LEPTIN, STAT3, AND CANCER

In 2015 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China were able to us that:

"Emerging evidence has suggested that leptin, an adipokine related to energy homeostasis, plays a role in cancer growth and metastasis."

They explain that "Leptin up-regulated the expression of matrix metalloproteinase-13 (MMP-13) via the JAK2/STAT3 signaling pathway. The overexpression of leptin was shown to significantly promote tumor growth and lymph node metastasis in a subcutaneous model and an orthotopic model of human pancreatic cancer, respectively. Furthermore, in human pancreatic cancer tissues, the expression of [leptin's functional receptor] Ob-Rb was positively correlated with the MMP-13 level."

Leptin up means metastasis up:

"Consistently, we also found the association of MMP-13 expression with lymph node metastasis and the pathological stage"

and

"Human MMP-13, also known as collagenase-3, is a matrix metalloproteinase originally identified in breast carcinomas. Recent studies have revealed that this enzyme is also produced by a variety of malignant tumors, including head and neck, breast and colorectal cancer. In all of the cases, the expression of MMP-13 is associated with aggressive tumors."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599260/ [426]

Obviously I do not want leptin to be too high or too low. But people have been regulating leptin with and without marijuana for thousands of years before 1994.

Its novelty means the current idea of a "normal" range has been obtained entirely during last 27 years of the unusually wealthy recent anthropocene.

It is increased by the carbohydrates which have replaced the hunter-gatherer diets with which early homo sapiens evolved. This trend is discussed in considerable detail here:
https://bmcendocrdisord.biomedcentral.com/articles/10.1186/1472-6823-5-10#Sec9 [427]

Hugh J Freeman of Vancouver University:

"Celiac disease may have developed as a distinct disorder with the transition of hunter-gatherer groups into human workforces capable of agriculture. This "Neolithic revolution" is believed to have permitted competitive survival over other hunter-gatherer groups owing to more secure food supplies. Over time, celiac disease has emerged as a major clinical disorder, currently thought on the basis of serological studies to affect up to about 2% of most genetically-predisposed human populations."

Celiac keeps popping up in areas of wheat consumption, faster than could be accounted for by genetic factors.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4282854/ [428]

Battista et al, in their paper "Altered Expression of Type-1 and Type-2 Cannabinoid Receptors in Celiac Disease" (2013) investigated CBR mRNA and protein as well as functional activity levels in the duodenal mucosa of UCD and TCD patients, and CS, and say:

"Our in vivo data showed that mRNA and protein levels of both CB1 and CB2 receptors are remarkably increased in UCD mucosa compared to TCD mucosa and normal mucosa. It is noteworthy that in TCD patients CB2, but not CB1, levels were reverted to normal values, pointing to CB2 rather than CB1 as main molecular target in celiac disease. Moreover, ex vivo experiments on organ culture confirmed that gluten-induced damage is responsible for this increase, at least at the protein level."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3631143/ [429]

It became clear by 2010 that The endocannabinoid system links gut microbiota to adipogenesis, and "that macrophage infiltration is not only dependent on the activation of the receptor CD14 by lipopolysaccharide, but is also dependent on the gut microbiota composition and the gut barrier function (gut permeability). Moreover, LPS controls the synthesis of eCBs both in vivo and in vitro through mechanisms dependent of the LPS receptor signalling pathway. Thus, obesity is nowadays associated with changes in gut microbiota and a higher endocannabinoid system tone, both having a function in the disease's pathophysiology." [Fig. 2, see ecb controls gut]

"in vivo experiments strongly suggest that an overactive eCB system increases gut permeability."

"we measured AEA levels and FAAH [Fatty acid amide hydrolase, an enzyme that breaks down anandamide] mRNA expression in adipose tissue. Prebiotics strongly decreased AEA levels and tended to increase FAAH mRNA levels (Figure 6C), further supporting the link between changes in gut microbiota and modulation of the eCB system."

"Blocking the CB1 receptor in obese mice also ameliorated gut barrier function as shown by improved distribution....CB1 activation increased gut permeability markers in vivo and in vitro. This demonstration that CB1 receptors control gut permeability suggests a new eCB system-dependent mechanism in the pathogenesis of obesity-associated inflammation (systemic and hepatic)."



"eCB system-LPS crosstalk participates in the regulation of adipogenesis by gut microbiota. Activation of the eCB system in the intestine (e.g. through gut microbiota) increases gut permeability, which enhances plasma LPS levels. This exacerbates gut barrier disruption and peripheral eCB system tone in both the intestine and adipose tissues. Increased fat mass results in enhanced eCB system tone. LPS inhibits both PPAR-induced and cannabinoid ligand-induced adipogenesis. Overall, the impairment of these regulatory loops within colon and adipose tissues found in obesity perpetuates the initial disequilibrium, leading to a vicious cycle. This cycle maintains the increased gut permeability, eCB system tone, adipogenesis and fat mass development that characterise obesity."

"it is clear that genetic or pharmacological blockade of the CB1 cannabinoid receptor protects against the development of obesity"
https://www.embopress.org/doi/full/10.1038/msb.2010.46 [430]

A paper about allosteric as opposed to orthosteric binding to CB receptors.
https://molpharm.aspetjournals.org/content/94/1/743 [1943]

"Studies have emphasized that gut microbiota modulates the intestinal eCB system tone, which, in turn, regulates gut permeability and plasma LPS, and is able to stimulate peripheral endocannabinoids in the gut and adipose tissue. This hyperactivity of the CB1 receptor increases the permeability of the gut barrier, favoring the translocation of more LPS into the bloodstream, which will further stimulate the eCB system, generating a cycle in which both remain altered. In adipose tissue, eCB disturbance leads to adipogenesis, contributing to the accumulation of body fat and, consequently, obesity. LPS and eCB regulate, in different ways, the apelinergic system in adipose tissue, reducing the secretion of apelin and the expression of its AP1 receptor. The apelinergic system plays a role in energy and glycemic homeostasis. Thus, gut microbiota seems to play a significant role in controlling the endocannabinoid system and, consequently, as modulators of obesity and energy homeostasis."

"In a mice model, it was observed that increasing the percentage of linoleic acid (18:2 n-6) in the diet led to increased levels of 2-AG and AEA, which are derived from arachidonic acid (20:4 n-6), which, in turn, is formed from linoleic acid in the body."

"dietary lipids can modulate eCB system tone."
https://www.intechopen.com/chapters/63663 [431]

Yap et al (2026) add some "In silico insights on the binding site and function of cannabinoids and cannabinoid acids on human 5-HT1A receptor", finding that

"CBD, CBG and CBGa are potential partial agonists of 5-HT1A receptor.
CBD, CBG and CBGa may compete with orthosteric ligand for binding.
CBDa, THCV and THCVa are potential allosteric modulators of 5-HT1A receptor.
CBDa, THCV and THCVa can block the exit of orthosteric ligand from its binding site.
MD + 7TM Open IC can accurately predict the activity of 5-HT1A binding ligands."
https://www.sciencedirect.com/science/article/pii/S1093326325002463 [5469]

However, and since we must allow alcoholics their freedom to drink, excess gut permeability may be undesirable in the progression of liver disease:

"Liver disease is often times associated with increased intestinal permeability. A disruption of the gut barrier allows microbial products and viable bacteria to translocate from the intestinal lumen to extraintestinal organs. The majority of the venous blood from the intestinal tract is drained into the portal circulation, which is part of the dual hepatic blood supply. The liver is therefore the first organ in the body to encounter not only absorbed nutrients, but also gut-derived bacteria and pathogen associated molecular patterns (PAMPs). Chronic exposure to increased levels of PAMPs has been linked to disease progression during early stages and to infectious complications during late stages of liver disease (cirrhosis)."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451427/ [432]

As, in the seventeenth year of the ZPPPD, Slovenia went from pretending cannabinoids had no medical uses to pretending only one cannabinoid had only one medical use, to carry on generating excuses to confiscate people's money, protect big pharma, and churn profits for its law businesses at the expense of drinkers' lives, Wang et al (2017) showed in binge drinking mice that "Cannabidiol attenuates alcohol-induced liver steatosis, metabolic dysregulation, inflammation and neutrophil-mediated injury", explaining that:

"Herein, we investigated the effects of CBD on liver injury induced by chronic plus binge alcohol feeding in mice. CBD or vehicle was administered daily throughout the alcohol feeding study. At the conclusion of the feeding protocol, serums samples, livers or isolated neutrophils were utilized for molecular biology, biochemistry and pathology analysis. CBD significantly attenuated the alcohol feeding-induced serum transaminase elevations, hepatic inflammation (mRNA expressions of TNFα, MCP1, IL1β, MIP2 and E-Selectin, and neutrophil accumulation), oxidative/nitrative stress (lipid peroxidation, 3-nitrotyrosine formation, and expression of reactive oxygen species generating enzyme NOX2). CBD treatment also attenuated the respiratory burst of neutrophils isolated from chronic plus binge alcohol fed mice or from human blood, and decreased the alcohol-induced increased liver triglyceride and fat droplet accumulation. Furthermore, CBD improved alcohol-induced hepatic metabolic dysregulation and steatosis by restoring changes in hepatic mRNA or protein expression of ACC-1, FASN, PPARα, MCAD, ADIPOR-1, and mCPT-1."

Note: mast cell protease 1 has no direct homolog in humans.
https://pmc.ncbi.nlm.nih.gov/articles/PMC6554654/ [5735]

De Ternay et al (2019) agreed CBD reduces hepatic alcohol damage:

"CBD modulated the ethanol-induced dysregulation of numerous genes and proteins involved in metabolism and liver steatosis, such as key genes of fatty acid biosynthetic and oxidation pathway, mitochondrial pathway, and transcription factor PPAR-α. Furthermore, in the ethanol-fed mice group, CBD attenuated hepatic neutrophils infiltration, oxidative and nitrative stress, decreased several markers of liver inflammation such as TNF-α, the expression of adhesion molecule E-selectin, proinflammatory chemokine and cytokines, and thus, attenuated liver injury induced by chronic plus binge ethanol exposure."

De Ternay et al review evidence in three areas of CBD benefit in AUD: reduction of drinking, modulation the inflammatory processes in the liver, and reduction of alcohol-related brain injury [ARBI]. Additionally, they say, CBD can reduce alcohol-related seizures, anxiety, and chronic pain. [1921]

Erukainure et al (2021) stirred up further evidence by using whole plant extracts to produce "Cannabis sativa L. (var. indica) Exhibits Hepatoprotective Effects by Modulating Hepatic Lipid Profile and Mitigating Gluconeogenesis and Cholinergic Dysfunction in Oxidative Hepatic Injury":

"This study sought to investigate the hepatoprotective effect of C. sativa on iron-mediated oxidative hepatic injury. Hepatic injury was induced ex vivo by incubating hepatic tissues with Fe2+, which led to depleted levels of reduced glutathione, superoxide dismutase, catalase and ENTPDase [ecto-nucleoside triphosphate diphosphohydrolase] activities, triglyceride, and high-density lipoprotein–cholesterol (HDL-C). Induction of hepatic injury also caused significant elevation of malondialdehyde, nitric oxide, cholesterol, and low-density lipoprotein–cholesterol (LDL-C) levels while concomitantly elevating the activities of ATPase, glycogen phosphorylase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, amylase, and lipase. Treatment with the hexane, dichloromethane (DCM), and ethanol extracts of C. sativa leaves significantly (p < 0.05) reversed these levels and activities to almost near normal. However, there was no significant effect on the HDL-C level. The extracts also improved the utilization of glucose in Chang liver cells. High-performance liquid chromatography (HPLC) analysis showed the presence of phenolics in all extracts, with the ethanol extract having the highest constituents. Cannabidiol (CBD) was identified in all the extracts, while Δ-9-tetrahydrocannabinol (Δ-9-THC) was identified in the hexane and DCM extracts only. Molecular docking studies revealed strong interactions between CBD and Δ-9-THC with the β2 adrenergic receptor of the adrenergic system. The results demonstrate the potential of C. sativa to protect against oxidative-mediated hepatic injury by stalling oxidative stress, gluconeogenesis, and hepatic lipid accumulation while modulating cholinergic and purinergic activities. These activities may be associated with the synergistic effect of the compounds identified and possible interactions with the adrenergic system."
https://pmc.ncbi.nlm.nih.gov/articles/PMC8724532/ [5737]

Gojani et al (2023) on the other hand took a reductive approach, examining specific CCx:

"Our findings indicate that all five phytocannabinoids reduce HG-HL-induced -cell loss likely through reducing apoptosis and pyroptosis. The protective effects of CBD, THCV, CBC, and CBN were seen in the GSIS impairment by HG-HL. Although all five phytocannabinoids tested in this research demonstrated the capability to inhibit β-cell dedifferentiation induced by HG-HL, CBD seems to be more effective compared to the other phytocannabinoids, as indicated by the specific biomarker responses of β-cells and progenitor cells to CBD."
https://www.preprints.org/manuscript/202309.0973 [5736]

Walsh et al (2021) would like us to know that:

"Unlike the continuous cellular synthesis and storage of neurotransmitters and neuropeptides, AEA and 2-AG are produced through 'on demand' cleavage of NAPE and PIP2. This provides for a temporal- and localization-dependent release of the endocannabinoids (Lu and Mackie, 2016). The actions of AEA and 2-AG are terminated following their cellular uptake and degradation by intracellular hydroxylase [fatty acid amide hydrolase (FAAH)] (for AEA) and lipase enzymes (monoacylglycerol lipase) (for 2-AG). Therefore, drugs that inhibit the cellular uptake of AEA and 2-AG or prevent their enzymatic degradation should result in a potentiation of endocannabinoid action."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8669157/ [854]

"Chemopreventive effect of the non-psychotropic phytocannabinoid cannabidiol on experimental colon cancer" is the subject of a 2012 paper by Aviello et al when

"...we investigated its possible chemopreventive effect in the model of colon cancer induced by azoxymethane (AOM) in mice. AOM treatment was associated with aberrant crypt foci (ACF, preneoplastic lesions), polyps, and tumour formation, up-regulation of phospho-Akt, iNOS and COX-2 and down-regulation of caspase-3. Cannabidiol-reduced ACF, polyps and tumours and counteracted AOM-induced phospho-Akt and caspase-3 changes. In colorectal carcinoma cell lines, cannabidiol protected DNA from oxidative damage, increased endocannabinoid levels and reduced cell proliferation in a CB(1)-, TRPV1- and PPARγ-antagonists sensitive manner. It is concluded that cannabidiol exerts chemopreventive effect in vivo and reduces cell proliferation through multiple mechanisms."
https://pubmed.ncbi.nlm.nih.gov/22231745/ [3685]

"Cannabidiol Targets Colorectal Cancer Cells via Cannabinoid Receptor 2, Independent of Common Mutations" say Moniruzzaman et al (2025):



"Our results demonstrate that CBD induces apoptosis and halts proliferation, migration, and invasion of CRC cell lines in a concentration-dependent manner. CBD showed potent antitumor effects in the tested cell lines with no obvious effect from different mutations such as KRAS, BRAF, APC, PTEN, etc. CBD also induced ER stress in CRC cells but not in healthy intestinal organoids. Cotreatment with SR144528 inhibited the effects of indicating involvement of CB2 receptor activation in the anticancer effects of CBD. Together, these results demonstrated that CBD could be effective for CRC regardless of the underlying mutation through CB2 receptor activation."
https://pubs.acs.org/doi/full/10.1021/acsptsci.4c00644 [3951]

Vago et al at the San Raffaele Scientific Institute, Milan have a subheading in their paper entitled "The Mediterranean Diet as a Source of Bioactive Molecules with Cannabinomimetic Activity in Prevention and Therapy Strategy" (2022):

"Modulation of the ECS Alters the Microbiota Composition

"Recent studies have proven that targeting the ECS directly can lead to an alteration in the composition of the gut microbiota in favor of species with a positive impact on health. It was seen that the microbiota and the endocannabidiome cooperate in a series of intertwined pathways, which, when disrupted, can worsen preexisting low-grade inflammation and insulin resistance in obese patients. The involvement of CB1 in intestinal and metabolic homeostasis has been studied in detail, identifying its antagonism as a possible way to improve gut barrier function. A higher ECS tone has been associated with an increase in gut permeability and treatment with a CB1 agonist HU-210 induced, as a consequence, severe metabolic disturbances such as glucose intolerance, lipid accumulation in the muscle and endotoxemia. Bahrami et al. have proven for the first time that CB1 blockade improves colonic inflammation, systemic inflammation and insulin resistance in diet-induced obesity (DIO) mice fed with a high-fat diet and treated with Rimonabant (SR141716A), a CB1 antagonist. Interestingly, CB1 antagonist administration also altered the gut microbiota composition in favor of more protective species such as Akkermansia muciniphila, which is known to ameliorate DIO and diabetes parameters such as endotoxemia, adiposity, glucose metabolism and insulin resistance when transferred live in mouse models. This species' abundance was suggested to be restored as a consequence of increased expression of MUC2, a transcription factor in charge of host mucin production regulation. Mucin is the main nutrient source for A. muciniphila and is essential for its growth. These outcomes were demonstrated to be rimonabant administration-dependent in obese mice and were also proven to be independent from caloric restriction and weight loss. In addition to increased abundance in A. muciniphila, the authors observed a decrease in the Lachnospiraceae and Erysipelotrichaceae families. This is a significant finding, as these two bacterial families belonging to the Firmicutes phylum are thought to be involved in weight gain and metabolic syndrome induction, but also in diabetes and inflammation-related GI disorders. What appears to make the link between CB1 antagonism and gut microbiota even stronger is the increased production of butyric and propionic acid evaluated by Bahrami et al. by conducting gas chromatography on the mice's cecal material. This increased production of short chain fatty acids can be explained by an increased abundance of beneficial butyrogenic and propionogenic species following the administration of Rimonabant. A. muciniphila is a prominent example of this statement, as propionic acid is its main metabolite. This interpretation, however, remains a hypothesis, as the authors believe the effects that Rimonabant had on the composition of the gut microbial community in toto could be secondary to its effect on the inflammatory state, which then led to a change in the environmental characteristics of the intestine."

They add:

"Markey et al. explored the impact of Candida albicans on the gut-brain axis and its ability to dysregulate the balance of the ECS. It has been seen that C. albicans colonization, while protecting the gut's health against pathobionts, induces an AEA-CB1 deficit which increases both stress-induced and basal corticosterone production related to anxiety-like behavior. By administering a FAAH blocker (URB597) to C. albicans colonized mice, the trend was reversed, while no effect was noted in mock-colonized mice. K-means cluster analysis supported the hypothesis that the AEA deficit was responsible for the changes in behavior, which was further proven by the increased abundance of two other NAEs (linoleoyl and linoleoyl ethanolamine) in the cecum of C. albicans colonized mice. The authors explain that the change in precursor abundance in the GI tract noticed through feeding studies could contribute to the alterations in AEA levels that were observed in this study. Despite not being involved in the lifestyle-related diseases that are in study in this review, this is an example of how there could be undiscovered links between certain species of the microbial community and a healthier ECS equilibrium. While Markey et al. showed that Candida albicans alone seems to have the ability to modulate the ECS, Lacroix et al. showed that there is a strong time-dependent association between the abundance of several bacterial genera of the intestinal microbiota and the concentration of AEA and 2-AG in the ileum and plasma of high-fat high sugar (HFHS) diet-fed mice. This study also showed a decrease in CB2 expression in the early stages of the HFHS diet, which could have shifted the ECS mediator profile to preferential binding to CB1, which then increased intestinal permeability, inflammation, insulin resistance and may have led to a subsequent change in the composition of the microbiota. It is undeniable that there are numerous undiscovered details that need to be clarified by future studies, but these observations confirm that there is some kind of cooperation between single microorganism species that, each with its own metabolism, can contribute to a healthy gut environment by acting on the ECS."
https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8839035/ [1014]

As Farooqi et al were to remind the medical profession in 2023 in the context of endometriosis:

"Endocannabinoids and exogenous cannabinoids exert opposite effects on gut permeability. For instance, when examining decreased permeability as a result of inflammation, it was demonstrated that 2-AG and AEA increased permeability, while THC and CBD decreased permeability." [5496]

Compare this to the state of knowledge fifteen years after General Smuts' gift to the world, when there was no concept of lipids as messengers. Chapter 46 of Bainbridge and Menzies' Essentials of Physiology 9th edition (1940) "Intestinal Digestion and Absorption" makes no special mention of gut commensals and the process is treated as if a machine, almost without life. The most that could be discerned about drug influences on peristalsis was that:

"Peristalsis continues in a normal fashion when all the nerves passing from the central nervous system have been divided, but it is abolished by painting the wall of the intestine with cocaine or nicotine, which puts the myoneural plexuses of Auerbach and Meissner out of action."
Bainbridge and Menzies' Essentials of Physiology 9th edition, 1940 [380]

But these were the Dark Ages of lipid biochemistry. The lipid hypothesis became lost in the hedgerows:

"Nikolai Anitschkow that laid the foundation of what would later be termed the “lipid hypothesis,” or the concept that elevated blood cholesterol concentrations induced atherosclerosis. He showed that feeding rabbits purified cholesterol raised blood cholesterol levels and induced atherosclerotic lesion formation, and that the extent of atherosclerosis was proportional to the absolute amount of and length of exposure to high blood cholesterol. In contrast, similar experiments in dogs and rats did not elicit a similar response, results that lent skepticism to the lipid hypothesis. The inability to induce atherosclerosis in these species was later found to be due to their relative resistance to diet-induced hypercholesterolemia."
https://www.jlr.org/article/S0022-2275(20)35387-6/fulltext [1724]

Daniel Steinberg in a history of the cholesterol controversy elaborates:

"Cholesterol feeding in these species [dogs and rats] failed to induce lesions. So, understandably, these investigators concluded that Anitschkow’s results must reflect some peculiarity of the rabbit. After all, it is a strict herbivore that normally has zero cholesterol intake and a very low fat intake. The rabbit model was dismissed as irrelevant to human disease. What was not appreciated was the fact that rats and dogs, unlike rabbits, are very efficient in converting cholesterol to bile acids. Consequently, even on very high cholesterol intakes the blood cholesterol in these species does not increase appreciably."

and

"During World War II, Cohn et al. and Oncley, Scatchard, and Brown at Harvard developed elaborate largescale methods for fractionating human serum to provide materials useful in treating the wounded. In the course of those systematic studies, they found that the lipids of serum were concentrated in two major fractions having α- and β-mobility, respectively."

To help us position the state of ignorance at this time in the context of the conquest of cannabis, Steinberg goes on to explain that at this time (i.e. after the League's last health investigation in 1935, after Reefer Madness came out (1936), after the Marijuana Tax Act 1937, and after the war was over) as far as these major fractions were concerned

"...nothing was known about their origin, their fate, or their biological significance."
https://www.jlr.org/article/S0022-2275(20)31274-8/pdf [1725]

What did the authors of the 1925 treaty and the 1961 SCND know about the effects of cannabinoids on bile acids and hypercholesteremia?

After some rather unpleasant experiments in dogs, in 1922 G. H. Whipple of the School of Medicine and Dentistry, University of Rochester, N. Y, writes:

"Evidently there is a mechanism in the normal animal which controls the production and destruction of bile salts within certain limits but this is a complete mystery."
https://journals.physiology.org/doi/pdf/10.1152/physrev.1922.2.3.440 [2045]

"In his seminal early paper (published in Dutch), [Cornelis] de Langen described clinical relationships among diet, serum cholesterol, and atherosclerosis: '. . . a cholesterol-rich diet and severe metabolic diseases, such as diabetes, obesity, nephritis, and arteriosclerosis, are associated with hypercholesterolemia.'"

de Langen (1916) is credited with the first credible epidemiological investigation of the role of cholesterol in atherosclerosis, although it went mostly unnoticed. Similar findings seemed to confirm his Diet-Heart theory in 1940.
http://www.epi.umn.edu/cvdepi/essay/cornelis-de-langen-diet-heart-theory-1916/ [2955]

Ancel Keys took the anti-fat crusade to town on behalf of the sugar and carbohydrate industries. But the debate rages on, as experimental design improved. For example "The fallacies of the lipid hypothesis" by Uffe Ravnskov in the Scandinavian Cardiovascular Journal, the author found as many or more than 50% of the relevant studies showed:

"High cholesterol may be beneficial
By 1992, a meta-analysis of 19 cohort studies including more than 600 000 men and women from many countries had found that cholesterol was inversely associated with mortality from respiratory and digestive diseases, most of which were of an infectious origin. The observation was in line with a large number of epidemiological, laboratory and experimental studies showing that high cholesterol protects against infections. The main effect seems to be exerted by the LDL molecule."
https://www.tandfonline.com/doi/full/10.1080/14017430801983082 [2956]

In 2005 Mielke et al cast further doubt on the alleged evils of cholesterol:

"Neuropsychiatric, anthropometric, laboratory, and other assessments were conducted for 392 participants of a 1901 to 1902 birth cohort first examined at age 70. Follow-up examinations were at ages 75, 79, 81, 83, 85, and 88. Information on those lost to follow-up was collected from case records, hospital linkage system, and death certificates. Cox proportional hazards regression examined lipid levels at ages 70, 75, and 79 and incident dementia between ages 70 and 88.

"Results: Increasing cholesterol levels (per mmol/L) at ages 70 (hazard ratio [HR] 0.77, 95% CI: 0.61 to 0.96, p = 0.02), 75 (HR 0.70, CI: 0.52 to 0.93, p = 0.01), and 79 (HR 0.73, CI: 0.55 to 0.98, p = 0.04) were associated with a reduced risk of dementia between ages 79 and 88. Examination of cholesterol levels in quartiles showed that the risk reduction was apparent only among the highest quartile at ages 70 (8.03 to 11.44 mmol/L [311 to 442 mg/dL]; HR 0.31, CI: 0.11 to 0.85, p = 0.03), 75 (7.03 to 9.29 mmol/L [272 to 359 mg/dL]; HR 0.20, CI: 0.05 to 0.75, p = 0.02), and 79 (6.82 to 9.10 mmol/L [264 to 352 mg/dL]; HR 0.45, CI: 0.17 to 1.23, p = 0.12). Triglyceride levels were not associated with dementia."
https://www.neurology.org/doi/10.1212/01.WNL.0000161870.78572.A5?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed [4788]

By 2023 the certainties of the previous century were undone. The title "A short history of saturated fat: the making and unmaking of a scientific consensus" speaks for itself.

Ignoring de Langen, it claims

"The diet-heart hypothesis was first proposed in the 1950s by Ancel Keys".

and says

"The idea that saturated fats cause heart disease, called the diet-heart hypothesis, was introduced in the 1950s, based on weak, associational evidence. Subsequent clinical trials attempting to substantiate this hypothesis could never establish a causal link. However, these clinical-trial data were largely ignored for decades, until journalists brought them to light about a decade ago. Subsequent reexaminations of this evidence by nutrition experts have now been published in >20 review papers, which have largely concluded that saturated fats have no effect on cardiovascular disease, cardiovascular mortality or total mortality. The current challenge is for this new consensus on saturated fats to be recognized by policy makers, who, in the United States, have shown marked resistance to the introduction of the new evidence. In the case of the 2020 Dietary Guidelines, experts have been found even to deny their own evidence. The global re-evaluation of saturated fats that has occurred over the past decade implies that caps on these fats are not warranted and should no longer be part of national dietary guidelines. Conflicts of interest and longstanding biases stand in the way of updating dietary policy to reflect the current evidence."

Among the revelations by The Nutrition Coalition founder Nina Teicholz:

"By the late 1960s, a bias in favor of the diet-heart hypothesis was strong enough that researchers with contrary results found themselves unable or unwilling to publish their results. For instance, the largest test of the diet-heart hypothesis, the Minnesota Coronary Survey, involving 9057 men and women over 4.5 years, tested a diet of 18% saturated fat against controls eating 9%, yet did not find any reduction in cardiovascular events, cardiovascular deaths, or total mortality. Although the study had been funded by the NIH, the results were not published for 16  years, after the principal investigator, Ivan Frantz, had retired. Frantz is reported to have said that there was nothing wrong with the study; ‘We were just disappointed in the way it came out’. Frantz's decision not to publish his results in a timely manner resulted in these contradictory data not being considered for another 40  years."

and concludes

"Until the recent science on saturated fats is incorporated into the U.S. Dietary Guidelines, the policy on this topic cannot be seen as evidence-based."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9794145/ [2957]

Another revelation concerns the AHA:

"'The 1961 AHA advice to limit saturated fat is arguably the single-most influential nutrition policy ever published, as it came to be adopted first by the U.S. government, as official policy for all Americans, in 1980, and then by governments around the world as well as the World Health Organization.'"

...

"However, they were paid off to distribute this information. The AHA accepted $20 million (in today's dollars) in funding from Procter & Gamble, a corporation that conveniently makes and sells Crisco Oil. The AHA recommended that everyone replace butter with 'heart healthy' alternatives like vegetable oil or Crisco Oil."

...

"It's no wonder more people than ever are skeptical of public health organizations and mainstream experts who claim to possess the final word on health and nutrition, when there is so much proof that information has been censored and even doctored in order to push a certain message that will help corporations like Procter & Gamble become richer and richer."
https://www.eviemagazine.com/post/american-heart-association-was-paid-procter-gamble-heart-disease-saturated-fat-seed-oils-sugar [4490]

Joy Y Kiddie MSc, RD shared some 1976 handouts from Procter and Gamble, who had tried to invent soap using waste cottonseed oil and ended up inventing Crisco shortening, in 1911.






"Looking back on the role of fat manufacturers and the sugar industry (outlined in the preceding article) on which foods were recommended and promoted, it makes me question what I was taught and who affected what I was taught. Given that it was known at the time the sugar industry funded the researchers that implicated saturated fat as the alleged cause of heart disease, I wonder what we don’t know about which industry funded which research. After all, the knowledge about the sugar industry having funded the researchers that implicated saturated fat only ‘came out’ in November 2016 when it had occurred decades earlier."
https://www.lchf-rd.com/2018/03/15/the-marketing-of-vegetable-oil-to-an-unsuspecting-public/ [4482]

The predilection amongst scientists to sail with the current was prevalent.

Says Teicholz in a 2024 Medscape article:

"Recognizing the need for rigorous data, governments around the world, including our own National Institutes of Health (NIH), spent billions of dollars in the ensuing decades on some of the largest and longest human clinical trials ever conducted. Somewhere between 10,000 and 53,000 people were tested on diets in which saturated fats were replaced by unsaturated vegetable oils (the tally depends on which trials are counted). However, the results did not turn out as hoped, and so researchers, either unable or unwilling to believe the outcomes, largely buried the data. For instance, the leaders of one large NIH-funded study with findings unfavorable to the diet-heart hypothesis did not publish them for 16 years. When asked why, one reportedly replied that there was nothing wrong with the study; 'We were just disappointed in the way it turned out.'"

https://www.medscape.com/viewarticle/882564?form=fpf#vp_5 [4481]

We are left wondering why, after decades of Proctor and Gamble's advice via the auspices of the American Heart Association, to avoid or reduce saturated fat, the average person is fatter than ever before.

Yet for the Huntley College of Agriculture, California State Polytechnic University, Pomona, "cholesterol is bad" was still an article of faith in 2020.
https://www.mdpi.com/2072-6643/12/8/2329/pdf?version=1596540267 [2958]

While in 2021 the e-Journal of Cardiology Practice does not question Ancel Keys' work, and takes a pretty uncritical view of the missteps of the past. But does provide details of other contributors to the discovery timeline, dietary debates and drug treatments. Several iterations of lipid profile modelling culminated in the US 1998 guidelines which became the "gold standard" for diagnosis.
https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-19/history-in-medicine-the-story-of-cholesterol-lipids-and-cardiology [2960]

Does it sound to you as if the role of cholesterol in atherosclerosis was settled at the time of the 1924/25 Conference?

How about by the time of the 1961 SCND?

And by the time of the 1971 Protocol, was it settled?

And when Slovenia inherited what it believed to be the drug treaty obligations of the former Yugoslavia (however translated) in 1991, was the cholesterol question satisfactorily resolved?

When the ZPPPD was enacted in 2000, was it settled then? For your information, "The fallacies of the lipid hypothesis" was published in 2009.

The attendees at these various measures wouldn't have known if cannabis contributed in any way, perhaps positively, to the regulation of bile salts?

Do you expect there is any evidence the Plenipotentiaries considered that at all?

By the time cannabis was dropped from the British Pharmacopoeia in 1932, work was afoot to find out what these bile acids were. In 1934 Rosenheim and King applied the studies of Bernal (1932) to elucidation of the structure of bile acids. Bile acids contribute to the digestion of exogenous fats, e.g. triglycerides. With Wieland and Windaus' formula of 1928

"...it seemed as if the last chapters in the story of one of the most brilliant researches of organic chemistry had been written. The ring system of an important group of natural subsyances had been established with a degree of certainty which seemed to be final."

But two carbon atoms remained "homeless" and

"It soon became apparent that the C2H5 group was not in Ring IV, and in spite of four years' systematic effort it proved to be impossible to place the two carbon atoms elsewhere in the ring system. The old formula thus became untenable."
https://www.annualreviews.org/doi/pdf/10.1146/annurev.bi.03.070134.000511 [2044]

So could the authors of the Opium Treaty known anything about cannabis and bile acids in 1925? Could the Kingdom of Yugoslavia have known on the 6 January 1929?

Clearly if they did not know what the bile acids were, what their structure was, and did not know what the active principles of cannabis were, they could not have predicted the results of their interaction, could they?

Once cannabis was banned, it couldn't be the object of respectable research, could it?

In 1956 J B Carey

"...identified chenodeoxycholic acid (CDCA) as a major biliary bile acid and proposed that lithocholic acid, its bacterial metabolite, caused liver injury in man."

"When a meal is ingested, the hormone cholecystokinin is released from the small intestine. Cholecystokinin induces gallbladder contraction as well as relaxation of the valve (sphincter of Oddi) at the end of the common bile duct where it empties into the small intestine. Bile then enters the duodenum. Some of the bile acids are absorbed in the jejunum, but most are transported by intestinal peristalsis to the distal ileum where they are efficiently absorbed. The bile acid molecules pass through ileal enterocytes and enter portal venous blood to return to the liver. One of the early illustrations of the enterohepatic circulation of bile acids with values for man was presented by Sune Bergström in 1959 and is shown in Fig. 8."



Now we've seen cannabis was widely used for antiemesis and digestive assistance in the UK from its arrival with O'Shaughnessy in the 1840s until its banishment after WW1.

Is there any way, in 1925, that the authors of the first international drug treaty to include cannabis, knew anything about the values for man for enterohepatic circulation of bile acids first revealed by Bergström in 1959?

In his "Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades" (2014) Hofmann and Hagey of the Department of Medicine, University of California, San Diego, San Diego, CA reveal that

"The first symposium devoted solely to bile acids was organized by Leon Schiff, a clinical hepatologist, who was one of the founders of the American Association for the Study of Liver Diseases. This symposium, held in 1967, was quite exciting for its participants who are shown in Fig. 1."



"However, it is safe to say that the study of bile acids was pursued by only a small number of laboratories, some in Departments of Biochemistry and some in Departments of Medicine. Erwin Mosbach, one of the early workers in bile acid metabolism, once stated to his wife, 'Whenever I go to the podium to give a paper on bile acids, everyone leaves the room'.

"In 1965, the senior author, working in the laboratory of E. H. Ahrens, began feeding studies with cholic acid in a patient with severe hypercholesterolemia, and showed that cholic acid feeding was a potent suppressor of bile acid and cholesterol biosynthesis, based on measurement of fecal bile acids and sterols, using the newly developed gas chromatographic method for fecal bile acids that had been developed in this laboratory. It was logical to test CDCA, the other primary bile acid, but at that time, the world's supply of pure CDCA was thought to be less than 10 g, and the synthesis from cholic acid was difficult. However, in the 1960s, a small English pharmaceutical company (Weddell Pharmaceuticals) began the manufacture of CDCA for unknown reasons. A kilogram was purchased for the senior author by the Mayo Clinic in 1967. Leslie Schoenfield returned to the Mayo Clinic in 1966 after having spent a year in the laboratory of Sjövall, and initiated a clinical trial with his fellow, Johnson Thistle, to test whether oral cholic acid or hyodeoxycholic acid would lower cholesterol in bile and ultimately induce cholesterol gallstone dissolution. The senior author persuaded Schoenfield to add CDCA to his protocol, and this study of Thistle and Schoenfield showed that CDCA feeding decreased biliary cholesterol saturation, whereas neither cholic acid nor hyodeoxycholic acid had any effect. In 1972, the first gallstone dissolution induced by the ingestion of CDCA was observed, initially at the Mayo Clinic, and later in London by a group led by Hermon Dowling. [This was not the first time that the efficacy of oral bile acids had been tested at the Mayo Clinic. In 1938, Philip Hench had fed a mixture of conjugated bile salts in an unsuccessful attempt to treat rheumatoid arthritis.]

"The discovery that CDCA [chenodeoxycholic acid] would induce gradual dissolution of cholesterol gallstones led to the next resurgence of interest in bile acids. For the very first time, CDCA was made in kilogram quantities by several manufacturers, and became the third bile acid available as a fine chemical."
https://www.sciencedirect.com/science/article/pii/S0022227520353232#bib34 [2042]

So would you agree that the authors of the international treaties of 1925 and 1961 did not know anything at those times about interactions between cannabis and bile acids?

We can observe, in fact, that the human diet has undergone its most dramatic modifications in the last 80 years. Ultraprocessed food, starting in the nineteenth century, developed further after the war with the wider entry of women into the workplace and the availability of home refrigeration and, later, microwaves.

Some say ultra-processed food - this does have a strict scientific definition - overtook smoking as the world's leading cause of death in 2019.

"The food system we live within is incredibly violent to our bodies," says Chris van Tulleken, "and it desperately needs changing. And people can't make choices that are healthy, many people are incredibly constrained by the world around them."

And the doctor says:

"Food made by massive companies with obligations to pension funds affects your body differently to food made at home by someone that loves you. It's what we've all believed for decades, now we have very robust evidence that proves it."
https://www.youtube.com/watch?v=l3U_xd5-SA8 [2668]

A prospective study with 105 159 participants examined "Ultra-processed food intake and risk of cardiovascular disease: prospective cohort study (NutriNet-Santé)" (2019) and here is the graphical version of their findings.



"In this large observational prospective study, higher consumption of ultra-processed foods was associated with higher risks of cardiovascular, coronary heart, and cerebrovascular diseases."
https://www.bmj.com/content/365/bmj.l1451 [2669]

"Ultra-processed food consumption, cancer risk and cancer mortality: a large-scale prospective analysis within the UK Biobank" in the Lancet (2023) found similar results.:

"The mean UPF consumption was 22.9% (SD 13.3%) in the total diet. During a median follow-up time of 9.8 years, 15,921 individuals developed cancer and 4009 cancer-related deaths occurred. Every 10 percentage points increment in UPF consumption was associated with an increased incidence of overall (hazard ratio, 1.02; 95% CI, 1.01–1.04) and specifically ovarian (1.19; 1.08–1.30) cancer. Furthermore, every 10 percentage points increment in UPF consumption was associated with an increased risk of overall (1.06; 1.03–1.09), ovarian (1.30; 1.13–1.50), and breast (1.16; 1.02–1.32) cancer-related mortality."
https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00017-2/fulltext [2667]

In a cohort study of 10,775 individuals followed for a median of 8 years, Goncalves et al (2022) found that consumption of UPF greater than 19.9% of total daily calories was associated with a faster decline in global cognitive performance and executive function.



In particular, individuals with ultraprocessed food consumption above the first quartile showed a 28% faster rate of global cognitive decline and a 25% faster rate of executive function decline compared with those in the first quartile.
https://jamanetwork.com/journals/jamaneurology/fullarticle/2799140 [5136]

Fructose is a cornerstone of the ultra-processed food industry and humans have never consumed so much fructose throughout human evolutionary history as they do today.

In 2009 Ross et al showed such a diet produces impairments in a rat water maze model, revealing one possible reason Americans elected Donald Trump twice:

"Over the past three decades there has been a substantial increase in the amount of fructose consumed by North Americans. Recent evidence from rodents indicates that hippocampal insulin signaling facilitates memory and excessive fructose consumption produces hippocampal insulin resistance. Based on this evidence, the present study tested the hypothesis that a high fructose diet would impair hippocampal-dependent memory. Adult male Sprague-Dawley rats (postnatal day 61) were fed either a control (0 % fructose) or high fructose diet (60 % of calories). Food intake and body mass were measured regularly. After 19 weeks, the rats were given 3 days of training (8 trials/day) in a spatial version of the water maze task, and retention performance was probed 48 h later. The high fructose diet did not affect acquisition of the task, but did impair performance on the retention test. Specifically, rats fed a high fructose diet displayed significantly longer latencies to reach the area where the platform had been located, made significantly fewer approaches to that area, and spent significantly less time in the target quadrant than did control diet rats. There was no difference in swim speed between the two groups. The retention deficits correlated significantly with fructoseinduced elevations of plasma triglyceride concentrations. Consequently, the impaired spatial water maze retention performance seen with the high fructose diet may have been attributable, at least in part, to fructose-induced increases in plasma triglycerides."

Some background:

"A high fructose diet causes numerous pathological changes, including oxidative stress, glucose intolerance, insulin resistance, type 2 diabetes, liver disease, hypertension, and cardiovascular disease (Busserolles, Gueux, Rock, Mazur, and Rayssiguier, 2002; Elliott, Keim, Stern, Teff, and Havel, 2002; Hwang, Ho, Hoffman, and Reaven, 1987; Montonen, Jarvinen, Knekt, Heliovaara, and Reunanen, 2007; Nandhini, Thirunavukkarasu, Ravichandran, and Anuradha, 2005; Zavaroni, Sander, Scott, and Reaven, 1980). Furthermore, a study from one of the present investigators showed that the damaging effects of a high fructose diet extend directly to the brain (Mielke, Taghibiglou, Liu, Zhang, Jia, Adeli, and Wang, 2005). Specifically, placing male Syrian hamsters on a 60 % fructose diet for 6 weeks produced hippocampal insulin resistance. This finding is particularly significant given that the hippocampus is integral to many forms of learning and memory (Ergorul and Eichenbaum, 2004) and that converging lines of evidence indicate that neural insulin signaling facilitates hippocampal-dependent memory (Park, 2001). For instance, extensive evidence suggests that peripheral insulin resistance and type 2 diabetes are associated with deficits in hippocampal-dependent declarative memory (Convit, 2005; Messier, 2005; Stewart and Liolitsa, 1999; Strachan, Deary, Ewing, and Frier, 1997; Zhao, Chen, Xu, Moore, Meiri, Quon, and Alkon, 1999). Moreover, learning and memory of a spatial water maze experience are correlated with activation of the hippocampal insulin signaling pathway (Dou, Chen, Dufour, Alkon, and Zhao, 2005; Zhao et al., 1999). Most importantly, direct infusions of insulin into the hippocampus enhance performance in a variety of memory tasks, and the memory-enhancing effects of hippocampal insulin administration are not observed in diabetic rats (Babri, Gholamipour, Rad, and Khameneh, 2006; McNay, Herzog, McCrimmon, and Sherwin, 2005; Moosavi, Naghdi, Maghsoudi, and Zahedi Asl, 2006).

"Given that fructose is preferentially metabolized by the liver into lipids (Havel, 2005; Topping and Mayes, 1971) and produces large increases in plasma triglyceride (TG) concentrations (Basciano, Federico, and Adeli, 2005; Havel, 2005; Kelley, Allan, and Azhar, 2004; Le, Faeh, Stettler, Ith, Kreis, Vermathen, Boesch, Ravussin, and Tappy, 2006; Park, Cesar, Faix, Wu, Shackleton, and Hellerstein, 1992), a high fructose diet is analogous to a high fat diet in many metabolic ways. Importantly, rats fed a diet high in saturated fatty acids exhibit impaired performance on a number of hippocampal-dependent memory tasks (Greenwood and Winocur, 1990; 1996; McNay et al., 2005). Moreover, high fat diets produce insulin resistance in the brain (Banas, Rouch, Kassis, Markaki, and Gerozissis, 2008), and injecting TGs directly into the brain ventricles impairs memory (Farr, Yamada, Butterfield, Abdul, Xu, Miller, Banks, and Morley, 2008). Collectively, the reviewed evidence led us to hypothesize that a high fructose diet would impair hippocampal-dependent memory, and that the deficits would be attributable, at least in part, to fructose-induced increases in plasma TGs. Consequently, the present experiment tested the effects of feeding rats a high fructose diet on hippocampaldependent spatial water maze learning and memory, and sought to determine whether any deficits would be correlated with fructose-induced increases in plasma TGs."
https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC2737072&blobtype=pdf [3667]

Such ingredients are all but impossible to avoid in today's society if you want to live a more-or less normal life. More efficient use of food value may be one of the most valuable (subliminal) positive outcomes, since food availability has grown immensely during the last century, but nutritional content has fallen just as dramatically.

According to Workinger et al in "Challenges in the Diagnosis of Magnesium Status" (2018)

"Many fruits and vegetables have lost large amounts of minerals and nutrients in the past 100 years with estimates that vegetables have dropped magnesium levels by 80–90% in the U.S. (Figure 2) and the UK [cited include USDA ]. It is important to note that the USDA mineral content of vegetables and fruits has not been updated since 2000, and perhaps even longer, given that the data for 1992 was not able to be definitively confirmed for this review. The veracity of the mineral content to support the claim of demineralization of our food sources should be verified, particularly since farming methods and nutrient fertilization has undoubtedly advanced in the last 50 years."

https://www.mdpi.com/2072-6643/10/9/1202 [2795]

"Magnesium is a cofactor in >300 enzymatic reactions. Magnesium critically stabilizes enzymes, including many ATP-generating reactions. ATP is required universally for glucose utilization, synthesis of fat, proteins, nucleic acids and coenzymes, muscle contraction, methyl group transfer and many other processes, and interference with magnesium metabolism also influences these functions. Thus, one should keep in mind that ATP metabolism, muscle contraction and relaxation, normal neurological function and release of neurotransmitters are all magnesium dependent. It is also important to note that magnesium contributes to the regulation of vascular tone, heart rhythm, platelet-activated thrombosis and bone formation."

And their Table 3 lists a few of the enzyme functions...

Kinases B
Hexokinase
Creatine kinase
Protein kinase
ATPases or GTPases
Na+ /K+-ATPase
Ca2+-ATPase
Cyclases
Adenylate cyclase
Guanylate cyclase
Direct enzyme activation
Phosphofructokinase
Creatine kinase
5-Phosphoribosyl-pyrophosphate synthetase
Adenylate cyclase
Na+/ K+-ATPase

...membrane functions...

Cell adhesion
Transmembrane electrolyte flux

...as a calcium antagonist...

Muscle contraction/relaxation
Neurotransmitter release
Action potential conduction in nodal tissue

...and with structural functions in...

Proteins
Polyribosomes
Nucleic acids
Multiple enzyme complexes
Mitochondria

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4455825/ [2796]

The Defendant therefore believes that the nutritional quality of mass-produced foods has declined as the quantity has increased, and that this is not against the interests of the producers. Indeed isn't the western deity of all our beverages full of empty calories?



As Lieber points out:

"Nutritional approaches can help prevent or ameliorate alcoholic liver disease. For example, a complete balanced diet can compensate for general malnutrition."

and

"Pure alcohol provides approximately 7.1 kilocalories per gram (kcal/g), compared with 4 kcal/g for carbohydrates. Thus, a 12-oz can of beer contains approximately 100 calories.

"At least under certain conditions, however, alcohol-derived calories when consumed in substantial amounts can have less biologic value than carbohydrate-derived calories, as shown in a study in which Pirola and Lieber (1972) compared the weights of two groups of participants who received balanced diets containing equal numbers of calories. In one of the groups, 50 percent of total calories was derived from carbohydrates, whereas in the other group the calories were derived from alcohol.

"Although all participants received the same number of calories, those in the alcohol group exhibited a decline in body weight compared with those in the carbohydrate group. Moreover, when the participants received additional calories in the form of alcohol, they did not experience any corresponding weight gain. This suggests that some of the energy contained in alcohol is 'lost' or 'wasted'—that is, it is not available to the body for producing or maintaining body mass. Under other conditions, however, alcohol-derived calories have the same biologic value as calories derived from other nutrients. The various mechanisms involved and the circumstances in which alcohol calories fully count or do not count are described in detail elsewhere (Lieber 1991a).

"Several mechanisms have been implicated in the apparent loss of alcohol-derived energy (Feinman and Lieber 1998). For example, some of the energy may be used up (wasted) during the breakdown of alcohol by a pathway known as the microsomal ethanol-oxidizing system (MEOS). (For more information on this system, see the section 'Relationships Between Nutritional Factors and Alcohol Metabolism,' below.) As described later in this article, alcohol may damage the liver cells’ mitochondria—small membrane-enclosed cell structures that serve as the cell’s power plants—and these damaged mitochondria may waste energy during the breakdown of fats." [787]

In fact

"Researchers worldwide published a record 4,300+ scientific papers on the subject of cannabis, according to the results of a keyword search of the National Library of Medicine/PubMed.gov website.

"This exceeds the total number of papers published during all of last year [i.e. 2021], when scientists published over 4,200 papers. At the time, that total was the highest number of cannabis-specific papers ever published in a single year.

"Since 2010, scientists have published over 30,000 peer-reviewed papers specific to cannabis, with the annual number of total papers increasing every year. By comparison, researchers published fewer than 3,000 total papers about marijuana in the years between 1990 and 1999 and fewer than 2,000 total studies during the 1980s.

"'Despite claims by some that marijuana has yet to be subject to adequate scientific scrutiny, scientists’ interest in studying cannabis has increased exponentially in recent years, as has our understanding of the plant, its active constituents, their mechanisms of action, and their effects on both the user and upon society,' NORML’s Deputy Director Paul Armentano said. 'It is time for politicians and others to stop assessing cannabis through the lens of "what we don’t know" and instead start engaging in evidence-based discussions about marijuana and marijuana reform policies that are indicative of all that we do know.'"
https://norml.org/blog/2022/12/27/record-number-of-science-papers-published-about-cannabis-in-2022/ [2064]

In 1991, what did the Slovenian inheritors of the international drug treaties of 1925, 1961 and 1971 know about the anti-emetic properties of cannabis?

Let us take a note of the dates of some papers referred to "Regulation of nausea and vomiting by cannabinoids and the endocannabinoid system" from North American authors Sharkey et al (2013):

"In clinical trials, cannabis-based medicines have been found to be effective anti-emetics and even surpass some modern treatments in their potential to alleviate nausea (Cotter, 2009; Tramèr et al., 2001). However, it was not until the early 1990s that the mechanism of action of cannabis was established following the cloning of the “cannabinoid” (CB) receptors (Howlett et al., 2002; Pertwee et al., 2010). The significance of this discovery was enhanced when it was realized that these receptors were part of an endogenous cannabinoid (endocannabinoid) system in the brain and elsewhere in the body (Di Marzo and De Petrocellis, 2012; Izzo and Sharkey, 2010; Mechoulam and Parker 2013; Piomelli, 2003). The endocannabinoid system serves to modulate the expression of nausea and vomiting when activated by central or peripheral emetic stimuli (Darmani and Chebolu, 2013; Parker et al., 2011)."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3883513/ [2043]

Does the Town Smell make me nauseous? I am not Slovenian, so yes.

If you had asked any of the authors of these international drug treaties, or the authors of the ZPPPD, about the effects of banning cannabis for people affected by Ptuj Town Smell or other nauseating experiences such as imbalances in microbiota caused by alcohol consumption or undesirable ratios of exogenous lipids in foodstuffs on the marketplace, they wouldn't have been able to refer to any of these papers would they?

But what do you think they would have said if you had asked them?

If you had gone to them and said, look, we've got people feeling queasy every time they go out of the house. We've got this Town Smell in Ptuj and we just can't do without it. We just can't stop it, they say, and you say why not. And they say "Because it's Ptuj."

So you say, well what about smoking cannabis to reduce the nausea and also block out the smell seeping into your home? What would they say?

When the ZPPPD was introduced, would the authors have been able to take into account results showing

"...that perturbation of bile acid homeostasis upon alcohol exposure is mediated by activation of Cb1r and its downstream effectors like phosphorylation of JNK signaling pathway and subsequent activation of Crebh."

or

" that under normal conditions insulin plays a crucial role in maintaining bile acid homeostasis via regulation of Crebh transcriptional activity."
https://www.researchgate.net/publication/253336408_Hepatic_Cannabinoid_Receptor_Type_1_Mediates_Alcohol-Induced_Regulation_of_Bile_Acid_Enzyme_Genes_Expression_Via_CREBH/link/00b7d5200f5e64016f000000/download [2046]

That was 2013. The experts you believe in already know about that in 1925, 1961 or 1971 or 1991 or when the ZPPPD was written in 1999?

And they couldn't have known in 1999 that

"Clearly, low doses of CB1 agonists (0.5 mg/kg Δ9-THC, Limebeer and Parker, 1999; 0.001–0.01 HU-210, Parker et al., 2003) attenuate nausea in the conditioned gaping model, an effect that is reversed by rimonabant (see Parker et al., 2011). At low doses (1–5 mg/kg, i.p.) the nonpsychoactive phytocannabinoid, CBD, also reduces these nausea-induced behaviors (without affecting any measures of motor activity) by its action as an indirect agonist of 5-HT1A receptors in the dorsal raphe nucleus (Rock et al., 2012; Parker et al., 2011). By acting as an agonist of the somatodendritic 5-HT1A autoreceptors located in the dorsal raphe, CBD would be expected to reduce the release of 5-HT in forebrain regions (e.g. possibly the interoceptive insular cortex, Tuerke et al., 2012a) to ultimately suppress toxin-induced nausea." [2043]

As the authors explain:

"These contextually elicited conditioned gaping or retching reactions represent animal models of anticipatory nausea analogous to that experienced by human chemotherapy patients, which can be produced following 3–4 conditioning trials. In human chemotherapy patients, when anticipatory nausea develops, the classic anti-emetic agent ondansetron is ineffective in reducing this symptom (Hickok et al., 2003); likewise rats and shrews pretreated with ondansetron do not show a suppression of contextually-elicited gaping and retching reactions, respectively (Limebeer et al., 2006; Parker and Kemp, 2001; Parker et al., 2006; Rock et al., 2008). On the other hand, Δ9- THC, URB597 and CBD all reduce these contextually-elicited conditioned nausea reactions (Parker et al., 2011). More recently, it has been shown that CBDA (Bolognini et al., 2012) were more potent than CBD and Δ9-THC respectively in attenuation of contextually-elicited conditioned gaping in rats. CBDA potently suppresses nausea and vomiting in a 5-HT1A receptor dependent manner (Bolognini et al., 2012). Since these compounds are both non-psychoactive, they are promising candidates for the treatment of anticipatory nausea, as there is no current therapeutic available once anticipatory nausea does develop. Currently, patients are given non-specific anti-anxiety drugs."

The authors do not explain why they think these psychoactive properties are unwanted. They may be unwanted. Or they may be a bonus. People do have the right to buy decaf and alkoholfrei also. The takeup is not great.

It's not up to these researchers to decide people shouldn't be happy as well as enjoying these particular benefits of, but not limited to, CBDA, which by the way is not available as an anti-nausea drug in Slovenia anyway, except as one of many useful components of cannabis.

The authors seem happy to have discovered a component incapable of making the patient happy. And the experts you believe in couldn't have known that as of 2016 that

"The integrity of the gastric mucosa is maintained due to a balance between ‘mucosal aggressive factors’ and the so called ‘gastric mucosal protective mechanisms’. The gastric mucosa is constantly exposed to high concentrations of luminal acid. Other aggressive factors in the lumen are pepsins, bile refluxed from incompetent pyloric sphincter, bacteria, ethanol and drugs especially the non-steroidal anti-inflammatory drugs (NSAIDs) capable of inhibiting the synthesis of cytoprotective prostaglandins. The mucosa's ability to withstand acid and other injurious agents is due to several mechanisms collectively is known as the gastric mucosal barrier. The mucus-bicarbonate layer together with surface-active phospholipids barrier constitute the first line of defence or the pre-epithelial barrier. The surface epithelial cells capable of rapid turnover and migration (restitution) and releasing mucins, bicarbonate, phospholipids, prostaglandins, trefoil peptides form the second line of defence. Other important defence mechanisms of gastric mucosa are cytoprotective prostaglandins, mucosal sulfhydryl content, adequate mucosal blood flow, and sensory afferent innervations. The development of gastric mucosa damage implies a breach in the balance between aggressive and defencive factor."

They couldn't have known anything about the mechanisms by which cannabis strengthens gastric mucosal defences?

"Several mechanisms are likely to account for the ability of Cannabis or individual cannabinoid agonists to protect the stomach against noxious injury. Cannabis and/or individual cannabinoids inhibit gastric acid secretion, thereby, lessening the ability of this most powerful aggressive factor to threaten the gastric mucosa. Studies also indicated that Cannabis administration increases mucus secretion in the gastric mucosa. Mucus is secreted by the mucous neck and surface epithelial cells and plays an important role in protecting the surface epithelial cells from luminal acid and other injurious agents. Mucus retards diffusion of luminal acid into the mucosa and together with bicarbonate secreted by the epithelium forms a pH gradient with near-neutral pH at the surface of the mucosa.

"Luminal pepsins constitute an important aggressive factor capable of digesting mucus and thereby increasing the susceptibility of gastric mucosa to other injurious factors. Studies in pylorus-ligated rats treated with Cannabis extract for 4 weeks indicated that Cannabis did not affect basal pepsin secretion. Cannabis, however, decreased pepsin secretion when the stomach is stimulated with pentagastrin and carbachol. Cannabis also decreased pepsin secretion following ethanol administration in rats.

"Reactive oxygen intermediates have been implicated in the development of gastric mucosal injury due to ischaemia/reperfusion, ethanol, NSAIDs, and bacteria. Cannabis has been shown to decrease lipid peroxidation and to increase reduced glutathione content and catalase activity in gastric mucosa. Cannabis also inhibited mucosal nitric oxide. Although a vasodilator effect of physiological concentrations of nitric oxide help the mucosa to withstand noxious challenge, high concentrations are likely to have a damaging effect. Cannabis thus might protect the gastric mucosa by virtue of an antioxidant action.

"Mucosal inflammation plays an important role in the development of gastric ulcers and although initial inflammatory response to the gastric mucosa helps to minimize or limit tissue damage, an exaggerated or uncontrolled response is detrimental to the mucosal integrity. Cannabis has been shown to inhibit the pro-inflammatory cytokine tumour necrosis factor-alpha in mucosal homogenates, an action which might help to minimize the extent of mucosal damage.

"Cannabis thus exerts antioxidant and anti-inflammatory effects in the gastric mucosa. It is to be noted, however, that these actions of Cannabis were evident only when the gastric mucosa was challenged with increased acid secretion or after exposing the mucosa to noxious agents such as acidified aspirin and ethanol and were not apparent under basal conditions.

"One important factor in determining the ability of the gastric mucosa to resist gastric acid and other noxious agents is gastric mucosal blood flow. This has been inferred from studies showing that interference with the blood supply to the mucosa i.e. ischaemia resulted in the development of gastric mucosal damage or aggravated the extent of mucosal damage evoked by NSAIDs or ethanol On the other hand, agents which increase gastric mucosal blood flow such as isoproterenol, vasodilator prostaglandins or capsaicin-type agents helped to protect against noxious challenge. In this context, data have been provided that the endocannabinoid anandamide increases gastric mucosal blood flow. There is also an evidence for a vaso-relaxant action for methanandamide in rat gastric arteries. This effect was independent of cannabinoid receptors. It is thus possible that a vasodilatory action is involved in the gastric protective effects of Cannabis and or cannabinoids."
https://www.sciencedirect.com/science/article/pii/S1995764516300712#bib54 [2047]

So now you're a bit more up to date on the role cannabis can play in these gastric mucosal protective mechanisms, at least up to May 2016, do you say this has all been considered and taken into account in your operations under the ZPPPD?

Now if cannabis helps gastric mucosal protective mechanisms, and someone has some cannabis and Mr Teodorovic or the Police or the Republic of Slovenia steal or confiscate someone's cannabis, or a population's cannabis, what would you expect the effect would follow from the removal of that cannabis on those gastric mucosal protective mechanisms on that person or population?

In fact it would be worse for a population than a single person, wouldn't it?

And there would be no difference between it being taken by a burglar or by the government, would it?

Since 2016 how long have Slovenia's experts had to investigate these negative effects of the ZPPPD on gastric mucosal protective mechanisms?

And what evidence can you offer about these investigations?

What do you think the authors of the international drug control treaties would have said at the time about cannabis and gut motility?

Wasn't the British Empire pro-dysentery, pro-cholera, for the black people?

Surely it would have been their own fault in colonial India? Would they have tried cannabis to treat dysentery in white patients?

Staff Surgeon S J Rennie of the Cawnpore (now Kanpur) Hospital reports unanimous success with treatment in a dozen or more such individuals, reporting four of his case histories in detail in the Indian Medical Gazette in December 1886 under the title "On the Therapeutic Value of Tinctura Cannabis Indica in the Treatment of Dysentery".
https://pmc.ncbi.nlm.nih.gov/articles/PMC5000962/ [4883]

General Smuts could not have known, could he, that as reported by Izzo et al in the AGA journal Gastroenterology in 2003:

"Previous studies have shown that activation of enteric CB1 inhibits esophageal and gastrointestinal motility, including in isolated human tissues, and in an experimental model of diarrhea in the mouse. In this study, we were able to show that the nonselective cannabinoid receptor agonist CP55,940 and the selective CB1 receptor agonist ACEA decreased CT-stimulated fluid accumulation in the mouse small intestine. The antidiarrheal effect of the cannabinoid agonists examined here is very likely mediated uniquely by CB1 receptors because: (1) the effect of both CP55,940 and ACEA was counteracted by the selective CB1 receptor antagonist SR141716A; (2) the CB2 receptor antagonist SR144528 did not modify the antisecretory effect of CP55,940; (3) the CB1 selective agonist ACEA reduced CT-stimulated fluid accumulation; and (4) the CB2 receptor agonist JWH-015 was without effect."
https://www.gastrojournal.org/article/S0016-5085(03)00892-8/fulltext [4884]

Statistics strongly supportive of an association between marijuana use and improved gut motility can be found in a nationwide US survey of 9645 adults 20-59 in 2019 by North Shore Medical Center, Salem, Massachusetts and Massachusetts General Hospital, Boston:

"Recent MJ use was associated with a 30% decreased odds of constipation (crude odds ratio: 0.71 [0.56–0.98], P = 0.005), which persisted after stepwise adjustment for age and other demographic factors including sex, ethnicity, education, body mass index, and socioeconomic status (AOR: 0.64 [0.49–0.83], P = 0.001); comorbidities, substance use (alcohol, tobacco, heroin, and cocaine), constipating medications, general health condition, rigorous physical activity, and emotional disturbances (AOR: 0.68 [0.48–0.93], P = 0.016); and diet (AOR: 0.68 [0.52–0.89], P = 0.006). There was no association between recent MJ use and diarrhea."
https://journals.lww.com/ajg/Abstract/2019/12000/Relationship_Between_Recreational_Marijuana_Use.15.aspx [785]

In "The effects of D9 -tetrahydrocannabinol and cannabidiol alone and in combination on damage, inflammation and in vitro motility disturbances in rat colitis" (2010) by Jamontt et al at the School of Life Sciences, University of Hertfordshire

"The 2,4,6-trinitrobenzene sulphonic acid (TNBS) model of acute colitis in rats was used to assess damage, inflammation (myeloperoxidase activity) and in vitro colonic motility. Sulphasalazine was used as an active control drug.

"Key results: Sulphasalazine, THC and CBD proved beneficial in this model of colitis with the dose-response relationship for the phytocannabinoids showing a bell-shaped pattern on the majority of parameters (optimal THC and CBD dose, 10 mg.kg(-1)). THC was the most effective drug. The effects of these phytocannabinoids were additive, and CBD increased some effects of an ineffective THC dose to the level of an effective one. THC alone and in combination with CBD protected cholinergic nerves whereas sulphasalazine did not.

"Conclusions and implications: In this model of colitis, THC and CBD not only reduced inflammation but also lowered the occurrence of functional disturbances. Moreover the combination of CBD and THC could be beneficial therapeutically, via additive or potentiating effects."
https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC2931570&blobtype=pdf [2939]

In a murine colitis model, Yekhtin et al (2022) found "Differential Effects of D9 Tetrahydrocannabinol (THC)- and Cannabidiol (CBD)-Based Cannabinoid Treatments on Macrophage Immune Function In Vitro and on Gastrointestinal Inflammation in a Murine Model" and this was the Dextran sulfate sodium (DSS)-induced colitis model. DSS is a sulfated polysaccharide. Administration of DSS in mice causes human ulcerative colitis-like pathologies due to its toxicity to colonic epithelial cells, which results in compromised mucosal barrier function.

"...aimed to evaluate the effects of the phytocannabinoids D9 tetrahydrocannabinol (THC) and cannabidiol (CBD) on macrophage activation. Macrophages from young and aged C57BL/6 mice were activated in vitro in the presence of pure cannabinoids or cannabis extracts. The phenotype of the cells, nitric oxide (NO•) secretion, and cytokine secretion were examined."

The treated mice did well and

"We identified higher activity of cannabis extracts as compared with pure cannabinoids. Each treatment had a unique effect on cytokine composition. Overall, our results establish that the effects of cannabinoid treatments differ."

They explain

"Immunological dysregulation in IBD is characterized by epithelial damage, expansion of inflammation driven by intestinal flora, a large number of cells infiltrating into the lamina propria, and a failure of immune regulation to control the inflammatory response. In IBD patients, the number of macrophages increase in the inflamed mucosa."

and

"Phytocannabinoids, the biologically active constituents of cannabis, possess a wide range of immune regulatory properties, mediated by the endocannabinoid system."

and as regards the two best known:

"D9 tetrahydrocannabinol (THC) and cannabidiol (CBD). THC and some of the other phytocannabinoids mediate their biological effects primarily through the classical cannabinoid receptors CB1 and CB2. In addition, THC can act as an agonist of the receptors/channels GPR55, GPR18, PPARγ, transient TRPA1, TRPV2, TRPV3, and TRPV4, and as an antagonist of the receptors/channels TRPM8 and 5-HT3A. Interestingly, although CBD affects the immune function, it has a very weak affinity to CB2 or CB1, where it can act as a negative allosteric modulator. Several reports have demonstrated that CBD acts as an agonist of other receptors/channels, such as TRPA1, TRPV1, TRPV2, TRPV3, PPARγ, and 5-HT1A, and as an antagonist of the receptors GPR55, GPR18, and 5-HT3A. CBD is also an inverse agonist of the receptors GPR3, GPR6, and GPR12."

and again

"Cannabis extracts and pure cannabinoids were used in a concentration of 5 µg/mL; the extracts had stronger effect than the pure cannabinoids, although cannabinoids constituted only 35–38% of their content. This could result either from inhibitory signaling of other molecules in the plant (not THC/CBD) or from a synergistic function of THC/CBD with other molecules."

and broadly their results showed

"Cannabinoid Treatments Reduce Nitric Oxide and Cytokine Production of LPS-Activated Peritoneal Macrophages....Cannabinoid Treatments Affect the Phenotype of Activated Peritoneal Macrophages....Cannabis Extracts Have Improved Effect in Murine Colitis DSS Model Mice as Compared with Pure Cannabinoids....Cannabinoid Treatments Reduce Intestinal Macrophage Infiltration and the Levels of Inflammatory Cytokines in the Plasma of DSS Mice".
https://www.mdpi.com/2227-9059/10/8/1793/pdf?version=1658831384 [2938]

For Becker et al (2020) one model of colitis was not enough.

"Female C57BL/6 mice were treated with either cannabidiol [CBD], Δ 9-tetrahydrocannabinol [THC], a combination of CBD and THC, or vehicle, in several models of chemically induced colitis. Clinical parameters of colitis were assessed by colonoscopy, histology, flow cytometry, and detection of serum biomarkers; single-cell RNA sequencing and qRT-PCR were used to evaluate the effects of cannabinoids on enterocytes. Immune cell transfer from CB2 knockout mice was used to evaluate the contribution of haematopoietic and non-haematopoietic cells to colitis protection.

"Results: We found that THC prevented colitis and that CBD, at the dose tested, provided little benefit to the amelioration of colitis, nor when added synergistically with THC. THC increased colonic barrier integrity by stimulating mucus and tight junction and antimicrobial peptide production, and these effects were specific to the large intestine. THC increased colonic Gram-negative bacteria, but the anti-colitic effects of THC were independent of the microbiome. THC acted both on immune cells via CB2 and on enterocytes, to attenuate colitis."

"Conclusions: Our findings demonstrate how cannabinoid receptor activation on both immune cells and colonocytes is critical to prevent colonic inflammation. These studies also suggest how cannabinoid receptor activation can be used as a preventive and therapeutic modality against colitis."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218712/ [2940]

From the Institute of Experimental and Clinical Pharmacology, Medical University of Graz, a summary of important and recent findings on the role of cannabinoid receptors and their ligands in the GI tract with emphasis on GI disorders, such as irritable bowel syndrome, inflammatory bowel disease and colon cancer:

"In ancient medicine, extracts of the marijuana plant Cannabis sativa were used against diseases of the gastrointestinal (GI) tract....After many anecdotal reports suggested beneficial effects of Cannabis in GI disorders, it was not surprising to discover that the GI tract accommodates and expresses all the components of the ECS. Cannabinoid receptors and their endogenous ligands, the endocannabinoids, participate in the regulation of GI motility, secretion, and the maintenance of the epithelial barrier integrity. In addition, other receptors, such as the transient receptor potential cation channel subfamily V member 1 (TRPV1), the peroxisome proliferator-activated receptor alpha (PPARα) and the G-protein coupled receptor 55 (GPR55), are important participants in the actions of CBs in the gut and critically determine the course of bowel inflammation and colon cancer."



"The FAAH enzyme...seems to be a key molecule for the regulation of endocannabinoid levels and colon motility, but not for GI pain sensation."

"So far, the human studies indicate increased endocannabinoid activity in colon cancer while the role of CB receptors remains less clear.

"Cannabinoids reduce carcinogenesis in animal models of colon cancer"

"The GI tract is one of the regions where cannabinoid signaling is involved in many physiological and pathophysiological regulatory mechanisms, this is now clearly understood."

"From a scientist's perspective and all the caveats in mind, it seems to be a matter of time when cannabinoid compounds will be used in the treatment of GI disease."



"A large number of studies have confirmed that the ECS is crucially involved in the control of motility, secretion and mucosal integrity of the gut and may even determine the course of intestinal inflammation and cancer."

"From a scientist's perspective and all the caveats in mind, it seems to be a matter of time when cannabinoid compounds will be used in the treatment of GI disease."

Just hang on, they're saying. They might be able to agree with something involving cannabis during my lifetime, just don't go doing anything like treating yourself without them.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5130148/ [433]

And from a 2021 review:

"A database search of peer reviewed articles published in English as full texts between January 1970 and April 2021 in Google Scholar, MEDLINE, PubMed and Web of Science was undertaken. References of relevant literature were searched to identify additional studies to construct a narrative literature review of oncological effects of cannabinoids in pre-clinical and clinical studies in various cancer types.
https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8310855/ [5131]

In 2018 Ferro et al demonstrated a threefold increase in survival in a mouse model of pancreatic cancer

"...inhibition of the G protein-coupled receptor GPR55, using genetic and pharmacological approaches, reduces pancreatic cancer cell growth in vitro and in vivo and we propose that this may represent a novel strategy to inhibit pancreatic ductal adenocarcinoma (PDAC) progression. Specifically, we show that genetic ablation of Gpr55 in the KRASWT/G12D/TP53WT/R172H/Pdx1-Cre+/+ (KPC) mouse model of PDAC significantly prolonged survival. Importantly, KPC mice treated with a combination of the GPR55 antagonist Cannabidiol (CBD) and gemcitabine (GEM, one of the most used drugs to treat PDAC), survived nearly three times longer compared to mice treated with vehicle or GEM alone. Mechanistically, knockdown or pharmacologic inhibition of GPR55 reduced anchorage-dependent and independent growth, cell cycle progression, activation of mitogen-activated protein kinase (MAPK) signalling and protein levels of ribonucleotide reductases in PDAC cells. Consistent with this, genetic ablation of Gpr55 reduced proliferation of tumour cells, MAPK signalling and ribonucleotide reductase M1 levels in KPC mice. Combination of CBD and GEM inhibited tumour cell proliferation in KPC mice and it opposed mechanisms involved in development of resistance to GEM in vitro and in vivo. Finally, we demonstrate that the tumour suppressor p53 regulates GPR55 protein expression through modulation of the microRNA miR34b-3p."
https://www.nature.com/articles/s41388-018-0390-1 [1769]

THC was not tested in this paper.

"Cannabinoids in the landscape of cancer" by Mangal et al (2021) presents in vitro and in vivo studies on pancreatic adenocarcinoma:

"Phyto-, endogenous and synthetic cannabinoids demonstrated antitumour effects both in vitro and in vivo. However, these effects are dependent on cancer type, the concentration and preparation of the cannabinoid and the abundance of receptor targets. The mechanism of action of synthetic cannabinoids, (−)-trans-Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) has mainly been described via the traditional cannabinoid receptors; CB1 and CB2, but reports have also indicated evidence of activity through GPR55, TRPM8 and other ion channels including TRPA1, TRPV1 and TRPV2.

"Cannabinoids have shown to be efficacious both as a single agent and in combination with antineoplastic drugs. These effects have occurred through various receptors and ligands and modulation of signalling pathways involved in hallmarks of cancer pathology."
https://link.springer.com/content/pdf/10.1007/s00432-021-03710-7.pdf#page=6.32 [786]

In 2019, a "Flavonoid Derivative of Cannabis Demonstrates Therapeutic Potential in Preclinical Models of Metastatic Pancreatic Cancer"

"This study reports on a new non-cannabinoid, non-psychoactive derivative of cannabis, termed FBL-03G, with the potential to treat pancreatic cancer. In vitro results show major increase in apoptosis and consequential decrease in survival for two pancreatic cancer models- Panc-02 and KPC pancreatic cancer cells treated with varying concentrations of FBL-03G and radiotherapy. Meanwhile, in vivo results demonstrate therapeutic efficacy in delaying both local and metastatic tumor progression in animal models with pancreatic cancer when using FBL-03G sustainably delivered from smart radiotherapy biomaterials. Repeated experiments also showed significant (P < 0.0001) increase in survival for animals with pancreatic cancer compared to control cohorts.
https://www.frontiersin.org/articles/10.3389/fonc.2019.00660/full [2413]

At the University of Camerino, Zeppa et al (2024) were less coy about the magic ingredient of their pancreatic cancer treatment, with "Cannabigerol Induces Autophagic Cell Death by Inhibiting EGFR-RAS Pathways in Human Pancreatic Ductal Adenocarcinoma Cell Lines":

"Immunoblots evidenced a decrease in EGFR expression in PANC-1 with the higher dose of CBG, while, for MIAPaCa-2, the reduction was significant with both doses (Figure 2A). Similar results were obtained for mTOR protein expression, which was reduced especially after the treatment with the highest dose of CBG (Figure 2A). Then, total Akt and its phosphorylated form were investigated. Data showed a slight modulation of total Akt protein with CBG at a dose of 11.06 μg/mL for PANC-1 cells and a reduction of phospho-Akt (pAkt) levels after the administration of both CBG doses (Figure 2B). In MIAPaCa-2 cells, the highest dose of CBG induced a marked reduction of total Akt and a significant decrease in its phosphorylation (Figure 2B)."

https://www.mdpi.com/1422-0067/25/4/2001 [3979]

While Turgut et al (2022) found "Anti-cancer effects of selective cannabinoid agonists in pancreatic and breast cancer cells":

"We found that selective CB1/2 agonists suppressed cell proliferation, clonogenicity and induced proapoptotic function in human PANC1 pancreatic and MDA-MB-231 breast cancer cells. Based on our findings, these agonists led to the inhibition of both cell viability and clonogenic growth in a dose dependent manner. CB1/2 agonists were observed to induce intrinsic apoptotic pathway by upregulating Bax, while downregulating Bcl-2 expression levels."
https://www.elis.sk/download_file.php?product_id=7812&session_id=oh602ctcv1tfhp3l0hill6ql85 [4968]

In "Cannabinoids as Potential Therapeutic Agents in the Treatment of Pancreatic Cancer" a review by Bimonte et al (2025)...

"The search identified 46 studies, with 19 meeting the inclusion criteria (14 preclinical and 5 clinical). Preclinical studies revealed that cannabinoids, primarily Δ9‑ tetrahydrocannabinol (THC) and cannabidiol (CBD), exert anti‑tumor effects through mechanisms such as apoptosis induction, cell cycle arrest, inhibition of angiogenesis, immune modulation, and reduction of oxidative stress. Most clinical studies emphasize cannabinoids’ role in symptom management rather than direct anti‑cancer effects. A notable exception is a case series suggesting improved survival in pancreatic cancer patients using CBD, though its preliminary findings warrant further investigation."
https://ar.iiarjournals.org/content/anticanres/45/7/2719.full.pdf [5130]

In 2021 Sultan et al showed the beneficial effects of anandamide (AEA) - and by implication phytogenic THC - in lungs, colon and the mesenteric lymph nodes experimentally infected with Staphylococcal enterotoxin B (SEB).

"Upon analysis of vascular and gut leakage, we noted that anandamide significantly decreased the leakage in the lungs (Figure 2D) and the gut (Figure 2E) in the SEB + AEA group, when compared to the SEB + VEH group."

and

"To further investigate the effect of AEA on gut-associated immune responses, we analyzed the effect of AEA on the mesenteric lymph nodes (MLNs). The data showed that AEA significantly decreased the percentage and absolute numbers of CD4 + T cells, CD8 + T cells, Vβ8 + T cells, and NKT cells in the SEB + AEA group when compared to the SEB + VEH group of mice (Figure 3A–D)."

and

"Because we noted significant induction of AMPs [antimicrobial peptides] following AEA treatment, we next investigated the microbial profile in the lungs and the gut following SEB treatment. SEB treatment increased the abundance of microbiota in the lungs, and AEA significantly reversed this, as shown using Chao1 rare fraction measure (Figure 5A). Beta diversity analysis, which measured the similarity or dissimilarity between various groups, showed that all three groups were well separated, with the SEB + AEA group clustered away from the SEB + VEH group (Figure 5B). Additionally, representatives of the orders of Caulobacterales and Pseudomonodales were significantly decreased in the SEB + AEA group compared to the SEB + VEH (Figure 5C,D). To distinguish significantly altered bacteria among the three groups, linear discriminant analysis effect size (LEfSe) analysis (Figure 6A) was performed and the corresponding cladogram (Figure 6B) was generated. Data showed that there were several bacteria found to be distinctly expressed in each of the three groups. Our LEfSe analysis of the lungs indicated that beneficial bacteria, such as Muribaculaceae (s24-7), was indicated in the SEB + AEA group only. Additionally, some beneficial bacteria, such as Lachnospiraceae and Clostridia which produce butyrate, were indicated in the SEB + AEA group but not in the Naïve or the SEB + VEH group. Interestingly, some pathogenic bacteria such as Pseudomonas and Enterobacteriaceae were indicated in the SEB + VEH group only but not in the Naïve or SEB + AEA."
https://www.mdpi.com/2073-4409/10/12/3305 [2710]

The Major Histocompatibility Complex (MHC) is the cellular machinery that flags tumor cells for the immune system. However, most metastatic tumor cells have lost their MHC expression, and thus escape immune system killing. Dada et al (2022) set out an explanation of why "Specific cannabinoids revive adaptive immunity by reversing immune evasion mechanisms in metastatic tumours":

"Fascinating ethnographic and experimental findings indicate that cannabinoids inhibit the growth and progression of several categories of cancer; however, the mechanisms underlying these observations remain clouded in uncertainty. Here, we screened a library of cannabinoid compounds and found molecular selectivity amongst specific cannabinoids, where related molecules such as Δ9-tetrahydrocannabinol, cannabidiol, and cannabigerol can reverse the metastatic immune escape phenotype in vitro by inducing MHC-I cell surface expression in a wide variety of metastatic tumours that subsequently sensitizing tumours to T lymphocyte recognition. Remarkably, H3K27Ac ChIPseq analysis established that cannabigerol and gamma interferon induce overlapping epigenetic signatures and key gene pathways in metastatic tumours related to cellular senescence, as well as APM genes involved in revealing metastatic tumours to the adaptive immune response. Overall, the data suggest that specific cannabinoids may have utility in cancer immunotherapy regimens by overcoming immune escape and augmenting cancer immune surveillance in metastatic disease. Finally, the fundamental discovery of the ability of cannabinoids to alter epigenetic programs may help elucidate many of the pleiotropic medicinal effects of cannabinoids on human physiology."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10010394/ [4659]

All of these discoveries were of course made up to eight decades after the last medicolegal assessment of cannabis by the international forces of prohibition (1935).

The Court will observe that if I wait as long as the United Nations took to discover that weed isn't like heroin, for it to factor these discoveries about what I have been doing to myself for the last 47 years into international law, by the time it percolates down to tell Slovenia what the medical establishment wants it to do, I would be 123 years old before being able to legally obtain a longer, healthier life, with less fat, better immunity, and less cancer.

Slovenia can be the country that fines people and drives them out of their homes for refusing to be fat, less immune and more cancer-prone if it wants to. This obviously puts this drug laws as currently imagined in conflict with the Constitution and laws to protect the person in health matters.

If people have to go to the ECHR to get their savings back from the bank, or get compensated for losing their house over a 100 euro bill, or as in the case of the erased, to establish their citizens' rights, you can obviously expect a challenge sooner or later to this idea of punishing the self-infliction of better health.

I'm not a member of a Christian death cult. I don't have any of the things cannabis prevents, and like any reasonable person I will make the choices required to keep it that way.

While all these discoveries were being made, prohibition continued in its peaceful slumbers, and weed was still legally the same as heroin.

----------------------------------------------------------------------------

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