted as macrophage chemoattractants. Surprisingly, neither pharmacological inhibition nor genetic ablation of CB2 had any effect on CB2 agonist-induced macrophage chemotaxis. As chemotaxis was pertussis toxin sensitive in both WT and CB2-/- macrophages, we concluded that a non-CB1/CB2, Gi/o-coupled GPCR must be responsible for CB2 agonist-induced macrophage migration. The obvious candidate receptors GPR18 and GPR55 could not mediate JWH133 or HU308-induced cytoskeletal rearrangement or JWH133-induced β-arrestin recruitment in cells transfected with either receptor, demonstrating that neither are the unidentified GPCR. Taken together our results conclusively demonstrate that CB2 is not a chemoattractant receptor for murine macrophages. Furthermore we show for the first time that JWH133, HU308, L-759,656 and L-759,633 have off-target effects of functional consequence in primary cells and we believe that our findings have wide ranging implications for the entire cannabinoid field."

They say:

"Real-time analysis of changes in cell morphology demonstrated that L-759,656 induced concentration dependent signalling (Fig. 3D), whereas the chemotaxis negative compounds CP55,950, AM1241 (Fig. 3D), GP1a and WIN55212-2 (Fig. 3E) did not induce signalling at any concentration tested. In summary, using both Boyden chamber and real-time chemotaxis assays we have shown that only a subset of CB2 agonists act as primary murine macrophage chemoattractants and only chemotaxis positive compounds were capable of inducing changes in cell morphology as measured by changes in electrical impedance.

https://www.nature.com/articles/srep10682.pdf [3352]

Writing in 2016, F Rohan Walker and Raz Yirmani describe the shift in thinking about microglia:

"The remarkable number of discoveries over the last decade concerning microglial involvement in the most fundamental CNS processes has caught many by surprise. To a certain extent, this surprise has been driven by long established assumptions concerning the primary role of microglia as immune type cells within the brain. Indeed, the literature prior to 2005 is filled with descriptions of microglia as the macrophages of the brain, with detailed investigation of how these cells function as the first-responders to tissue injury or insult (Kreutzberg, 1996). However, 2005 represented a departure from this classical outlook, with the first observation of these cells in real time being reported (Davalos et al., 2005, Nimmerjahn et al., 2005). These multiphoton imaging studies revealed that microglia are incredibly active, rapidly extending and retracting their processes, apparently in an effort to scan their microenvironment. The question on all microgliologists minds at the time was, scanning for what? In rapid succession, it became apparent that rather than patrolling for threats (or only for threats), microglia were in fact making continuous contact with pre- and post-synaptic terminals to monitor synaptic activity (Kettenmann et al., 2013, Tremblay et al., 2010, Wake et al., 2009). Furthermore, during development, such microglial-neuronal interactions were found to be crucial for synaptic maturation and pruning, which underlie the activity-dependent tuning and refinement of neuronal circuits and the brains global connectivity pattern (Paolicelli et al., 2011, Schafer et al., 2012, Zhan et al., 2014). These discoveries subsequently proved to be immensely important, as there was now a credible chain of evidence through which immunological activity could directly influence both neuronal architecture and function."
https://www.sciencedirect.com/science/article/abs/pii/S0889159116300514 [3533]

According to "Neuroscience" 2nd edition (2001):

"By acting as an electrical insulator, myelin greatly speeds up action potential conduction (Figure 3.14). For example, whereas unmyelinated axon conduction velocities range from about 0.5 to 10 m/s, myelinated axons can conduct at velocities up to 150 m/s. The major reason underlying this marked increase in speed is that the time-consuming process of action potential generation occurs only at specific points along the axon, called nodes of Ranvier, where there is a gap in the myelin wrapping (see Figure 1.4F). If the entire surface of an axon were insulated, there would be no place for current to flow out of the axon and action potentials could not be generated. As it happens, an action potential generated at one node of Ranvier elicits current that flows passively within the myelinated segment until the next node is reached. This local current flow then generates an action potential in the neighboring segment, and the cycle is repeated along the length of the axon. Because current flows across the neuronal membrane only at the nodes (see Figure 3.13), this type of propagation is called saltatory, meaning that the action potential jumps from node to node. Not surprisingly, loss of myelin, as occurs in diseases such as multiple sclerosis, causes a variety of serious neurological problems."
https://www.ncbi.nlm.nih.gov/books/NBK10921/ [2273]

A 2019 view of multiple sclerosis:

"The pathogenesis of this disease is characterized by neuroinflammation leading to demyelination and consequently paralysis. Although the complete etiology and the pathogenesis of MS remains unclear, there is evidence that increased migration of myelin-reactive CD4 + Th1 and Th17 cells across the blood-brain barrier (BBB) causing inflammation in the CNS which leads to axonal demyelination of neurons, axonal injury, oligodendrocyte loss, neuronal damage, and glial plaques (Wu and Chen, 2016)." [1285]

In 2022 Biomedicine published "Neurological Benefits, Clinical Challenges, and Neuropathologic Promise of Medical Marijuana: A Systematic Review of Cannabinoid Effects in Multiple Sclerosis and Experimental Models of Demyelination" by Longoria et al.

"Despite current therapeutic strategies for immunomodulation and relief of symptoms in multiple sclerosis (MS), remyelination falls short due to dynamic neuropathologic deterioration and relapses, leading to accrual of disability and associated patient dissatisfaction. The potential of cannabinoids includes add-on immunosuppressive, analgesic, neuroprotective, and remyelinative effects."

and

"MS exhibits heterogeneity with respect to clinical, genetic, radiographic, and pathologic features. Triggers for MS development and relapses involve interactions between genetic, lifestyle, and environmental factors. Genome-wide association studies (GWAS) have identified over 230 genetic risk loci for MS, revealing a ~5-fold increase in the risk of MS when the presence of the class II variant HLA-DRB1*15:01 is combined with an absence of the class I variant HLA-A*02. Other risk factors for MS include smoking, alcohol consumption, obesity, low dietary intake of vitamin D, lower sun exposure, latitude farther away from equator, and certain chronic viral infections. Longitudinal analysis using data from US military recruits over a period of 20 years has revealed that EpsteinBarr virus (EBV) increased the risk of subsequent MS by 32-fold. MS patients have significantly higher serum anti-EBV nuclear antigen-1 (EBNA-1) titers as compared to healthy controls, and the higher EBV responses correlate with more extensive lesion and gray matter tissue destruction as measured by magnetization transfer imaging in RRMS patients. Molecular mimicry may explain the association between EBV titers and more severe neuropathology since ~2025% of MS patients have anti-EBNA1 antibodies that cross-react with the CNS protein glial cell adhesion molecule (GlialCAM].

"In humanized non-obese diabetic-severe combined immunodeficiency (NOD-scid) IL2 receptor γ-chain-deficient (huNSG) mice, EBV infection was found to synergize with HLA-DR15 by priming cross-reactive CD4+ T-cell clones which control the viral infection less efficiently. It is hypothesized that EBV might activate ancestral human endogenous retroviruses (HERVs) in the human genome. Antibodies to other viruses have been associated with increased MS conversion and relapse including human herpes virus 6 (HHV-6). It is believed that the induction of demyelination in the brain and spinal cord in MS may be initiated by excess innate and myelin-specific autoimmune activation mechanisms that are sensitive to chronic viral infections and gut microbiome status and perpetuated by the loss of oligodendrocytes and their progenitors through either perforin-mediated lysis or apoptotic cell death."

and

"Early studies also demonstrated that cannabinoids could ameliorate clinical progression, downregulate proinflammatory T cells, and promote remyelination in TMEV-IDD."

and

"Clinical studies suggest that combinations of the cannabinoids derived from the Cannabis sativa plant, cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC), are comparably as effective for short-term symptomatic relief as conventional pharmacotherapeutic agents while causing less side effects. An oromucosal spray formulation, Sativex (nabiximols), which contains Δ9-THC and CBD in a nearly 1:1 ratio, was licensed in the United Kingdom in 2010 as a prescription-only medicine for the treatment of spasticity in multiple sclerosis."

14 animal and 14 human studies were reviewed. In the human tests:

"Spasticity outcomes were reported in nine studies: three randomized, double-blind, placebo-controlled clinical trials, and six cohort/observational studies. The quality of evidence [Cochrane] GRADE [Grading of Recommendation Assessment, Development and Evaluation] was moderate in six and low in three of the studies (Table 7 and Table 8). The total number of subjects for spasticity studies was 1582. The mean maximal change in NRS [numerical rating scale] spasticity scores was 2.8 (range 0.04 to 7.4) lower than baseline. Assessments were repeated more than once within a period of 4 months, and two of the studies extended up to 12 months. In the three clinical trials, the mean difference in NRS spasticity scores was 0.62 (range 0.5 to 0.83) points lower in the treatment groups as compared to controls, as a placebo effect was noted in two of the trials."

"Cannabis-based medicine has long been known to be useful in pain management including central pain in multiple sclerosis and post-operative pain. Promising benefits of cannabis use and medical marijuana have also been observed for relief of neurologic symptoms in patients with movement disorders, including Parkinson disease and Huntington disease. Furthermore, oral CBD has been used for the treatment of drug-resistant seizures in children with tuberous sclerosis (TSC), and Epidiolex (pure CBD) has been approved for the treatment of intractable epilepsy in patients with developmental epileptic encephalopathies including Dravet syndrome and LennoxGastaut syndrome (LGS). Multiple mechanisms are implicated in the ability of CBD to modulate seizures that include antagonism of CB1, CB2, GPR18, GPR55, and voltage-gated sodium channel (VGSC) receptors; agonism of GABAA receptors; activation and desensitization of TRPV1/2 receptors; and allosteric modulation of opioid receptor types μ [mu] and δ [delta], leading to inhibition of glutaminergic N-methyl-D-aspartate (NMDA) receptors."

...

"In addition to neuroprotective effects, cannabinoid treatment in vitro and in vivo has antiseizure, antiemetic, anti-inflammatory, and antitumor effects which include antiproliferative, proapoptotic, autophagic, antiadhesion, antimigration, and antiangiogenic mechanisms affecting cancer cells, cell lines, human tumor xenografts, and animal cancer models."

...

"Recent studies have provided evidence implicating lysophosphatidic acid (LPA) signaling through its G protein-coupled receptor, LPA1, as a mechanism of macrophage activation that correlates with the onset of relapses and greater disease severity in both EAE and MS. Interactions between the endocannabinoid system and the LPA system in the mouse brain have been identified in studies demonstrating upregulation of LP1 receptor activity in CB1 knockout mice. Cannabinoids have also been shown to promote a reparative activation state of microglia and macrophages, diminishing the reactivity and the number of microglia in Theilers virus-induced demyelination disease. RNA sequencing analysis has revealed that oral CBD treatment of EAE mice can reduce the expression of CXCL9, CXCL10, and IL-1β, leading to decreased macrophage infiltration into the CNS, and also induce myeloid-derived suppressor cells (MDSCs)."

...

"CB2-mediated facilitation of oligodendrocyte survival involved decreases in the phosphorylation of the protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase (PERK), eIF2α, ATF4, and GADD34 (Growth Arrest and DNA Damage-inducible protein) signaling pathway in microglia."

...

"Treatment with Δ9-THC also promoted axonal remyelination in organotypic cerebellar cultures. CB1 receptors regulate the mTORC1 signaling pathway during oligodendrocyte development, and the remyelination effects could be abrogated by both mTORC1 blockade and CB1 receptor-selective antagonism."

...

"Analysis of patient-reported outcome measures in 312 patients from the UK medical cannabis registry revealed statistically significant improvements at 6 months in the Generalized Anxiety Disorder Scale score (GAD-7, p < 0.001), the EuroQol Group EQ-5D-5L index value (p < 0.001), the EQ-5D Visual Analog Scale score (VAS, p < 0.012), and the Sleep Quality Scale (SQS, p < 0.001) score."
https://www.mdpi.com/2227-9059/10/3/539 [1938]

In 2022, examining the effects of cannabinoids on toll-like receptors, Fitzpatrick et al

"...employed the use of poly(I:C) and lipopolysaccharide (LPS) to induce viral TLR3 and bacterial TLR4 signalling, and [peripheral blood mononuclear cells] PBMCs were pre-exposed to plant-derived highly purified THC (10 μM), CBD (10 μM), or a combination of both phytocannabinoids (1:1 ratio, 10:10 μM), prior to LPS/poly(I:C) exposure. TLR3 stimulation promoted the protein expression of the chemokine CXCL10 and the type I IFN-β in PBMCs from both cohorts. THC and CBD (delivered in 1:1 combination at 10 μM) attenuated TLR3-induced CXCL10 and IFN-β protein expression in PBMCs from [people with multiple sclerosis] pwMS and HCs, and this effect was not seen consistently when THC and CBD were delivered alone."

As their paper "Botanically-Derived ∆ 9 -Tetrahydrocannabinol and Cannabidiol, and Their 1:1 Combination, Modulate Toll-like Receptor 3 and 4 Signalling in Immune Cells from People with Multiple Sclerosis" explains:

"A body of preclinical data indicate that THC and CBD have anti-inflammatory and antioxidant propensity, and TLRs are cannabinoid targets. Indeed, recent findings from our laboratory indicate that both THC and CBD target inflammatory signalling governed by TLRs in human macrophages, specifically TLR3 and TLR4. Such data, particularly with regard to THC, are important in the context of evidence linking the endocannabinoid system (ECS) with the pathogenesis of MS. Indeed, the expression of the endocannabinoid anandamide (AEA) is enhanced in CSF, lymphocytes, and plasma of pwMS, while knock-out of the cannabinoid receptors CB1 and CB2, and administration of the AEA metabolising enzyme fatty acid amide hydrolase (FAAH), alters the clinical progression of [experimental autoimmune encephalomyelitis] EAE in mice."
https://www.mdpi.com/1420-3049/27/6/1763/pdf?version=1646732841 [1547]

"Δ9-Tetrahydrocannabinol and cannabidiol selectively suppress toll-like receptor (TLR) 7 and TLR8-mediated interleukin-1β production by human CD16+ monocytes by inhibiting its post-translational maturation" say Sermet et al (2025):

"We hypothesized that THC and CBD suppress toll-like receptor (TLR) 7 or TLR8-induced inflammatory profiles by CD16+ and CD16− monocytes, specifically interleukin (IL) 1β maturation. Cannabinoid receptor 2 selective agonist, JWH-015, was used to deduce whether cannabinoid receptor 2 signaling alone can mimic immune-modulating properties of THC. Primary human CD16+ and CD16− monocytes were pretreated with THC, CBD, or JWH-015 and then activated through TLR7 or TLR8. Activated monocytes mainly produced IL-1β, tumor necrosis factor-⍺, and IL-6. We show that THC and CBD, but not JWH-015, exert anti-inflammatory effects on primary human monocyte apoptosis-associated speck-like proteinincorporating inflammasome formation and subsequent caspase-1 activity, contributing to suppressed IL-1β production. In addition, mRNA expression of IL1B, CASP1, NLRP3, and PYCARD were unaffected by THC. Minimal THC effects were observed on TLR8-mediated AIM2 mRNA expression. Collectively, results from these studies suggest THC and CBD may be useful in mitigating IL-1βmediated acute or chronic inflammation."
https://jpet.aspetjournals.org/article/S0022-3565(25)39828-9/abstract  [5109]

https://iris.unibs.it/retrieve/ddc633e2-aede-4e2e-e053-3705fe0a4c80/Ziegler%20Blood%202010.pdf [5110]

So we need to know a bit more about oligodendrocytes. These were discovered by the application of a novel silver carbonate staining method in 1918 by Pio Del Ro Hortega.

"After developing modifications of Achcarros ammoniacal silver method (Del Ro Hortega, 1916), Del Ro Hortega challenged the accuracy of Ramn y Cajals concept about the third element of CNS which grouped non neuronal (first element) and non-astrocytic (second element) cells (Ramn y Cajal, 1913b, 1916; Garca-Marn et al., 2007). Later, he described his silver carbonate staining technique which was the methodological key to identify two distinct elements: the microglia, the true third element, and what he called initially interfascicular cells and later oligodendroglia (Del Ro Hortega, 1918, 1920, 1921)."

And, writing in 2015, Achucarro Basque Center for Neuroscience authors say that:

"He established their ectodermal origin and suggested that they built the myelin sheath of CNS axons, just as Schwann cells did in the periphery. Notably, he also suggested the trophic role of OLGs for neuronal functionality, an idea that has been substantiated in the last few years....Yet, the difficulty of metal impregnation methods and their variability in results, delayed for some decades the confirmation of his great insights into oligodendrocyte biology until the development of electron microscopy and immunohistochemistry."
https://www.frontiersin.org/articles/10.3389/fnana.2015.00092/full [1557]

From whence does damage to oligodendrocytes originate? All around us, in everyday household products, in my home and yours. According to Cohn et al at the Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, who...

"...revealed environmental chemicals in two classes that disrupt oligodendrocyte development through distinct mechanisms. Quaternary compounds, ubiquitous in disinfecting agents, hair conditioners, and fabric softeners, were potently and selectively cytotoxic to developing oligodendrocytes through activation of the integrated stress response. Organophosphate flame retardants, commonly found in household items such as furniture and electronics, were non cytotoxic but prematurely arrested oligodendrocyte maturation. Chemicals from each class impaired human oligodendrocyte development in a 3D organoid model of prenatal cortical development. In analysis of epidemiological data from the CDCs National Health and Nutrition Examination Survey, adverse neurodevelopmental outcomes were associated with childhood exposure to the top organophosphate flame retardant identified by our oligodendrocyte toxicity platform."
https://www.biorxiv.org/content/biorxiv/early/2023/02/12/2023.02.10.528042.full.pdf [4518]

A Madrid-Boston collaboration states that it is not just a matter of maintenance for people already diagnosed with MS, but also of remyelination - i.e. repair of myelin - and prevention of demyelination in the first place that cannabinoids impart to the user population, and they say:

"Neuroprotective therapies, and those targeting oligodendrocyte progenitors and other CNS cells, such as astrocytes and microglia, are likely to promote recovery and prevent long-term neurodegeneration. Indeed, the neuroprotective effects of CBs have been confirmed in different models of injury and CNS disease, like Alzheimers Disease (Martn-Moreno et al., 2012; Schubert et al., 2019), stroke (Zarruk et al., 2012; Kolb et al., 2019), ischemic injury (Fernndez-Lpez et al., 2007), Parkinsons Disease (Garca et al., 2011) and ALS (Rodrguez-Cueto et al., 2018). In the TMEV-IDD model of progressive MS, the administration of synthetic CBs (Arvalo-Martn et al., 2003) or pCBs (Mecha et al., 2013; Feli et al., 2015) has been associated with an improvement in neurological defects, also observed by inhibiting selective AEA uptake (Ortega-Gutirrez et al., 2005) or the enzymatic hydrolysis of 2-AG (Feli et al., 2017). In this latter study, both remyelination and axon preservation was showed, while chondroitin sulfate proteoglycans diminished through the involvement of CB1R and CB2R. In addition, 2-AG administration or inhibition of its hydrolysis favors oligodendrocyte precursor cell (OPC) differentiation (Gomez et al., 2015) and, by diminishing the excitotoxicity of oligodendrocytes, demyelination is prevented in the EAE (Bernal-Chico et al., 2015) and the cuprizone model (Manterola et al., 2018)."
https://www.frontiersin.org/articles/10.3389/fncel.2020.00034/full [1549]
https://link.springer.com/article/10.1007/s11481-015-9609-x [1550]
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4052930/ [3563]

Next, to a recent but flawed review, "Drugs and Bugs: The Gut-Brain Axis and Substance Use Disorders":

"CBD is immune suppressive in both in vitro and in vivo models (Nichols and Kaplan 2019). In contrast, when whole cannabis was explored in individuals with cannabis use disorder, IL-1β, IL-6, IL-8 and TNF⍺ were increased in cannabis users compared to controls."
https://link.springer.com/article/10.1007%2Fs11481-021-10022-7 [784]

Kaplan's review of 2021 concluded:

"The risks of respiratory symptoms and of COPD seemed to be related to a synergistic interaction between marijuana and tobacco, but did not occur in cannabis-only smokers."
https://link.springer.com/content/pdf/10.1007/s41030-021-00171-8.pdf[4640]

By 2016 Omar Abdel-Salam at the Department of Toxicology and Narcotics in the Medical Division of the National Research Centre, in Cairo, Egypt, was convinced that "The effects of Cannabis are, however, the sum of its constituents."

This is an article which begins with the sentence:

"Cannabis is the most commonly abused illicit substance worldwide."

But he could have said, "Cannabis is the most commonly prohibited substance used worldwide."

It's clear from the context of the following paragraph that what Abdel-Salam means to say is:

"The effects of Cannabis are, however, [more than] the sum of its constituents. There are more than 70 different cannabinoids and these may have effects that are synergistic with or antagonistic to Δ9-THC effects. Other important constituents are terpenoids and the flavonoids flavocannabiside. One terpenoid that is beta-caryophyllene has been shown to inhibit the development of gastric lesions evoked by ethanol or 0.6 N HCl when given orally to rats."
https://www.sciencedirect.com/science/article/pii/S1995764516300712 [788]

A year later mrstinkysgreengarden.com discussing the benefits of linalool:

"Modern research has confirmed the practices of ancient civilizations, revealing strong medical efficacy for many severe conditions.

"Linalool has been shown to be a major anti-inflammatory, meaning it helps those with cancer and arthritis. Research has also proven the value of this terpene for treating anxiety and insomnia due to its sedative properties.

"Linalool is actually one of the minor terpenes available in certain strains of cannabis. It is found in smaller quantities than major terpenes like myrcene (the most common), pinene, and limonene. It emits a floral, sometimes spicy aroma. Hundreds of species of plants produce linalool, including a variety of mints and herbs."
http://www.mrstinkysgreengarden.com/2017/06/the-terpene-linalool-vs-opioid-addiction.html [975]

"It comes in two main forms: an R isomer (R-linalool, also known as licareol) and an S isomer (S-linalool, or coriandrol).

"Linalool smells floral and musky with a faint hint of spice much like lavender. However it is far more ubiquitous in nature, with R-Linalool found in over 200 different plants such as flowering plants in the Lamiaceae family (lavender, lemon balm, bergamot, rosemary, sage) as well as the present in the Lauraceae and Apiaceae plant families."
https://cannigma.com/plant/terpenes/linalool/ [5447]

One starting point for a consideration of CCx synergistic or antagonistic effects is sleep.

In your mission to construct an artificial optimally balanced mix of CCx so you can patent a drug affecting pathway Y for condition Z, you might start by varying the simplest variables, THC and CBD, then add linalool, or any one or more of these major or minor cannabinoids or terpenes, or not.

As you can see, there will be quite a lot of sleep experiments to do, to invent cannabis.

More sleep might not be the only solution. If you are simply unable to get enough "β-Caryophyllene (BCP) prevented cognitive deficits induced by acute sleep deprivation" according to Cao et al (2026):

"Here we administered β-caryophyllene (BCP), the highly selective CB2R agonist, and observed whether cognitive impairment following acute sleep deprivation (ASD) was prevented. Our results demonstrated that administration of BCP for 3 days before ASD markedly prevented both long-term spatial learning and memory, along with short-term episodic recall in mice exposed to ASD, but the four experimental groups of mice exhibited comparable hippocampal CB2R expression without marked differences. In addition, BCP effectively reversed the disruption of long-term potentiation (LTP) in the hippocampal CA1 area induced by ASD, but failed to reestablish long-term depression (LTD) or paired pulse ratio (PPR). Furthermore, BCP prevented synaptic ultrastructural alterations and promoted the recovery of both dendritic spine density and morphological complexity within the CA1 subfield of the hippocampus. Overall, these results indicate that BCP prevented cognitive impairment after ASD by preventing damage to synaptic function and structural plasticity, preventing alterations of pyramidal cell dendritic complexity and density of dendritic spines within CA1 subregion of hippocampi of mice."
https://www.sciencedirect.com/science/article/abs/pii/S0028390825004605 [5542]

The Court may wish to note that no clergyman or superstition-encouraging politician has a problem with in BCP in broccoli, beer, black currant, citrus fruits, pepper (oil), rosemary, or thyme.

Advances in the relatively recent tools to study sleep mean that, as with the microbiome and the inflammasome, most of the findings postdate the applicable treaties and legislation.

Matthew P Walker is a British author, scientist and professor of neuroscience and psychology at the University of California, Berkeley. He is a public intellectual focused on the subject of sleep. A list of studies to which has contributed can be located at
https://scholar.google.com/citations?user=11L5sOQAAAAJ&hl=en [3090]

Matt Walker has a 19 minute talk about the deleterious effects of poor sleep. (Warning: contains testicles).

"Sleep is your life-support system and Mother Nature's best effort yet at immortality, says sleep scientist Matt Walker. In this deep dive into the science of slumber, Walker shares the wonderfully good things that happen when you get sleep -- and the alarmingly bad things that happen when you don't, for both your brain and body. Learn more about sleep's impact on your learning, memory, immune system and even your genetic code..."

In case you are too tired to watch it all, Walker emphasizes that sleep is not a luxury but a biolgical necessity, and declares

"the shorter your sleep, the shorter your life"

The genetic profile of healthy adults limited to six hours' sleep for one week was compared to their baseline profile when they received a "normal" eight hours.

"First, a sizeable and significant 711 genes were distorted in their activity, caused by a lack of sleep. The second result was that about half of those genes were actually increased in their activity. The other half were decreased.

"Now those genes that were switched off by a lack of sleep were genes associated with your immune system....in contrast, those genes that were actually upregulated or increased by way of a lack of sleep were genes associated with the promotion of tumours, genes associated with long-term chronic inflammation of the body, and genes associated with stress, and, as a consequence, cardiovascular disease. There is simply no aspect of your wellness that can retreat at the sign of sleep deprivation."

and

"And let me just tell you about one area that we've moved this work out into, clinically, which is the context of aging and dementia. Because it's of course no secret that, as we get older, our learning and memory abilities begin to fade and decline. But what we've also discovered is that a physiological signature of aging is that your sleep gets worse, especially that deep quality of sleep that I was just discussing. And only last year, we finally published evidence that these two things, they're not simply co-occurring, they are significantly interrelated. And it suggests that the disruption of deep sleep is an underappreciated factor that is contributing to cognitive decline or memory decline in aging, and most recently we've discovered, in Alzheimer's disease as well."
https://www.ted.com/talks/matt_walker_sleep_is_your_superpower [3086]

In a poll of 229 "mental health experts" the statement "sleep deprivation can reduce mental health" was pronounced true by a ratio of 110:1. We may conclude from the 1.8% don't-knows that in fact only 2 experts disagreed with this idea.

[sleep deprivation number 2 5046]
https://podcasts.apple.com/us/podcast/what-experts-really-think-about-smartphones-and/id1594471023?i=1000711141508 [5046]

NECUD may affect quality of sleep. According to Mller-Levet et al (2013):

"Insufficient sleep and circadian rhythm disruption are associated with negative health outcomes, including obesity, cardiovascular disease, and cognitive impairment, but the mechanisms involved remain largely unexplored. Twenty-six participants were exposed to 1 wk of insufficient sleep (sleep-restriction condition 5.70 h, SEM = 0.03 sleep per 24 h) and 1 wk of sufficient sleep (control condition 8.50 h sleep, SEM = 0.11). Immediately following each condition, 10 whole-blood RNA samples were collected from each participant, while controlling for the effects of light, activity, and food, during a period of total sleep deprivation. Transcriptome analysis revealed that 711 genes were up- or down-regulated by insufficient sleep. Insufficient sleep also reduced the number of genes with a circadian expression profile from 1,855 to 1,481, reduced the circadian amplitude of these genes, and led to an increase in the number of genes that responded to subsequent total sleep deprivation from 122 to 856. Genes affected by insufficient sleep were associated with circadian rhythms (PER1, PER2, PER3, CRY2, CLOCK, NR1D1, NR1D2, RORA, DEC1, CSNK1E), sleep homeostasis (IL6, STAT3, KCNV2, CAMK2D), oxidative stress (PRDX2, PRDX5), and metabolism (SLC2A3, SLC2A5, GHRL, ABCA1). Biological processes affected included chromatin modification, gene-expression regulation, macromolecular metabolism, and inflammatory, immune and stress responses. Thus, insufficient sleep affects the human blood transcriptome, disrupts its circadian regulation, and intensifies the effects of acute total sleep deprivation. The identified biological processes may be involved with the negative effects of sleep loss on health, and highlight the interrelatedness of sleep homeostasis,
circadian rhythmicity, and metabolism."


https://www.pnas.org/doi/pdf/10.1073/pnas.1217154110 [3651]

Erin C Hanlon (2021) examined diurnal patterns of AEA and 2-AG and the possible effect of sleep deprivation. However:

"The 24-hr rhythm of AEA is markedly different from that of 2-AG, being of lesser amplitude and biphasic, rather than monophasic. These observations suggest distinct regulatory pathways of the two eCB and indicate that time of day needs to be carefully controlled in studies attempting to delineate their relative roles. Moreover, unlike 2-AG, AEA is not altered by sleep restriction, suggesting that physiological perturbations may affect AEA and 2-AG differently. Similar 24-hr profiles were observed for OEA and PEA following normal and restricted sleep, further corroborating the validity of the wave-shape and lack of response to sleep loss observed for the AEA profile. Therapeutic approaches involving agonism or antagonism of peripheral eCB signaling will likely need to be tailored according to time of day."
https://pmc.ncbi.nlm.nih.gov/articles/PMC7001881/ [6013]

Forbes (6 April 2025) reports:

"Medical cannabis is a significantly more effective sleep aid than prescription and over-the-counter sleep remedies, according to a survey of medical cannabis patients....The survey of more than 1,000 people who have been using medical cannabis to help them sleep found that nearly 70% of patients reported that cannabis is a better sleep aid than prescription sleeping pills. More than nine out of 10 (91.2%) said medical cannabis was more effective than OTC sleep remedies.

"The survey was conducted by Bloomwell Group GmbH, a Frankfurt, Germany-based medical cannabis company. The survey included 1,086 people who have been using cannabis to treat sleep disorders since 2023. The survey is the largest in Europe to date to study the effectiveness of medical cannabis as a sleep aid, Bloomwell reports."
https://www.forbes.com/sites/ajherrington/2025/04/06/medical-cannabis-is-a-better-sleep-aid-than-otc-and-rx-pills-new-survey/ [4915]

"Effectiveness of a Cannabinoids Supplement on Sleep and Mood in Adults With Subthreshold Insomnia: A Randomized Double-Blind Placebo-Controlled Crossover Pilot Trial" from Hausenblas et al (2025) at Jacksonville University, Florida reported results in 20 insomnia patients:

"When compared to PC [Placebo Condition], the CS [Cannabinoids Supplement] Condition had significantly improved sleep quality/efficiency, insomnia symptoms, and health-related quality of life, p < 0.05."
https://onlinelibrary.wiley.com/doi/10.1002/hsr2.70481 [5209]

NECUD can accelerate aging by inducing sleep deprivation. Even one night's sleeplessness increases amyloid accumulation. [see 3557 on cannabis and amyloid clearance]. The study "β-Amyloid accumulation in the human brain after one night of sleep deprivation" is from Shokri-Kojori et al (2018) at the NIH Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism:

"The effects of acute sleep deprivation on β-amyloid (Aβ) clearance in the human brain have not been documented. Here we used PET and 18F-florbetaben to measure brain Aβ burden (ABB) in 20 healthy controls tested after a night of rested sleep (baseline) and after a night of sleep deprivation. We show that one night of sleep deprivation, relative to baseline, resulted in a significant increase in Aβ burden in the right hippocampus and thalamus. These increases were associated with mood worsening following sleep deprivation, but were not related to the genetic risk (APOE genotype) for Alzheimers disease. Additionally, baseline ABB in a range of subcortical regions and the precuneus was inversely associated with reported night sleep hours. APOE genotyping was also linked to subcortical ABB, suggesting that different Alzheimers disease risk factors might independently affect ABB in nearby brain regions. In summary, our findings show adverse effects of one-night sleep deprivation on brain ABB and expand on prior findings of higher Aβ accumulation with chronic less sleep."
https://www.pnas.org/doi/10.1073/pnas.1721694115 [4802]

NECUD-induced poor sleep quality could make your balls smaller. Here's Figure 2 from one testicle study by Zhang et al (2018):




"Sleep duration and architecture were measured by actigraphy and polysomnography, testicular volume by Prader orchidometer, total testosterone by liquid chromatography tandem mass spectrometry, free testosterone by equilibrium dialysis, and luteinizing hormone and follicle-stimulating hormone (FSH) by immunochemiluminometric assay."

They note:

"An earlier study showed inverse-U shaped relationships between sleep duration and semen parameters and concluded that semen volume and total sperm count fell with sleep durations less than or equal to 6.5 hours or more than 9 hours."

While...

"Testicular volumes measured by Prader orchidometer remain the foundation of the standard andrological examination, and such measurements have long been accepted as important clinical markers of male fertility that correlate positively with sperm count."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175801/ [3089]

Does Slovenia want or need a law to prevent the dimensional adequacy of its testicles?

Along the way we should not exclude the possibility of cannabis effects on semen quality. Avoiding the expectancy of preconceptions by the use of direct measurements, Joseph et al (2025) found a similarly non-linear association:

"Overall, 22.6% of participants reported current cannabis use and 3.3% reported daily use. Nearly 6% of participants had low semen volume (≤1.5 mL), 13% low sperm concentration (≤15 million/L), 8% low TSC (≤39 million), 25% low sperm motility (≤40%), and 11% low TMSC (≤16 million). Adjusted %Ds (95% CIs) comparing current cannabis use versus non-use were −3.2 (−9.1, 2.7) for semen volume, 3.5 (−10.3, 19.5) for sperm concentration, −0.6 (−14.3, 15.3) for TSC, 2.5 (−2.9, 8.0) for motility, and 3.0 (−13.4, 22.4) for TMSC. Cannabis use ≥1 times/week (vs. non-use) was associated with low semen volume (RR = 2.16, 95% CI = 0.935.04). Associations were imprecise and showed no monotonic association between frequency of cannabis use and the semen parameters evaluated.

"Conclusion
In this North American preconception cohort study, current cannabis use was not appreciably associated with semen quality."
https://onlinelibrary.wiley.com/doi/10.1111/andr.70056 [5533]

In 2021 scientists stumbled upon an amazing discovery for sufferers of chronic insomnia.

Happily the restorative effect on testicles via REM sleep latency is not confined to cannabis, as reported by Dudysov et al in Czechia in "The Effects of Daytime Psilocybin Administration on Sleep: Implications for Antidepressant Action" (2020):

"Serotonergic agonist psilocybin is a psychedelic with antidepressant potential. Sleep may interact with psilocybins antidepressant properties like other antidepressant drugs via induction of neuroplasticity. The main aim of the study was to evaluate the effect of psilocybin on sleep architecture on the night after psilocybin administration. Regarding the potential antidepressant properties, we hypothesized that psilocybin, similar to other classical antidepressants, would reduce rapid eye movement (REM) sleep and prolong REM sleep latency. Moreover, we also hypothesized that psilocybin would promote slow-wave activity (SWA) expression in the first sleep cycle, a marker of sleep-related neuroplasticity. Twenty healthy volunteers (10 women, age 2853) underwent two drug administration sessions, psilocybin or placebo, in a randomized, double-blinded design. Changes in sleep macrostructure, SWA during the first sleep cycle, whole night EEG spectral power across frequencies in non-rapid eye movement (NREM) and REM sleep, and changes in subjective sleep measures were analyzed. The results revealed prolonged REM sleep latency after psilocybin administration and a trend toward a decrease in overall REM sleep duration. No changes in NREM sleep were observed. Psilocybin did not affect EEG power spectra in NREM or REM sleep when examined across the whole night. However, psilocybin suppressed SWA in the first sleep cycle. No evidence was found for sleep-related neuroplasticity, however, a different dosage, timing, effect on homeostatic regulation of sleep, or other mechanisms related to antidepressant effects may play a role. Overall, this study suggests that potential antidepressant properties of psilocybin might be related to changes in sleep."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744693/ [3088]

While the Defendant completely understand Slovenians' desire to limit the size of each others' testicles, on a careful viewing of the antediluvian condition of the legislative instruments compared to these researches with implications for testicle health, I'd like to see the ZPPPD's classification of cannabis and psychedelics justified in the context of everything we do know about these substances and sleep, and by extension the measurement in question.

Zhai et al (2025) examined "The Intersection of Psychedelics and Sleep: Exploring the Impacts on Sleep Architecture, Dream States, and Therapeutic Implications", saying:

"Psychedelics hold promise as therapeutic agents for sleep disorders such as insomnia, PTSD, and nightmares, which are often linked to underlying psychological conditions like anxiety, depression, and trauma. These substances, particularly psilocybin, LSD, and DMT, may offer novel treatment options by modulating sleep architecture, emotional processing, and neurotransmitter activity."
https://pubs.acs.org/doi/10.1021/acsptsci.5c00234 [5089]

In "Treating insomnia symptoms with medicinal cannabis: a randomized, crossover trial of the efficacy of a cannabinoid medicine compared with placebo" (2021) Walsh et al

"...employed a double-blind, randomized, placebo-controlled, crossover design to evaluate the safety and efficacy of a cannabinoid formulation which included THC, CBD, and CBN (ZTL-101), for treating insomnia symptoms in patients with chronic insomnia disorder."

and

"Of the 23 participants who completed the protocol, 12 (52%) were taking a double dose of ZTL-101 on the 14th night. Sixteen (69.5%) were taking a double dose of placebo on the 14th night. Twenty-one of 21 participants (100%) (n = 2 missing data) guessed that they were receiving the active medication when taking ZTL-101. 'Improvement in sleep quality' was the reason for their guess in 17 (81%) with adverse reactions the reason in the remaining four participants. When taking the placebo, 18 of 23 participants (78%) thought they were receiving placebo. Sixteen noted 'lack of improvement in sleep quality' as the reason for their guess that they were receiving placebo."

...leading Walsh et al to conclude:

"Two weeks of nightly sublingual administration of a cannabinoid extract (ZTL-101) is well tolerated and improves insomnia symptoms and sleep quality in individuals with chronic insomnia symptoms."
https://academic.oup.com/sleep/article/44/11/zsab149/6296857#311780504

[3087]

We have a graphic from the Sleep Foundation about brain waves:



"Alpha brain waves are the main brain wave pattern that develops when a person becomes drowsy and transitions from wakefulness to sleep. They continue during the early phase of sleep until they are replaced by slower theta waves.

"Alpha waves are also present when a person is awake and relaxing, such as with the eyes closed or during meditation Alpha wave production is associated with states of creativity, but they tend to disappear when a person performs mental activity requiring greater attention."

and

"Alpha-delta sleep is an abnormal brain wave pattern associated with certain health conditions. In alpha-delta sleep, the brain produces alpha waves during deep sleep, when it would normally be producing slow delta waves. The intrusion of alpha waves can make sleep unrefreshing and leave people feeling sleepy during the day.

"Alpha-delta sleep is found in many people with fibromyalgia, a chronic pain condition. It can also affect people with arthritis, depression, sleep disorders, and lupus. Some evidence suggests that alpha-delta sleep can cause pain or make pain worse for people with fibromyalgia. But more research is needed to determine whether alpha-delta sleep causes pain, or if it is caused by pain instead."
https://www.sleepfoundation.org/how-sleep-works/alpha-waves-and-sleep [3091]

Data of interest to those willing to risk illegal sleeping continued in 2022's "Acute effects of combined cannabidiol (CBD) and ∆9-tetrahydrocannabinol (THC) in insomnia disorder: A randomised, placebo-controlled trial using high-density EEG" by Suarez et al:

"Compared to placebo, CBD/THC significantly decreased TST [total sleep time] (-24.5 min, p=0.047) with no significant change to WASO [wake after sleep onset] (+10.7 min, p=0.422). CBD/THC significantly decreased time spent in REM (rapid eye movement] sleep (-33.9min, p<0.001) and increased REM sleep latency (+65.6 min, p=0.008). Preliminary high-density EEG analysis revealed increased alpha activity during REM sleep overlying the parietal cortex (p<0.05). CBD/THC did not impair next-day (+12 h post-treatment) cognitive performance, alertness or simulated driving performance (all ps>0.05). Eighty-five mild, non-serious, adverse events were reported (55 during CBD/THC; most common dry mouth, drowsiness, and fatigue).

"Conclusions
An acute dose of 200 mg CBD and 10 mg THC reduced TST and the time spent in REM sleep. Analysis of all high-density EEG outcomes is ongoing. CBD/THC did not affect next-day performance. Further research is required to determine the impact of chronic cannabinoid dosing on REM sleep and other objective sleep outcomes in insomnia disorder."
https://academic.oup.com/sleepadvances/article/3/Supplement_1/A3/6811668?login=false [1875]

The trials continued. In 2024 Surayev et al looked at possible "next day" impairment in insomnia patients using an oral THC/CBD cannabis product:

"Here, we examined possible next day impairment following evening administration of a typical medicinal cannabis oil in adults with insomnia disorder, compared to matched placebo. This paper describes the secondary outcomes of a larger study investigating the efects of THC/CBD on insomnia disorder. Twenty adults [16 female; mean (SD) age, 46.1 (8.6) y] with physician-diagnosed insomnia who infrequently use cannabis completed two 24 h in-laboratory visits involving acute oral administration of combined 10 mg THC and 200 mg CBD (THC/CBD) or placebo in a randomised, double-blind, crossover trial design. Outcome measures included next day (≥9 h post-treatment) performance on cognitive and psychomotor function tasks, simulated driving performance, subjective drug efects, and mood. We found no diferences in next day performance on 27 out of 28 tests of cognitive and psychomotor function and simulated driving performance relative to placebo. THC/CBD produced a small decrease (-1.4%, p=.016, d=-0.6) in accuracy on the Stroop-Colour Task (easy/congruent) but not the Stroop-Word Task (hard/incongruent). THC/ CBD also produced a small increase (+8.6, p=.042, d=0.3) in self-ratings of Sedated at 10 h post-treatment, but with no accompanying changes in subjective ratings of Alert or Sleepy (ps>0.05). In conclusion, we found a lack of notable next day impairment to cognitive and psychomotor function and simulated driving performance following evening use of 10 mg oral THC, in combination with 200 mg CBD, in an insomnia population who infrequently use cannabis."
https://link.springer.com/content/pdf/10.1007/s00213-024-06595-9.pdf [3124]

On the other hand, Suraev et al found in "Acute effects of combined cannabidiol (CBD) and ∆9-tetrahydrocannabinol (THC) in insomnia disorder: A randomised, placebo-controlled trial using high-density EEG" (2022) that a high THC:CBD ratio product actually shortened total sleep time (TST).

"Compared to placebo, CBD/THC significantly decreased TST (-24.5 min, p=0.047) with no significant change to WASO [wake after sleep onset] (+10.7 min, p=0.422). CBD/THC significantly decreased time spent in REM sleep (-33.9min, p<0.001) and increased REM [rapid ey movement] sleep latency (+65.6 min, p=0.008). Preliminary high-density EEG analysis revealed increased alpha activity during REM sleep overlying the parietal cortex (p<0.05). CBD/THC did not impair next-day (+12 h post-treatment) cognitive performance, alertness or simulated driving performance (all ps>0.05). Eighty-five mild, non-serious, adverse events were reported (55 during CBD/THC; most common dry mouth, drowsiness, and fatigue)." [1875]

In 2024 prohibition was no longer able to prevent Arnold et al publishing "A sleepy cannabis constituent: cannabinol and its active metabolite influence sleep architecture in rats" in Nature:

"Medicinal cannabis is being used worldwide and there is increasing use of novel cannabis products in the community. Cannabis contains the major cannabinoids, Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), but also an array of minor cannabinoids that have undergone much less pharmacological characterization. Cannabinol (CBN) is a minor cannabinoid used in the community in isolate products and is claimed to have pro-sleep effects comparable to conventional sleep medications. However, no study has yet examined whether it impacts sleep architecture using objective sleep measures. The effects of CBN on sleep in rats using polysomnography were therefore examined. CBN increased total sleep time, although there was evidence of biphasic effects with initial sleep suppression before a dramatic increase in sleep. CBN increased both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. The magnitude of the effect of CBN on NREM was comparable to the sleep aid zolpidem, although, unlike CBN, zolpidem did not influence REM sleep. Following CBN dosing, 11-hydroxy-CBN, a primary metabolite of CBN surprisingly attained equivalently high brain concentrations to CBN. 11-hydroxy-CBN was active at cannabinoid CB1 receptors with comparable potency and efficacy to Δ9-THC, however, CBN had much lower activity. We then discovered that the metabolite 11-hydroxy-CBN also influenced sleep architecture, albeit with some subtle differences from CBN itself. This study shows CBN affects sleep using objective sleep measures and suggests an active metabolite may contribute to its hypnotic action."
https://www.nature.com/articles/s41386-024-02018-7 [3844]

Wu et al (2025) found that "Cannabidiol regulates circadian rhythm to improve sleep disorders following general anesthesia in rats":

"An electrode was embedded in the skull for cortical EEG recording in 24 male SD rats, which were randomized into control, propofol, CBD treatment, and diazepam treatment groups (n=6). Eight days later, a single dose of propofol (10 mg/kg) was injected via the tail vein with anesthesia maintenance for 3 h in the latter 3 groups, and daily treatment with saline, CBD or diazepam was administered via gavage; the control rats received only saline injection. A wireless system was used for collecting EEG, EMG, and body temperature data within 72 h after propofol injection. After data collection, blood samples and hypothalamic tissue samples were collected for determining serum levels of oxidative stress markers and hypothalamic expressions of the key clock proteins.

"Results: Compared with the control rats, the rats with CBD treatment showed significantly increased sleep time at night (20:00-6:00), especially during the time period of 4:00-6:00 am. Compared with the rats in propofol group, which had prolonged SWS time and increased sleep episodes during 18:00-24:00 and sleep-wake transitions, the CBD-treated rats exhibited a significant reduction of SWS time and fewer SWS-to-active-awake transitions with increased SWS aspects and sleep-wake transitions at night (24:00-08:00). Diazepam treatment produced similar effect to CBD but with a weaker effect on sleep-wake transitions. Propofol caused significant changes in protein expressions and redox state, which were effectively reversed by CBD treatment."
https://pubmed.ncbi.nlm.nih.gov/40294924/ [5181]

According to "Pilot Study on the Effect of Cannabidiol-Coated Fabric for Pillow Covers Improves the Sleep Quality of Shift Nurses" by Afzal et al (2025):

"Of the 55 participants, 10 were men (18.2%) and 45 were women (81.8%). At baseline, all participants exhibited poor sleep quality (PSQI ≥ 5). However, after three weeks of using CBD-coated pillow covers, subjective sleep quality significantly improved, with 7.3% of participants achieving PSQI scores <5. Additionally, slight changes in sleep patterns were observed, with increases in both light sleep and deep sleep durations. Light sleep duration increased from a baseline of 196.21 65.28 to 206.57 59.15 min two weeks after intervention (p = 0.337). Similarly, deep sleep duration showed a modest increase from 61.97 21.01 min to 64.35 22.19 min (p = 0.288). Furthermore, a significant reduction in anxiety levels was reported (p < 0.005)."
https://www.mdpi.com/2227-9032/13/6/585 [5205]

Twelve years after the ZPPPD came into force, the importance of the glymphatic system, a CNS garbage disposal system, was discovered. Here's a beginners' guide.
https://pmc.ncbi.nlm.nih.gov/articles/PMC4636982/ [3653]

Was General Smuts right to interfere with the human race's sleep? Overall, authors find equivocal help with sleep from CBD but more positive results with THC [5522]. Assistance to the recently discovered glymphatic system has downstream benefits in dementia and cardiovascular health via improved sleep - Hong et al (2025) find support for this in "MRI markers of cerebrospinal fluid dynamics predict dementia and mediate the impact of cardiovascular risk":

"Using the UK Biobank, we measured CSF dynamics: perivascular space (PVS) volume, diffusion tensor image analysis along the PVS (DTI-ALPS), blood oxygen leveldependent CSF (BOLD-CSF) coupling, and choroid plexus (CP) volume. We assessed cardiovascular risk factors and their associations with CSF dynamics and dementia based on general practitioner, mortality, and hospital records. Mediation analysis evaluated CSF dysfunction in cardiovascular riskdementia relationships.

"RESULTS
Lower DTI-ALPS, lower BOLD-CSF coupling, and higher CP volume predicted dementia, but PVS volume did not. DTI-ALPS and CP volume mediated the effect of white matter hyperintensities and diabetes duration on dementia.

"DISCUSSION
Impaired CSF dynamics may lead to dementia and partially mediate cardiovascular riskdementia associations."
https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.70699 [5528]

In 2025 hemifusomes, a new organelle, arrived:

"Hemifusomes are fused vesicles, or sacs of fluid, that were previously unknown to exist inside cells.

"They were discovered using cryo-electron tomography, which literally freezes them in time, and confirmed to be actual organelles and not just background noise.

"Because hemifusomes collect and recycle junk proteins, they could mean more effective treatments for diseases caused and aggravated by protein plaque buildup, such as Alzheimers."
https://www.popularmechanics.com/science/health/a65284366/new-cell-organelle/ [5148]

According to the NIH authors of the discovery:

"The pleiomorphic structure and dynamic behavior of cellular endomembrane systems have been extensively studied using classical electron microscopy. However, fixation and staining constraints limit the in situ visualization of transient interactions, such as membrane fusion, scission, and intraluminal vesicle formation, potentially overlooking intermediate structures like membrane hemifusion. Using in situ cryo-electron tomography in four mammalian cell lines, we identify heterotypic hemifused vesicles featuring an extended hemifusion diaphragm consistently associated with a 42-nanometer proteolipid nanodroplet (PND). We designate these vesicular organelle complexes as 'hemifusomes.' Hemifusomes constitute up to 10% of vesicular organelles at the cell periphery but do not engage in canonical endocytic pathways. These structures exhibit diverse conformations and frequently contain intraluminal vesicles. Building on the continuum of related morphologies observed, we propose that hemifusomes serve as platforms for vesicular biogenesis, mediated by the PND. These findings provide direct in situ evidence of long-lived hemifused vesicle complexes and introduce an ESCRT-independent model for multivesicular body (MVB) formation."

Asked about these and their apparent common aim with the glymphatic system, Grok offered its opinion as follows:

"At first glance, hemifusomes and the glymphatic system operate at different scales and contexts: hemifusomes are intracellular organelles found across various cell types, while the glymphatic system is a macroscopic network specific to the brains waste clearance. However, there are intriguing points where they might intersect or complement each other:

"Shared Goal of Waste Management:Hemifusomes are hypothesized to recycle or dispose of cellular membranes and junk proteins within individual cells. The glymphatic system, on the other hand, clears interstitial waste (including proteins like amyloid-beta) from the brains extracellular space. If hemifusomes are involved in breaking down intracellular protein aggregates, they could feed into the glymphatic system by preparing waste for extracellular clearance. For instance, proteins processed by hemifusomes might be exocytosed into the interstitial space, where the glymphatic system could then transport them out via CSF.

"Cellular vs. Systemic Scale:
The glymphatic system relies on the coordinated action of glial cells, blood vessels, and CSF flow, but the efficiency of this system depends on the health of individual cells, including their ability to manage internal waste. If hemifusomes enhance intracellular protein recycling, they could reduce the burden on the glymphatic system by preventing excessive waste accumulation that would otherwise need to be cleared externally. This aligns with Ebrahims hypothesis that hemifusomes prevent the 'buildup of stuff' that could 'gum up' cellular operations, as noted in the Live Science article.

"Neurodegenerative Disease Link:
Both systems are relevant to neurodegenerative diseases. The glymphatic systems role in clearing amyloid-beta during sleep is well-documented, while hemifusomes potential to manage protein plaques could address the intracellular origins of such aggregates. A study from PMC on protein recycling pathways in neurodegenerative diseases highlights how impaired intracellular mechanisms lead to aggregate formation, suggesting that hemifusomes might act as an upstream regulator, feeding into the glymphatic systems downstream clearance process.

"Independence from Endosomes:
Ebrahims research indicates hemifusomes do not work with endosomes, which are involved in endocytosis and vesicle trafficking. This independence suggests hemifusomes might represent a novel pathway for waste handling, potentially interfacing with the glymphatic system in brain cells where both processes could coexist. For example, hemifusomes might process waste internally, while the glymphatic system handles the extracellular efflux, creating a two-tiered waste management strategy."

And Grok's suggestions for future research as of 8 July 2025:

"To confirm any relationship, researchers could:Use cryo-ET to image hemifusomes in brain tissue, particularly in glial cells where AQP4 channels are active.

"Track fluorescently labeled proteins processed by hemifusomes to see if they enter the glymphatic pathway.

"Conduct longitudinal studies in mouse models, combining glymphatic tracers with hemifusome-specific markers, to observe waste flow from intracellular to systemic levels."
https://x.com/i/grok/share/g4OriPUD4oT3VIy2CfnWT2psv [5147]

While it is too soon to speculate on interactions between the ECS and vesiculogenesis via hemifusomes, endocannabinoids have been shown to have an influence on the canonical ESCRT endocytic pathways, as DeMarino et al reported in 2022:

"Our data suggest that CBD significantly reduces the number of EVs released from infected cells and that this may be mediated by reducing viral transcription and autophagy activation. Therefore, CBD may exert a protective effect by alleviating the pathogenic effects of EVs in HIV-1 and CNS-related infections."
https://pmc.ncbi.nlm.nih.gov/articles/PMC8869966/ [5149]

And of the "Interplay between the Glymphatic System and the Endocannabinoid System: Implications for Brain Health and Disease" (2023) Osuna-Ramos et al say:

"The GS is subject to dynamic regulation by various factors. Sleep plays a crucial role in modulating glymphatic function, with increased glymphatic activity occurring during non-rapid eye movement stage 3 (NREM 3). Arousal level, blood-brain barrier (BBB) permeability, and neurotransmitters such as norepinephrine, adenosine, and gamma-aminobutyric acid (GABA) influence glymphatic clearance efficiency. The GS is also influenced by vascular pulsatility, glial cell activity, and the glymphatic-lymphatic interaction."

and

"Scientific evidence has effectively showcased the potential of cannabinoids, both endogenous and exogenous in origin (derived from cannabis or synthesized), in mitigating symptomatic manifestations associated with diverse neurodegenerative ailments encompassing MS, HD, PD, AD, and ALS. This influence may stem from their effects on the GS, facilitating the clearance of neurotoxic substances and protein aggregates, regulating neuroinflammatory responses, and upholding cerebral equilibrium (Figure 2). Increased expression of cannabinoid receptors, particularly CB2R, has been noted in human brain tissues afflicted by ALS, MS, and AD. The interplay between the BBB and potential shifts in the expression of cannabinoid receptors within cerebral endothelium has been the subject of investigation.

"These insights collectively suggest that a compromised or dysregulated ECS could potentially contribute to the symptomatology observed in these conditions through direct modulation of the GS and the BBB."

See the aforementioned Figure 2 for a schematic representation of the BBB under varying conditions.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10743431/ [3654]

Lundgaard et al (2018) propose "Beneficial effects of low alcohol exposure, but adverse effects of high alcohol intake on glymphatic function":

"Prolonged intake of excessive amounts of ethanol is known to have adverse effects on the central nervous system (CNS). Here we investigated the effects of acute and chronic ethanol exposure and withdrawal from chronic ethanol exposure on glymphatic function, which is a brain-wide metabolite clearance system connected to the peripheral lymphatic system. Acute and chronic exposure to 1.5 g/kg (binge level) ethanol dramatically suppressed glymphatic function in awake mice. Chronic exposure to 1.5 g/kg ethanol increased GFAP expression and induced mislocation of the astrocyte-specific water channel aquaporin 4 (AQP4), but decreased the levels of several cytokines. Surprisingly, glymphatic function increased in mice treated with 0.5 g/kg (low dose) ethanol following acute exposure, as well as after one month of chronic exposure. Low doses of chronic ethanol intake were associated with a significant decrease in GFAP expression, with little change in the cytokine profile compared with the saline group. These observations suggest that ethanol has a J-shaped effect on the glymphatic system whereby low doses of ethanol increase glymphatic function. Conversely, chronic 1.5 g/kg ethanol intake induced reactive gliosis and perturbed glymphatic function, which possibly may contribute to the higher risk of dementia observed in heavy drinkers."
https://www.nature.com/articles/s41598-018-20424-y [3655]

An explanation of aquaporin:
https://x.com/NikoMcCarty/status/1969407466141335631 [5445]

GFAP appeared in 1969, becoming a standard marker for fundamental and applied CNS and research into neurodegenerative diseases, TBI, genetic disorders, and chemical insults (such as going outside in Ptuj or drinking in Ptuj) in 1989.
https://www.uniprot.org/uniprotkb/P14136/publications [3656]
https://pubmed.ncbi.nlm.nih.gov/11059815/ [3658]

The glymphatic system was characterized and named by Maiken Nedergaard in 2012.
https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC3551275&blobtype=pdf [3657]

Alcohol also affects REM and slow wave sleep:

"Alcohol before sleep increased the rate of slow-wave-sleep (SWS) accumulation across all three nights and decreased the rate of REM sleep accumulation at the start of each night. Alcohol also decreased the total amount of REM sleep but did not affect the total amount of SWS each night.

"Conclusions
These data indicate that drinking alcohol before sleep substantially affects sleep architecture, including changes to the rate of accumulation of SWS and REM sleep. We show that alcohol disrupts normal sleep architecture, leading to a significant decrease in REM sleep; thus, the use of alcohol as a sleep aid remains a public health concern."
https://academic.oup.com/sleep/advance-article-abstract/doi/10.1093/sleep/zsae003/7515846?redirectedFrom=fulltext&login=false [4390]

To complete the circle, Davis et al (2025) found "Daily associations between sleep quality, stress, and cannabis or alcohol use among veterans":

"Poor sleep quality predicts increased stress and higher next-day alcohol use in veterans.

"Cannabis use is linked to reduced stress and better same-night sleep quality.

"Stress mediates the relationship between poor sleep quality and alcohol consumption.

"Dynamic structural equation modeling reveals bidirectional sleep-stress interactions.

"Results emphasize the need for tailored sleep and substance use interventions for veterans."
https://www.sciencedirect.com/science/article/abs/pii/S0376871625001140 [5186]

A not unreasonable belief is that you might get away with less sleep if sleep is of higher quality.

In 2000 Cantero observed:

"...transient REM-alpha bursts, which lasted about 3 s and were accompanied by no increase in the EMG amplitude, appeared in all subjects who participated in this study, showing a higher density in the third and fourth REM cycle during phasic in comparison with tonic periods. The bandpass filtered signals showed the highest spectral contribution for the slower alpha components (8-9 Hz), the occipital scalp regions being the main generator source of this brain activity."

This led "Alpha burst activity during human REM sleep: descriptive study and functional hypotheses" (2000) to conclude

"...that REM-alpha bursts may work as micro-arousals (or incomplete arousals) facilitating the brain connection with the external world in this cerebral state, whereas REM-alpha arousals - usually longer and accompanied by changes in the EMG amplitude - generate a shift of brain state associated with sleep fragmentation (complete arousal)."

"REM-alpha bursts described in this work should not be mistaken for arousals or, at least, for complete arousals."
https://www.sciencedirect.com/science/article/abs/pii/S1388245799003181?via%3Dihub [3092]

And back in 1984, when government decisions about the quantity and quality of your sleep were not perceived as an issue, Tyson et al found:

"Alpha activity during REM sleep without signs of awakening can discriminate between the blind classification of prelucid, lucid, and nonlucid dreams. 10 good dream recallers (aged 1931 yrs) were aroused after relatively high or low amplitude REM alpha. The spectral and temporal characteristics of EEG alpha within each REM period were associated with lucidity and other content dimensions. Each type of dream had a reasonably distinct pattern of REM alpha. High amplitude alpha was found to be associated with prelucid dreams and bizarre content, which is consistent with theories of waking alpha activity and the hypothesis that lucidity sometimes emerges from prelucid experiences. Data are also consistent with the idea that lucidity is a viable dream content dimension. When interpreted in terms of systems theory, results imply that training that emphasizes dream content control may constrain the potential information integration function of lucid dreams."
https://psycnet.apa.org/record/1985-11505-001 [3092]

One thing that could keep you awake is an addiction of some kind. In 2021 when Oru Yunusoğlu at the Department of Pharmacology, Faculty of Medicine, Bolu Abant Izzet Baysal University, Bolu, Turkey, using the CPP technique, found that linalool has anti-addiction properties:

"Treatment with linalool reduced the acquisition and reinstatement, and precipitated the extinction of ethanol-induced CPP in mice. Acquisition and reinstatement of alcohol-induced CPP were significantly reduced by acamprosate, which also precipitated extinction. Ethanol alone and the combination with linalool or acamprosate did not alter locomotor activity. The results of this study suggest that linalool may have pharmacological effects for the treatment of alcohol addiction."
https://www.sciencedirect.com/science/article/abs/pii/S0741832921001385 [977]

An addiction not everyone goes to the doctor about.

So can linalool be bad in cannabis but good in mint? Was Plato on to something with the kykeon?

We haven't tried to make a pill to replace a cup of tea, have we?

So why do it to replace cannabis?

The greater good, the public good, and the good news for pharmaceutical companies, are not continguous benefits.

So to the extent that cannabis is being used medically, cannabis interdiction therefore represents commercial favouritism as well as inflicting unnecessary suffering.

Thomas Clark, in "Cannabis Use Is Associated with a Substantial Reduction in Premature Deaths in the United States", published by Indiana University South Bend, 11 Aug. 2017, writes:

"Cannabis use prevents thousands of premature deaths each year, and Cannabis prohibition is revealed as a major cause of premature death in the U.S."

"Marijuana use is estimated to reduce premature deaths from diabetes mellitus, cancer, and traumatic brain injury by 989 to 2,511 deaths for each 1% of the population using Cannabis."

"prohibition is estimated to lead to similar numbers of premature deaths as drunk driving, homicide, or fatal opioid overdose."

"23,500 to 47,500 deaths [would be] prevented annually if medical marijuana were legal nationwide".

This, though, is "an underestimate" says the Professor and Chair of the Department of Biology at South Bend Tom Clark - this is because, and this was published August 2017, "a number of other potential causes of reduced mortality due to Cannabis use were revealed, but were excluded from the analysis because quantitative data were lacking."

His estimate of the odds ratio for cancers of the head and neck is 0.83 for cannabis users.

"The relationship between Cannabis and cancer is complex. Cancer is positively correlated with obesity, and obesity decreases in a dose-dependent fashion with Cannabis use, whereas Cannabis smoke contains carcinogens. On the other hand, a casual examination of the literature reveals numerous laboratory studies demonstrating that cannabinoids have potent anti-tumoral properties in vitro and in mouse models. Cancers inhibited by cannabinoids include gliomas, thyroid epithelioma, lymphoma, neuroblastoma, and carcinomas of the oral region, lung, skin, uterus, breast, prostate, pancreas, and colon. Thus, Cannabis may reduce the risk of getting cancer by reducing obesity rates and by direct inhibition of tumor formation or growth."
https://scholarworks.iu.edu/dspace/handle/2022/21632 [501]

Returning in 2021 with a broader look at cancer and cannabis data, Clark published "Scoping Review and Meta-Analysis Suggests that Cannabis Use May Reduce Cancer Risk in the United States":

"A total of 55 data points, consisting of risk ratios of cancer in Cannabis users and nonusers, were identified from 34 studies. Of these, 5 did not contain data essential for inclusion in the meta-analysis. The remaining data showed a nonsignificant trend to an association with reduced risk (relative risk [RR]=0.90, p>0.06, N=50) although heterogeneity is high (I2=72.4%). Removal of data with high risk of selection bias (defined as those from North Africa and those that failed to adjust for tobacco) and data with high risk of performance bias (defined as those with fewer than 20 cases or controls among Cannabis users) resulted in an RR <1.0 (RR=0.86, p<0.017, N=24) and large effect size (Hedges g=0.66), but did not decrease heterogeneity (I2=74.9). Of all cancer sites, only testicular cancer showed an RR value >1, although this was not significant and had a negligible effect size (RR=1.12, p=0.3, Hedges g=0.02). Following removal of testicular cancers the remaining data showed a decrease in risk (RR=0.87, p<0.025, N=41). Cancers of the head and neck showed a negative association with cancer risk (RR=0.83, p<0.05), with a large effect size (Hedges g=0.55), but high heterogeneity (I2=79.2%). RR did not reach statistical significance in the remaining cancer site categories (lung, testicular, obesity-associated, other). The data are consistent with a negative association between Cannabis use and nontesticular cancer, but there is low confidence in this result due to high heterogeneity and a paucity of data for many cancer types."
https://www.liebertpub.com/doi/10.1089/can.2019.0095 [2779]

Clark's findings were further confirmed in a 2025 meta-analysis by Castle et al:

"This meta-analysis was conducted to determine the scientific consensus on medical cannabis's viability in cancer treatment. Objective: The aim of this meta-analysis was to systematically assess the existing literature on medical cannabis, focusing on its therapeutic potential, safety profiles, and role in cancer treatment. Methods: This study synthesized data from over 10,000 peer-reviewed research papers, encompassing 39,767 data points related to cannabis and various health outcomes. Using sentiment analysis, the study identified correlations between cannabis use and supported, not supported, and unclear sentiments across multiple categories, including cancer dynamics, health metrics, and cancer treatments. A sensitivity analysis was conducted to validate the reliability of the findings. Results: The meta-analysis revealed a significant consensus supporting the use of medical cannabis in the categories of health metrics, cancer treatments, and cancer dynamics. The aggregated correlation strength of cannabis across all cancer topics indicates that support for medical cannabis is 31.38X stronger than opposition to it. The analysis highlighted the anti-inflammatory potential of cannabis, its use in managing cancer-related symptoms such as pain, nausea, and appetite loss, and explored the consensus on its use as an anti-carcinogenic agent.
https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1490621/abstract [4853]

According to "Psychedelics for Brain Injury: A Mini-Review" by Khan et al (2021), NECUD has a poor prognosis in TBI patients:

"Presence of THC on urine drug screen is associated with decreased mortality in adult patients sustaining TBI. However, randomized control trials of a non-psychoactive cannabinoid analog, dexanabinol, administered once after TBI has failed to show benefit over placebo in increasing Glasgow Coma Scores at 6 months post-injury. One explanation for this discrepancy may be the lack of 'entourage' effect whereby various cannabinoids and cannabis phytochemicals are clinically more efficacious when working synergistically compared to administration of a single cannabinoid in isolation, though the existence of such an effect with cannabis is contentious with mixed evidence for its existence. Of note, an 'entourage' effect has been demonstrated with psychedelic mushrooms in which whole mushroom extracts are on the order of 10 times more potent than purified psilocin administered alone in neurobehavioral rat models."
https://www.frontiersin.org/articles/10.3389/fneur.2021.685085/full [776]

Meanwhile, "Inside One of the World's Biggest Magic Mushroom Farms", similar issues to those of cannabis strength and nature-identicalness have been carefully considered for the (probably US not Canadian) $22 million investment:

"The companys operation could have been much more straightforward: Many mushroom companies just produce pure psilocybin through chemical processes in the lab. Others simply grow mycelial grain and sell it packaged as mushrooms. But Marshall believes that the botanical route, to organically grow real mushrooms, is more beneficial.

To do so, the company had to invest around $22 million to create this state-of-the-art farm. It includes rooms in which levels of humidity, moisture, and heat can be altered to replicate the climates of places where particular mushrooms thrive, like parts of Oregon and Costa Rica; enabling them to grow such a diverse range, from phallic wands to fluffy mycelial growths. Marshall has also built up a genetics bank of around 100 different strains, as he seeks to cultivate the most powerful mushrooms possible so that patients can consume less."
https://www.vice.com/en/article/3akw7j/inside-one-of-the-worlds-biggest-magic-mushroom-farms [3230]

Shahar et al (2024) compared "Effect of chemically synthesized psilocybin and psychedelic mushroom extract on molecular and metabolic profiles in mouse brain":

"In most clinical studies chemically synthesized forms of these compounds are used. Naturally occurring psychedelic compounds do not exist in isolation but are produced by the organism as part of an extensive milieu that includes molecules of many different types. It is possible that these molecules exert significant biological effects or modulate the action of the active molecule in different ways. In regard to cannabis, it is recognized that not only cannabidiol, but a number of other 'entourage' molecules exert significant biological effects."

Once again, as with cannabinoids, nature did it better:

"We compared the effects of PME to those of PSIL on the head twitch response (HTR), neuroplasticity-related synaptic proteins and frontal cortex metabolomic profiles in male C57Bl/6j mice. HTR measurement showed similar effects of PSIL and PME over 20 min. Brain specimens (frontal cortex, hippocampus, amygdala, striatum) were assayed for the synaptic proteins, GAP43, PSD95, synaptophysin and SV2A, using western blots. These proteins may serve as indicators of synaptic plasticity. Three days after treatment, there was minimal increase in synaptic proteins. After 11 days, PSIL and PME significantly increased GAP43 in the frontal cortex (p = 0.019; p = 0.039 respectively) and hippocampus (p = 0.015; p = 0.027) and synaptophysin in the hippocampus (p = 0.041; p = 0.05) and amygdala (p = 0.035; p = 0.004). PSIL increased SV2A in the amygdala (p = 0.036) and PME did so in the hippocampus (p = 0.014). In the striatum, synaptophysin was increased by PME only (p = 0.023). There were no significant effects of PSIL or PME on PSD95 in any brain area when these were analyzed separately. Nested analysis of variance (ANOVA) showed a significant increase in each of the 4 proteins over all brain areas for PME versus vehicle control, while significant PSIL effects were observed only in the hippocampus and amygdala and were limited to PSD95 and SV2A. Metabolomic analyses of the pre-frontal cortex were performed by untargeted polar metabolomics utilizing capillary electrophoresis Fourier transform mass spectrometry (CE-FTMS) and showed a differential metabolic separation between PME and vehicle groups. The purines guanosine, hypoxanthine and inosine, associated with oxidative stress and energy production pathways, showed a progressive decline from VEH to PSIL to PME. In conclusion, our synaptic protein findings suggest that PME has a more potent and prolonged effect on synaptic plasticity than PSIL. Our metabolomics data support a gradient of effects from inert vehicle via chemical psilocybin to PME further supporting differential effects. Further studies are needed to confirm and extend these findings and to identify the molecules that may be responsible for the enhanced effects of PME as compared to psilocybin alone."

and

"The variability in effects produced mushroom extracts compared to chemical psilocybin may be explained by differing psilocybin content as well as by the presence and varying levels of other potentially bioactive compounds in the different species of mushrooms. These include tryptamines, such as 4- phosphoryloxy-N-methyltryptamine (baeocystin), 4-phosphoryloxy-N,N,N-trimethyltryptamine (aeruginascin), 4-hydroxy-Nmethyltryptamine (norpsilocin) and 4-phosphoryloxytryptamine (norbaeocystin) as well as β-carbolines such as harmine and harmaline, and terpenes. Little is known about the effects of these additional components of psychedelic mushrooms in animal models, although there is accumulating evidence regarding the effect of some of the tryptamines of the psilocybin biosynthetic chain. Glatfelter et al. recently showed that only the tertiary amines, psilocybin, psilocin, and 4- acetoxy-N,N-dimethyltryptamine (psilacetin) induced HTR in mice while secondary amines such as baeocystin and norpsilocin and quaternary ammonium compounds such as aeruginascin had little or no effect. It is possible, however, that these tryptamines present in psychedelic mushroom extracts may modulate the effects of psilocybin. In particular, it has been speculated that baeocystin or norpsilocin could potentially contribute to variable subjective effects. Furthermore, additional components of mushroom extract such as betacarbolines may exert biologically meaningful effects in spite of their low concentrations."
https://www.nature.com/articles/s41380-024-02477-w.pdf [3246]

"When an animal is given a drug, different metabolites accumulate as a result of the drugs interaction with the body. Predictably, the results showed that the extract, which included a number of compounds in addition to psilocybin, created a larger metabolic response. But more surprising, [Hadassah BrainLabs, a center for psychedelics research
affiliated with Hebrew University's Bernard] Lerer says, was the extracts effect on proteins involved in making new connections between brain cells. 'What we found was that there is a greater production of synaptic proteins following administration of mushroom extract containing psilocybin than there is giving psilocybin alone,' Lerer says. The researchers used Western blot analysis to measure synaptic protein production. It would appear that mushroom extract increases synaptic plasticity."

...

"Further differences between mushroom extract and synthetic psilocybin were seen in a second study on mice. Lerer and his colleagues found the mushroom extract produced a stronger effect on reducing behaviors associated with anxiety than did the synthetic psilocybin. But they found mushroom extract and synthetic psilocybin had the same effect on reducing excessive self-grooming, a trait representing OCD. While the study has seen some criticism for its methods and analysis, the findings, if proven, could help demonstrate the potential for targeted strategies using magic mushrooms to treat OCD and anxiety."
https://pubs.acs.org/doi/pdf/10.1021/acscentsci.5c01146?ref=article_openPDF [5362]

That study, Brownstien et al (2024) "Striking long-term beneficial effects of single dose psilocybin and psychedelic mushroom extract in the SAPAP3 rodent model of OCD-like excessive self-grooming" relates how...

"There is increasing interest in the use of psilocybin and other tryptaminergic psychedelics to treat a range of psychedelic disorders including major depression, alcohol and nicotine addiction, and end of life anxiety. In an open study, 9 patients with OCD were administered 29 doses of psilocybin ranging from sub-hallucinogenic to frankly hallucinogenic. Reductions in OCD symptoms were observed in all subjects and these generally lasted for at least 24 h."

The study set out to elucidate any differences between the synthetic psilocybin and a natural mushroom extract containing the same amount of psilocybin, attributable to the entourage ingredients in the extract, given to OCD-prone mice:

https://www.nature.com/articles/s41380-024-02786-0 [5363]

"Even if magic mushrooms secondary compounds are ultimately not found to have any medical benefits, a natural product could still have value. When psilocybin is administered medically, the patients environment and mindset are important in the outcome of the psychedelic trip. 'Having the participant know that this drug youre taking came from a natural source and was actually grown and things like that might, at least for some people, offer some reassurance in the sometimes challenging experience,' [chief science officer at Filament Health Ryan] Moss says."

[5362]

Addressing the problem that "few empirical studies have systematically evaluated" the entourage effect, it became a clinical reality three years later with the publication of "Vaporized D-limonene selectively mitigates the acute anxiogenic effects of Δ9-tetrahydrocannabinol in healthy adults who intermittently use cannabis" (2024) in which Spindle et al report:

"Administration of 15 mg and 30 mg THC alone produced subjective, cognitive, and physiological effects typical of acute cannabis exposure. Ratings of anxiety-like subjective effects qualitatively decreased as d-limonene dose increased and concurrent administration of 30 mg THC+15 mg d-limonene significantly reduced ratings of anxious/nervous and paranoid compared with 30 mg THC alone. Other pharmacodynamic effects were unchanged by d-limonene. D-limonene plasma concentrations were dose orderly, and concurrent administration of d-limonene did not alter THC pharmacokinetics."

Leading to the conclusion that:

"D-limonene selectively attenuated THC-induced anxiogenic effects, suggesting this terpenoid could increase the therapeutic index of THC."
https://www.sciencedirect.com/science/article/abs/pii/S0376871624001881 [4519]



As for connectivity within the associative, limbic, and sensorimotor striata, results have been mixed. A 2022 fMRI study found it reduced less by THC+CBD than by THC alone.

No one has tested to this level for combinations of coffee and cigarettes, nicotine and alcohol, or alcohol and caffeine.

There has been no discussion of legislating against these particular types of alterations in connectivity, or for what reasons that might be desirable, or how this would be measured in vivo on a continuous basis.
https://journals.sagepub.com/doi/10.1177/02698811221092506 [1415]

Research into alcohol's effects on brain biochemistry is full of holes. For instance Urbanik et al in Poland (2020) considered themselves the first to examine changes in brain lipids after administration, using proton magnetic resonance spectroscopy (1HMRS) and diffusion weighted imaging (DWI):

"A peak corresponding to lipids (Lip) is not visible in 1H MR spectrum of a healthy brain. In pathological conditions it reflects either damage to cell membrane or necrosis (Cichocka and Urbanik, 2017). It was established that concentrations of lipids in tissues correlate with the intensity of necrosis (Cichocka and Urbanik, 2017). Lipids are visible in 1H MR spectra during ischemic stroke (Seeger et al., 2003, Gasparovic et al., 2001). In the current study lipid concentrations in the volunteers exposed to alcohol tended to increase during the first hour, and then the levels started to decrease. These changes were statistically significant, and their profile was positively correlated to the changes in EtOH levels. No analyses of changes in Lip levels, in relation to alcohol consumption, were found in the available literature."
https://academic.oup.com/alcalc/article/56/4/415/5974947 [2144]

WebMD lists some physical characteristics of a genius brain.

"Signs of a Genius Brain

"There are some certain physical traits shared by the brains of people who are geniuses or who have extreme intelligence.‌

"Larger regional brain volume. Contrary to popular myth, intellect does not result from brain size. But brain scans have shown that gifted people or geniuses have more grey matter. This is the part of your brain responsible for computing and processing information. It directs your attention, memory, language, perception, and interpretations.‌

"Increased brain region connectivity. Highly gifted or genius individuals typically have more active white matter in their brains. White matter is responsible for the communication between different parts of your brain. Genius brains seem to have a better network of these connections. It results in very quick and complex thinking.

"Increased sensory sensitivity and emotional processing. Genius brains can experience 'superstimulability.' Some genius brains are highly sensitive to other peoples emotions. This can help relate to other people. But at times it can be overwhelming and tiring."
https://www.webmd.com/balance/what-are-signs-of-genius [1588]

Measuring white matter phospholipid damage from alcohol exposure (in 2001):

"Background: Phosphorus magnetic resonance spectroscopy (31P MRS) allows for the measurement of phospholipids and their breakdown products in the human brain. Fairly mobile membrane phospholipids give rise to a broad signal that co-resonates with metabolic phosphodiesters. Chronic alcohol exposure increases the rigidity of isolated brain membranes and, thus, may affect the amount and transverse relaxation times (T2) of MRS-detectable phospholipids. We tested the hypothesis that subjects who were heavy drinkers have stiffer membranes than controls who were light drinkers, as reflected in a smaller broad signal component and a shorter T2 of the broad signal in 31P MR spectra of the brain.

"Methods: Thirteen alcohol-dependent heavy drinkers (mean age 44 years) were studied by localized 31P MRS in the centrum semiovale and compared with 17 nondependent light drinkers of similar age. The broad component signal was separated from the metabolite signal by convolution difference, which is based on the large difference in line widths of these two signals. Longitudinal and T2 relaxation times were measured using standard methods.

"Results: The broad component integral was 13% lower in the brain of heavy drinkers compared with light drinkers (p < 0.001) and remained significantly smaller after corrections for both longitudinal and transverse relaxations (p < 0.01). The T2 distribution of the broad component consistently showed two resolvable components in both groups. The fast relaxing component had the same T2 in both groups (T2 = 1.9 msec). The slower relaxing component T2 was 0.6 msec shorter in heavy drinkers compared with light drinkers (p = 0.08).

"Conclusions: These results, observed in the absence of white matter volume loss, are consistent with biochemical alterations and higher rigidity of white matter phospholipids associated with long-term chronic alcohol abuse. The observed smaller broad signal component in these relatively young heavy drinkers is a sensitive measure of white matter phospholipid damage."
https://pubmed.ncbi.nlm.nih.gov/11198719/ [2141]

Happily. according to Chamoso-Sanchez (2025):

"The comprehensive characterization of cellular lipids unveiled several classes significantly affected by CBD treatment. Most of the differences correspond to phospholipids, including cardiolipins (CL), phosphatidylcholines (PC) and phosphosphingolipids (SM), and also triacylglycerols (TG), being many TG species increased after CBD treatment in the acute and chronic models, whereas phospholipids were found to be decreased. The results highlight some important lipid alterations related to CBD treatment, plausibly connected with different metabolic mechanisms involved in the process of cell death by apoptosis in cancer cell lines."
https://pubmed.ncbi.nlm.nih.gov/39824876/ [2841]

Meanwhile, for those who just want to get high, an unpublished study by Bosnjak et al has compared THC alone with THC plus other CCx.

"...finding that cannabis products with a more diverse array of natural cannabinoids produce an even stronger psychoactive experience that lasts longer than the high generated by pure THC products.



"The study utilized novel electroencephalogram (EEG) technology supported by AI to quantify the high people experienced when vaping two different products: 1) a full-spectrum live rosin with average 85 percent THC as well as other natural cannabinoids and terpenes, and 2) a high purity THC oil with 82-85 percent potency.

The first group exhibited a considerably faster and more potent psychoactive response compared to the latter group.

"A total of 28 adults participated in the study, strapping on the EEG headset developed by the cannabis technology company Zentrela and taking two hits (8 mg) of either the full-spectrum or pure THC varieties from a vape manufactured by PAX, which also supported the study.

"After getting a baseline reading before the participants consumed the products, the EEG monitored activity in eight regions of the brain over the course of 90 minutes. The tests were then converted into psychoactive effect levels (PEL) in a standardized scale from zero percent to 100 percent.

"The results showed that the full-spectrum live rosin with THC and other cannabinoids and terpenes had a slightly earlier onset of three minutes, a higher potency reading for the onset (20.8 percent) and higher potency at the peak after 15 minutes (40 percent) and after 90 minutes (30.2 percent)."
https://zentrela.com/publication/cusic-6/ [4047]

https://www.marijuanamoment.net/marijuana-entourage-effect-with-multiple-cannabinoids-produces-a-stronger-and-longer-lasting-high-than-pure-thc-study-finds/ [4048]

To add to the fun, CCx do not end with cannabinoids and terpenes, says a 2023 paper by Oswald et al:

"Here, we show that across Cannabis sativa L. varieties with divergent aromas, terpene expression remains remarkably similar, indicating their benign contribution to these unique, specific scents. Instead, we found that many minor, nonterpenoid compounds correlate strongly with nonprototypical sweet or savory aromas produced by Cannabis sativa L. Coupling sensory studies to our chemical analysis, we derive correlations between groups of compounds, or in some cases, individual compounds, that produce many of these diverse scents. In particular, we identified a new class of volatile sulfur compounds (VSCs) containing the 3-mercaptohexyl functional group responsible for the distinct citrus aromas in certain varieties and skatole (3-methylindole) as the key source of the chemical aroma in others. Our results provide not only a rich understanding of the chemistry of Cannabis sativa L. but also highlight how the importance of terpenes in the context of the aroma of Cannabis sativa L. has been overemphasized."
https://pubs.acs.org/doi/10.1021/acsomega.3c04496 [4049]

The indica/sativa dichotomy and talk of "strains" of cannabis is an irrelevant distraction, says Ethan B Russo (2019):

"The Cannabis species controversy, Cannabis sativa vs. indica vs. afghanica, has continued unabated to the current day with impassioned arguments advanced by the protagonists (Clarke and Merlin, 2013, 2016; Small, 2015; McPartland and Guy, 2017; Small, 2017). This author, having been on every side of the issue at one time or another, has chosen to eschew the irreconcilable taxonomic debate as an unnecessary distraction (Piomelli and Russo, 2016), and rather emphasize that only biochemical and pharmacological distinctions between Cannabis accessions are relevant. In his recent seminal review, McPartland agreed, “Categorizing Cannabis as either ‘Sativa’ and ‘Indica’ has become an exercise in futility. Ubiquitous interbreeding and hybridization renders their distinction meaningless.” (McPartland, 2018) (p. 210).

"An additional non-sensical nomenclature controversy pertains in common parlance to Cannabis “strains,” an appellation that is appropriate to bacteria and viruses, but not plants (Bailey and Bailey, 1976; Usher, 1996; Brickell et al., 2009), especially so with Cannabis where the chemical variety, abbreviated “chemovar” is the most appropriate appellation (Lewis et al., 2018).Further studies provide strong support for synergy:

"In a randomized controlled trial of oromucosal Cannabis-based extracts in patients with intractable pain despite optimized opioid treatment, a THC-predominant extract failed to demarcate favorably from placebo, whereas a whole plant extract (nabiximols, vide infra) with both THC and cannabidiol (CBD) proved statistically significantly better than both (Johnson et al., 2010), the only salient difference being the presence of CBD in the latter.

"In animal studies of analgesia, pure CBD produces a biphasic dose-response curve such that smaller doses reduce pain responses until a peak is reached, after which further increases in dose are ineffective. Interestingly, the application of a full spectrum Cannabis extract with equivalent doses of CBD eliminates the biphasic response in favor of a linear dose-response curve such that the botanical extract is analgesic at any dose with no observed ceiling effect (Gallily et al., 2014).

"A recent study of several human breast cancer cell lines in culture and implanted tumors demonstrated superiority of a Cannabis extract treatment to pure THC, seemingly attributable in the former to the presence of small concentrations of cannabigerol (CBG) and tetrahydrocannabinolic acid (THCA) (Blasco-Benito et al., 2018).

"Anticonvulsant effects of cannabidiol were noted in animals in the 1970s with the first human trials in 1980 (Cunha et al., 1980). A recent experiment in mice with seizures induced by pentylenetetrazole employed five different Cannabis extracts with equal CBD concentrations (Berman et al., 2018). Although all the extracts showed benefits compared to untreated controls, salient differences were observed in biochemical profiles of non-CBD cannabinoids, which, in turn, led to significant differences in numbers of mice developing tonic-clonic seizures (21.5–66.7%) and survival rates (85–100%), highlighting the relevance of these “minor” components. This study highlights the necessity of standardization in pharmaceutical development, and although it could be construed to support the single molecule therapeutic model (Bonn-Miller et al., 2018), it requires emphasis that complex botanicals can meet American FDA standards (Food and Drug Administration, 2015). Specifically, two Cannabis-based drugs have attained regulatory approval, Sativex®(nabiximols, US Adopted Name) in 30 countries, and Epidiolex® in the United States.

"The question then arises: Can a Cannabis preparation or single molecule be too pure, thus reducing synergistic potential? Recent data support this as a distinct possibility. Anecdotal information from clinicians utilizing high-CBD Cannabis extracts to treat severe epilepsy, such as Dravet and Lennox-Gastaut syndromes, showed that their patients demonstrated notable improvement in seizure frequency (Goldstein, 2016; Russo, 2017; Sulak et al., 2017) with doses far lower than those reported in formal clinical trials of Epidiolex, a 97% pure CBD preparation with THC removed (Devinsky et al., 2016, 2017, 2018; Thiele et al., 2018). This observation was recently subjected to meta-analysis of 11 studies with 670 patients in aggregate (Pamplona et al., 2018). Those results showed that 71% of patients improved with CBD-predominant Cannabis extracts vs. 36% on purified CBD (p < 0.0001). The response rate at 50% improvement in seizure frequency was not statistically different in the two groups and both groups achieved seizure-free status in about 10% of patients. However, the mean daily doses were markedly divergent in the groups: 27.1 mg/kg/d for purified CBD vs. only 6.1 mg/kg/d. for CBD-rich Cannabis extracts, a dose only 22.5% of that for CBD alone. Furthermore, the incidence of mild and severe adverse events was demonstrably higher in purified CBD vs. high-CBD extract patients (p < 0.0001), a result that the authors attributed to the lower dose utilized, which was achieved in their opinion by the synergistic contributions of other entourage compounds. Such observations support the hypothesis of greater efficacy for Cannabis extracts combining multiple anticonvulsant components, such as CBD, THC, THCA, THCV, CBDV, linalool, and even caryophyllene (Lewis et al., 2018)."
https://www.frontiersin.org/journals/plant-science/articles/10.3389/fpls.2018.01969/full [6062]

Therefore the answers we seek are not susceptible to single-substance definitions, not medically and not legally. The law would do the least harm by getting out of the way.

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The Englishman stands for the rights of everyone disadvantaged, discriminated against, persecuted, and prosecuted on the false or absent bases of prohibition, and also believes the victims of these officially-sanctioned prejudices have been appallingly treated and should be pardoned and compensated.

The Englishman requests the return of his CaPs and other rightful property, for whose distraint Slovenia has proffered no credible excuse or cause.

The Benedictions represent both empirical entities as well as beliefs. Beliefs which the Defence evidence shows may be reasonably and earnestly held about the positive benefits of CaPs at the population level, in which the good overwhelmingly outweighs the bad. Below, the latest version of this dynamic list.




THE BENEDICTIONS                            REFERENCES                        TIMELINE OF DRUG LAW v. SCIENCE