"The 'silent epidemic' of traumatic brain injury (TBI) has been placed in the spotlight as a result of clinical investigations and popular press coverage of athletes and veterans with single or repetitive head injuries," University of Pittsburgh/Maryland physicians Simon et al wrote in Nature Reviews Neurology in 2017.
In fact you don't need to take up arms in defence of somebody's capital or ideology, or ski, score, or smash your way towards a trophy to get a TBI. You do not have to try that hard: you can simply go to the pub or nightclub, or maybe get your traumatic brain injury waiting for a taxi. The Defendant got his for making a joke about the Town Smell at Ptuj's poetry festival.
"Neuroinflammation can cause acute secondary injury after TBI, and has been linked to chronic neurodegenerative diseases; however, anti-inflammatory agents have failed to improve TBI outcomes in clinical trials."
Their Figure 1 gives an overview of TBI.
While Table 1 shows factors modulating neuroinflammation in patients with TBI: TNF, IFNγ, IL-1β, IL-6, IL-10, IL-12p70, GM-CSF, TGFβ, CCL2 (MCP-1), CCL3 (MIP1α), CXCL8 (IL-8), microglia, astrocytes, adenosine, complement. glutamate, HMGB1, NLRP1, caspase-1, and mitochondrial DNA.
Figure 2 shows:
"Polarization of microglia and macrophages following TBI. Molecular signals from injured tissue drive phenotypic and functional responses in microglia or macrophages after traumatic brain injury (TBI). Damage-associated molecular patterns (DAMPs) released by injured neurons, and proinflammatory or oxidative mediators released by infiltrating immune cells polarize cells towards an M1-like phenotype. M1-like populations are characterized by expression of proteins such as IL-1β, TNF, IL-6, NOS2, IL-12p40, and NOX2. Molecular pathways that regulate the M1 phenotype include signal transducer and activator of transcription 1 (STAT1), interferon regulatory factor (IRF)-3/5, nuclear factor-κB (NF-κB), p50/p65 and microRNA (miR)-155. M1-like cells release proinflammatory factors and free radicals that promote neuroinflammation, oxidative stress and neurodegeneration. In response to anti-inflammatory and neurotrophic signals, microglia and macrophages can be polarized towards an M2-like phenotype, characterized by expression of proteins such as CD206, CD163, arginase-1, FCγR, Ym1, IL-10, and TGFβ. Molecular pathways that regulate M2-like phenotypic transitions include STAT6/3, IRF-4/7, NF-κB p50/p50, Nrf2 and miR-124. M2-like microglia and macrophages release anti-inflammatory and trophic factors that resolve inflammation. They have increased phagocytic activity and promote repair by modulating neurogenesis, axonal regeneration, synaptic plasticity, and angiogenesis. Microglia and macrophages demonstrate marked plasticity and can switch between M1-like and M2-like phenotypes. Following TBI, mixed phenotypes are present during the acute phase, transitioning to an M1-like-dominant phenotype in the chronic phase."
The gut-brain axis gets a mention:
"Potential involvement of the gut–brain axis. Type 17 responses are promoted by cytokines, particularly IL-1β, that are known to be released after TBI in humans, and induce CXCL8 and neutrophil recruitment. In ischaemic stroke modelled in mice, harmful IL-17 is largely produced by ‘type 17’ γδT cells that rapidly infiltrate the injured brain. These cells are strongly influenced by the remote gut environment, as shown in another mouse study in which antibiotic-induced dysbiosis of gut microbial flora resulted in protection from stroke, an effect that could be linked to reduced numbers of IL-17+ γδT cells100. The profound impact of the gut microbiome on peripheral tissue immune responses, including the CNS, is a recurring theme in immunology. Besides CNS injury, the gut–CNS communication has been suggested to influence cognition, mood and anxiety. Thus, it is possible that administration of antibiotics or changes in diet during intensive care unit hospitalization after severe TBI could inadvertently alter this gut microbiome–brain inflammation axis."
Links to adaptive immune response and the effect of secondary trauma are discussed.
"Secondary insults occur in as many as two-thirds of patients with severe TBI"
https://www.nature.com/articles/nrneurol.2017.13.pdf [2994]
According to Walah et al in 2021 "Minor Cannabinoids: Biosynthesis, Molecular Pharmacology and Potential Therapeutic Uses":
"Traumatic brain injury (TBI)—a severe clinical problem—is compounded by a lack of effective treatments and impeded intracranial metabolic waste clearance. The glymphatic system and meningeal lymphatic vessels are instrumental in TBI pathophysiology and crucial for clearing harmful substances. Cannabidiol (CBD) has the potential to address metabolic imbalances and improve cognitive functions in neurodegenerative diseases, but its specific effect on TBI remains unclear. Using a fluid percussion injury model, we adopted a comprehensive approach that included behavioral testing, various imaging techniques, and deep cervical lymph node (dCLN) ligation to evaluate CBD’s effects on neurological outcomes and lymphatic clearance in a TBI mouse model. Our results demonstrated that CBD markedly enhanced motor, memory, and cognitive functions, correlating with reduced levels of detrimental neural proteins. CBD also expedited the removal of intracranial tracers, increased cerebral blood flow, and improved tracer migration from lymphatic vessels to dCLNs. Intriguingly, CBD treatment modified aquaporin-4 polarization and diminished neuroinflammatory indicators. A key observation was that disrupting efferent lymphatic channels nullified CBD’s positive effects on waste removal and cognitive enhancements, whereas its anti-inflammatory benefits continued. This finding suggests that CBD’s ability to improve waste clearance may operate via the lymphatic system, thereby improving neurological outcomes in TBI patients. Therefore, our study underscores CBD’s potential therapeutic role in TBI management."
https://www.liebertpub.com/doi/10.1089/neu.2023.0539 [4517]
But according to MacNicol et al (2025), "Acute cannabidiol (CBD), tetrahydrocannabinol (THC) and their mixture (THC:CBD) exert differential effects on brain activity and blood flow in rats: A translational neuroimaging study":
"THC increased whole-brain FC and clustering coefficient, with elevated CBF in cortical and subcortical regions. CBD decreased FC metrics without affecting CBF, while THC:CBD induced moderate increases in both. Seed-based analysis revealed THC-driven increases in cortical-hippocampal and cortical-striatal connectivity, attenuated in the THC:CBD group. A multivariate combined analysis of FC and CBF revealed a divergent pattern of changes induced by each drug.
"Conclusions: In conclusion, we show that THC and CBD induce distinct neurophysiological profiles in rats, with THC increasing both connectivity and perfusion, moderated by CBD when combined. These findings corroborate existing knowledge about the effects of cannabinoids on the brain, while also supporting the potential of preclinical functional neuroimaging to delineate cannabinoid-induced endophenotypes, offering insights for therapeutic development."
https://pubmed.ncbi.nlm.nih.gov/40838351/ [5319]
Friedman et al (2026) also think this ratio is important, finding "The cannabidiol (CBD): Tetrahydrocanabinol (THC) concentration ratio is critical for neuroprotection and recovery following traumatic brain injury" - although the Court must be reminded many other ingredients influence effects.
In this study:
"Restored Neuroscores and vestibulomotor performance post-TBI was superior with dose ratios of CBD:THC300:1–10:1.
"THC dominant treatments resulted in early onset to spontaneous seizures post-TBI.
"Both CBD and THC were required for restored learning and memory and afford bilateral neuroprotection.
"Rescue of bilateral PV-INs with CBD dominant treatment supports their anticonvulsant effect.
"Loss of PV-INs with THC dominant treatment supports their proconvulsant effect"
"The novel object recognition memory task showed CBD300:1 treated animals had the best performance, while TBI or THC100:1 treated groups had the worst. The forced swim test (FST) revealed immobility time was highest after TBI and lowest after THC20:1 or THC100:1 treatment post-TBI. The elevated plus maze (EPM) revealed the CBD0 group spent the most time in closed arms. Both tests indicate that reduced anxiety was THC dependent. In the absence of TBI, THC20:1 treatment resulted in the highest mobility. All combinations resulted in reduced injury post-TBI but CBD10:1 and THC20:1 afforded the most protection and THC100:1 the least."
https://www.sciencedirect.com/science/article/pii/S0014488626001196?via%3Dihub [6141]
Pioneering cannabis treatment expert Dr Ben Caplan says "While intriguing, I remain cautious about extrapolating optimal ratios from experimental models to clinical practice. The complexity of TBI pathophysiology and individual patient variability make standardized ratio recommendations premature without robust human trial data."
The Court is invited to notice that nowhere does this discussion about ratios say NO cannabinoids are required for TBI prevention and recovery. Nor does it say no cannabinoids would lead to a better recovery. It only concerns which. It doesn't say the head trauma patient shouldn't be able to choose his own ratio from whatever supplies are available. It doesn't say this ratio should be decided by the law. It doesn't say the CBD:THC ratio in recreational cannabis will act any differently to the same ratio medical cannabis.
According to Lins et al, in their 2023 review "Cannabinoids in traumatic brain injury and related neuropathologies: preclinical and clinical research on endogenous, plant-derived, and synthetic compounds":
"A well-established role of the endocannabinoid system in the CNS is the suppression of both excitatory and inhibitory signaling in an activity-dependent manner, an efect mediated by AEA and 2-AG binding to CB1R in neurons. Te production of AEA and 2-AG is initiated by increased cellular fring rates and the associated elevation of intracellular Ca2+ levels within the postsynaptic neuron. AEA and 2-AG are then released from the postsynaptic cell membrane to bind CB1R on the presynaptic membrane, subsequently blocking Ca2+ channels to inhibit further neurotransmitter release. This is known as inhibitory retrograde neuromodulation. The ‘on-demand’ production of endocannabinoids allows them to act as a negative feedback mechanism in response to high levels of neural activity, a phenomenon known as depolarization-induced suppression of excitation, or depolarization-induced suppression of inhibition, depending on whether the presynaptic neuron is excitatory or inhibitory, respectively. This is relevant to TBI, where increased cellular fring and excitotoxicity are prominent pathological events, and suppression of these efects may be neuroprotective. Another important role of the end."
https://jneuroinflammation.biomedcentral.com/counter/pdf/10.1186/s12974-023-02734-9.pdf [2911]
"Upregulation of GLT-1 Expression Attenuates Neuronal Apoptosis and Cognitive Dysfunction via Inhibiting the CB1-CREB Signaling Pathway in Mice with Traumatic Brain Injury" say Bu et al (2025):
"Background: Glutamate transporter 1 (GLT-1) plays a vital role in maintaining glutamate homeostasis in the body. A decreased GLT-1 expression in astrocytes can heighten neuronal sensitivity to glutamate excitotoxicity after traumatic brain injury (TBI). Despite its significance, the mechanisms behind the reduced expression of GLT-1 following TBI remain poorly understood. After TBI, the endocannabinoid 2-arachidonoyl glycerol (2-AG) is elevated several times. 2-AG is known to inhibit key positive transcriptional regulators of GLT-1. This study aims to investigate the role of 2-AG in regulating GLT-1 expression and to uncover the underlying mechanisms involved. Methods: A controlled cortical impact (CCI) model was used to establish a TBI model in C57BL/6J mice. The CB1 receptor antagonist (referred to as AM281) and the monoacylglycerol lipase (MAGL) inhibitor (referred to as JZL184) were administered to investigate the role and mechanism of 2-AG in regulating GLT-1 expression following TBI. Behavioral tests were conducted to assess neurological functions, including the open field, Y-maze, and novel object recognition tests. Apoptotic cells were identified using the TUNEL assay, while Western blot analysis and immunofluorescence were employed to determine protein expression levels. Results: The expression of GLT-1 in the contused cortex and hippocampus following TBI showed an initial decrease, followed by a gradual recovery. It began to decrease within half an hour, reached its lowest level at 2 h, and then gradually increased, returning to normal levels by 7 days. The administration of AM281 alleviated neuronal death, improved cognitive function, and reversed the reduction of GLT-1 caused by TBI in vivo. Furthermore, 2-AG decreased GLT-1 expression in astrocytes through the CB1-CREB signaling pathway. Mechanistically, 2-AG activated CB1, which inhibited CREB phosphorylation in astrocytes. This decreased GLT-1 levels and ultimately increased neuronal sensitivity to glutamate excitotoxicity. Conclusions: Our research demonstrated that the upregulation of GLT-1 expression effectively mitigated neuronal apoptosis and cognitive dysfunction by inhibiting the CB1-CREB signaling pathway. This finding may offer a promising therapeutic strategy for TBI."
They say:
"Our results indicate that mice with TBI display short-term memory impairment and depression-like behavior, accompanied by a significant amount of neuronal apoptosis in the CA3 and DG subregions of the hippocampus. Importantly, inhibiting the CB1 receptor through the injection of AM281 significantly reduced neuronal apoptosis and abnormal behaviors while enhancing GLT-1 expression. The DG and CA3 are critical structures involved in the editing and storing of memory within the hippocampus, each with distinct cellular structures and functions. The DG plays a vital role in forming hippocampal memories by receiving information from the entorhinal cortex and transmitting it to the CA3 region, which is responsible for encoding, storing, and retrieving memories. Therefore, improving neuronal apoptosis in these specific hippocampal subregions can help mitigate memory and cognitive impairments resulting from TBI. Neuronal damage and necrosis following TBI are exacerbated by glutamate accumulation, which leads to excitotoxicity associated with downregulated GLT-1 expression. Consistent with our findings, several studies have demonstrated that increasing GLT-1 expression may provide neuroprotective effects in TBI models."
https://www.mdpi.com/2218-273X/15/10/1408 [5570]
Writing in the Journal of Psychiatry Neuroscience in 2004, Jessica E. Malberg Wyeth Research, Princeton, NJ explains:
"The relatively recent finding that the birth of new neurons (neurogenesis) occurs in the hippocampal formation throughout the lifespan of mammals and humans has changed the way we think about the adult brain and central nervous system (CNS) disease. Although cell proliferation and neurogenesis had been previously identified in the olfactory bulb and the subventricular zone of the lateral ventricle, the idea that cells were continually born in the adult hippocampus was not accepted until relatively recently. The search for factors that regulate adult hippocampal neurogenesis has produced a large and varied field of study, and a number of findings have had a significant impact on basic and clinical research in depression."
Various 2004 hypotheses about interactions between neurogenesis and antidepressants are explored. What was unproven at that time supports the view that nobody knew how SSRIs were meant to work.
https://www.jpn.ca/content/29/3/196.long [2121]
The following year, the Journal of Clinial Investigation published Jiang et al: "Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects"
"The hippocampal dentate gyrus in the adult mammalian brain contains neural stem/progenitor cells (NS/PCs) capable of generating new neurons, i.e., neurogenesis. Most drugs of abuse examined to date decrease adult hippocampal neurogenesis, but the effects of cannabis (marijuana or cannabinoids) on hippocampal neurogenesis remain unknown. This study aimed at investigating the potential regulatory capacity of the potent synthetic cannabinoid HU210 on hippocampal neurogenesis and its possible correlation with behavioral change. We show that both embryonic and adult rat hippocampal NS/PCs are immunoreactive for CB1 cannabinoid receptors, indicating that cannabinoids could act on CB1 receptors to regulate neurogenesis. This hypothesis is supported by further findings that HU210 promotes proliferation, but not differentiation, of cultured embryonic hippocampal NS/PCs likely via a sequential activation of CB1 receptors, Gi/o proteins, and ERK signaling. Chronic, but not acute, HU210 treatment promoted neurogenesis in the hippocampal dentate gyrus of adult rats and exerted anxiolytic- and antidepressant-like effects. X-irradiation of the hippocampus blocked both the neurogenic and behavioral effects of chronic HU210 treatment, suggesting that chronic HU210 treatment produces anxiolytic- and antidepressant-like effects likely via promotion of hippocampal neurogenesis."
"both the synthetic cannabinoid HU210 and endocannabinoid AEA profoundly promoted embryonic hippocampal NS/PC proliferation"
https://www.jci.org/articles/view/25509 [2124]
Measurement of neurogenesis itself went through some changes, with the challenges discussed in a 2011 Nature article.
"Type-1 cells (radial-glia-like stem cells) in the subgranular zone divide asymmetrically, maintaining their population while producing Type-2 daughter cells (neural progenitor cells). These continue to divide symmetrically as they mature into Type-3 cells (neuroblasts) and migrate into the granule cell layer. Type-4 cells, which have ceased mitosis, extend axons toward the CA3, leading to the development of mature granule cells that integrate with the mossy fiber pathway. SGZ, subgranular zone; GCL, granule cell layer; ML, molecular layer."
Papers concerning antidepressant-neurogenic effects are listed at Table 2.
In 2011 there was still some fumbling around in the dark:
"The effects of chronic stress or experimentally elevated corticosterone concentrations on dendritic atrophy and loss of synapses have been well documented in laboratory animals (Sousa et al, 2000; Vyas et al, 2002; Tata and Anderson, 2010). This atrophy can be reversed by the administration of antidepressants of multiple classes, and in fact, the behavioral effects of chronic stress and antidepressants in the sucrose consumption test and forced swim test have been found to be associated more closely with the complexity of the dendritic arbor of granule and pyramidal cells than with neurogenesis (Bessa et al, 2009). In addition, fluoxetine and paroxetine have been seen to induce mature granule cells to revert to an immature phenotype, wherein expression of c-fos and calretinin are decreased and calbindin increased to early postmitotic levels. Such changes in the expression of maturation-associated proteins might result in experimental mistaking of these granule cells for truly newborn ones. Synaptic plasticity in SSRI-treated granule cells is also altered to resemble patterns seen in immature neurons, including enhanced LTD and suppressed LTP (Kobayashi et al, 2010). This ‘dematuration’ of older granule cells to more plastic functional states may allow many of the putative cognitive processing functions of newborn neurons to be performed without requiring a high volume of new cell generation as has been proposed previously (Deisseroth et al, 2004; Wiskott et al, 2006)."
As Scott Duncan et al (2024) explain in "Cannabinoids and endocannabinoids as therapeutics for nervous system disorders: preclinical models and clinical studies":
"CB2R is upregulated during inflammation in brain tissue, predominantly in microglia, and primary brain microvascular endothelial cells (BMVECs) (Cabral et al., 2008; Ramirez et al., 2012). The addition of CB2 agonist increased transendothelial electrical resistance and upregulated tight junction proteins. CB2 agonists reduced vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 surface expression in brain microvascular endothelial cells when exposed to proinflammatory conditions (Ramirez et al., 2012)."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10664133/ [4520]
Clinical data was provided by Jerzy and Magdalena Szaflarski (2024) in "Traumatic Brain Injury Outcomes After Recreational Cannabis Use" published in Neuropsychiatric Disease and Treatment, which
"...used i2b2 (a scalable informatics framework; www.i2b2.org) to identify all patients presenting with acute TBI between 1/1/2014 and 12/31/2016, then conducted a double-abstraction medical chart review to compile basic demographic, urine drug screen (UDS), Glasgow Coma Scale (GCS), and available outcomes data (mortality, modified Rankin Scale (mRS), duration of stay, disposition (home, skilled nursing facility, inpatient rehabilitation, other)) at discharge and at specific time points thereafter. We conducted multivariable nested ordinal and logistic regression analyses to estimate associations between cannabis use, other UDS results, demographic factors, and selected outcomes.
"Results: i2b2 identified 6396 patients who acutely presented to our emergency room with TBI. Of those, 3729 received UDS, with 22.2% of them testing positive for cannabis. Mortality was similar in patients who tested positive vs negative for cannabis (3.9% vs 4.8%; p = 0.3) despite more severe GCS on admission in the cannabis positive group (p = 0.045). Several discharge outcome measures favored the cannabis positive group who had a higher rate of discharge home vs other care settings (p < 0.001), lower discharge mRS (p < 0.001), and shorter duration of hospital stay (p < 0.001) than the UDS negative group. Multivariable analyses confirmed mostly independent associations between positive cannabis screen and these post-TBI short- and long-term outcomes.
"Conclusion: This study adds evidence about the potentially neuroprotective effects of recreational cannabis for short- and long-term post-TBI outcomes."
https://www.dovepress.com/getfile.php?fileID=98051 [4521]
Bhatt et al, "Investigating the cumulative effects of Δ9-tetrahydrocannabinol and repetitive mild traumatic brain injury on adolescent rats" (2020) tell us:
"The prevalence of mild traumatic brain injury is highest amongst the adolescent population and can lead to complications including neuroinflammation and excitotoxicity. Also pervasive in adolescents is recreational cannabis use. Δ9-Tetrahydrocannabinol, the main psychoactive component of cannabis, is known to have anti-inflammatory properties and serves as a neuroprotective agent against excitotoxicity. Thus, we investigated the effects of Δ9-tetrahydrocannabinol on recovery when administered either prior to or following repeated mild brain injuries. Male and female Sprague-Dawley rats were randomly assigned to receive Δ9-tetrahydrocannabinol or vehicle either prior to or following the repeated injuries. Rats were then tested on a behavioural test battery designed to measure post-concussive symptomology. The hippocampus, nucleus accumbens and prefrontal cortex were extracted from all animals to examine mRNA expression changes (Bdnf, Cnr1, Comt, GR, Iba-1 and Vegf-2R). We hypothesized that, in both experiments, Δ9-tetrahydrocannabinol administration would provide neuroprotection against mild injury outcomes and confer therapeutic benefit. Δ9-Tetrahydrocannabinol administration following repeated mild traumatic brain injury was beneficial to three of the six behavioural outcomes affected by injury (reducing anxiety and depressive-like behaviours while also mitigating injury-induced deficits in short-term working memory). Δ9-Tetrahydrocannabinol administration following injury also showed beneficial effects on the expression of Cnr1, Comt and Vegf-2R in the hippocampus, nucleus accumbens and prefrontal cortex. There were no notable benefits of Δ9-tetrahydrocannabinol when administered prior to injury, suggesting that Δ9-tetrahydrocannabinol may have potential therapeutic benefit on post-concussive symptomology when administered post-injury, but not pre-injury."
In respect of telomeres (and see other section):
"Telomeres are evolutionarily conserved sequences of repetitive DNA at the ends of chromosomes that maintain the integrity of the genome and protect the DNA from oxidative stress (Zhu et al., 2011). While telomere shortening has been recognized as a marker of biological aging and neurodegeneration (Klapper et al., 2001), research in our laboratory has demonstrated that telomere shortening is a characteristic of mTBI and can be used as a prognostic tool in rodent models (Hehar and Mychasiuk, 2016; Wright et al., 2018). Consistent with our previous studies, RmTBI reduced telomere length but interestingly, there was no RmTBI-induced reduction in telomere length for animals who were administered THC providing further support for the therapeutic benefits of THC."
https://academic.oup.com/braincomms/article/2/1/fcaa042/5819138 [2387]
By 2022...
"Newborn neurons were identified in the neurogenic paradigm by identifying cells expressing both the neuronal specific marker NeuN and BrdU using confocal microscopy. Only the SSRI fluoxetine significantly altered the basal mitogenic and neurogenic rates in adolescent rats. Treatment with the monoamine oxidase inhibitor (MAOI) tranylcypromine (TCP) and the TCA desipramine did not alter the rate of hippocampal neurogenesis in the adolescent rats. This is consistent with human clinical observations, where only SSRIs have efficacy for treatment of depression in patients under the age of 18. In pre-adolescent rats, postnatal days 11–24, none of the drugs tested significantly altered the basal mitogenic or neurogenic rates. All of the classes of antidepressant drugs are known to induce hippocampal neurogenesis in adult rats. The mechanisms of action underlying this developmental difference in antidepressant drug action between juveniles and adults are not known."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9267057/ [2123]
The Defendant has had at least three traumatic brain injuries.
BBC News reported Oct 26 2022 that soccer referee Michael Grant died from a bleed on the brain after being hit by a football.
https://www.bbc.com/news/uk-england-lincolnshire-63392921 [1694]
Subclinical brain injury such as a period of football heading practice can cause damage. Effects of 40 headers in a 20 minute period were detectable one month later.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135427/ [772]
Heading research continues, including an MRI study "The Acute Effects of Non-concussive Head Impacts on Brain Microstructure, Chemistry and Function in Male Soccer Players: A Pilot Randomised Controlled Trial" by Delang et al (2025):
"Fifteen healthy male soccer players participated in a randomised, controlled, crossover pilot trial. The intervention was a non-concussive soccer heading task (‘Heading’) and the control was an equivalent ‘Kicking’ task. Participants underwent MRI scans ~ 45 min post-task which took ~60 min to complete. Blood was also sampled, and cognitive function assessed, pre-, post-, 2.5 h post-, and 24 h post-task. Brain chemistry: Heading increased total N-acetylaspartate (p = 0.012; g = 0.66) and total creatine (p = 0.010; g = 0.77) levels in the primary motor cortex (but not the dorsolateral prefrontal cortex) as assessed via proton magnetic resonance spectroscopy. Glutamate-glutamine, myoinositol, and total choline levels were not significantly altered in either region. Brain structure: Heading had no significant effects on diffusion weighted imaging metrics. However, two blood biomarkers expressed in brain microstructures, glial fibrillary acidic protein and neurofilament light, were elevated 24 h (p = 0.014; g = 0.64) and ~ 7-days (p = 0.046; g = 1.19) post-Heading (vs. Kicking), respectively. Brain Function: Heading decreased tissue conductivity in 11 clusters located in the white matter of the frontal, occipital, temporal and parietal lobes, and cerebellum (p’s < 0.001) as assessed via electrical properties tomography. However, no significant differences were identified in: (1) connectivity within major brain networks as assessed via resting-state functional MRI; (2) cerebral blood flow as assessed via pseudo continuous arterial spin labelling; (3) activity within electroencephalography frequencies (infra-slow [0.03–0.06 Hz], theta [4–8 Hz], alpha [9–12 Hz], or beta [13–25 Hz]); or (4) cognitive (memory) function."
https://sportsmedicine-open.springeropen.com/articles/10.1186/s40798-025-00867-0 [5091]
A 2016 Swedish paper "Serum neurofilament light protein predicts clinical outcome in traumatic brain injury" explains why they were looking for NF-L protein:
"Axonal white matter injury is believed to be a major determinant of adverse outcomes following traumatic brain injury (TBI). We hypothesized that measurement of neurofilament light protein (NF-L), a protein found in long white-matter axons, in blood samples, may serve as a suitable biomarker for neuronal damage in TBI patients....we tested our newly developed method on serial serum samples from severe TBI (sTBI) patients (n = 72) and controls (n = 35)....NF-L levels were markedly increased in sTBI patients compared with controls....Importantly, initial NF-L levels predicted poor 12-month clinical outcome."
https://www.nature.com/articles/srep36791 [775]
Some jargon: DTI is diffusion tensor imaging, NODDI is neurite orientation dispersion density imaging, GWI is the gray matter (GM)-white matter (WM) interface, and FA is fractional anisotropy.
Using newer imaging techniques, subsequent researches were able to provide further insight and, importantly, longitudinal evidence of damage from soccer heading, as reported by Columbia University in 2023:
"Compared to the baseline test results, the high-heading group (over 1,500 headers in two years) demonstrated measureable changes in brain microstructure similar to findings seen in mild traumatic brain injuries.
and
"High levels of heading were also associated with a decline in verbal learning performance on a memory test. In contrast, participants who engaged in low or no heading demonstrated an improvement in verbal learning performance over a two-year period."
and
"Dr. [Michael L] Lipton and colleagues also presented a second study in which they analyzed heading over 12 months prior to assessment with DTI and testing of verbal learning performance. The study looked at 353 amateur soccer players between the ages of 18 and 53.
"Unlike previous research that has focused on deep white matter regions, this study employed a new approach assessing change of DTI parameters to evaluate the integrity of the interface between the brain’s gray and white matter closer to the skull.
"The researchers found that the normally sharp gray matter - white matter interface was blurred in proportion to high repetitive head impact exposure, consistent with injury at the gray matter - white matter interface. Further analysis showed that the change in brain structure at the gray matter - white matter interface plays a causal role in the association of greater heading with worse cognitive performance."
https://www.columbiaradiology.org/news/soccer-heading-linked-measurable-decline-brain-function [4668]
The two studies mentioned here are "Soccer Heading Is Associated with White Matter Microstructural and Cognitive Abnormalities" and "Adverse Association of Soccer Heading with Verbal Learning (VL) is Mediated by Microstructure of the Orbitofrontal Gray Matter-White Matter Interface" (both 2023). In the first, Lipton et al say:
"We confirmed an association of higher RHI [repetitive head impacts] with worse VL (p=0.0305). High RHI was associated with lower orbitofrontal GWI FA slope (p= 0.00745). The orbitofrontal GWI FA slope was a significant mediator (p= 0.0186) of the association of higher RHI with worse VL.
"CONCLUSIONS GWI microstructure integrity in the orbitofrontal region, as quantified by FA slope, mediates the association of RHI with VL. These results support a mechanistic role for juxtacortical white matter in adverse associations of soccer RHI with worse cognitive performance."
https://translationalneuroimaging.org/wp-content/uploads/2023/12/Lipton-and-Song-Abstract.pdf [4669]
And in the second Columbia paper:
"Participants had headed 32–5400 times (median, 432 times) over the previous year. Heading was associated with lower FA at three locations in temporo-occipital white matter with a threshold that varied according to location (885–1550 headings per year) (P < .00001). Lower levels of FA were also associated with poorer memory scores (P < .00001), with a threshold of 1800 headings per year. Lifetime concussion history and demographic features were not significantly associated with either FA or cognitive performance.
"Conclusion:
Heading is associated with abnormal white matter microstructure and with poorer neurocognitive performance. This relationship is not explained by a history of concussion."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3750422/ [4670]
Understanding of the role of the neurofilaments takes us back some way. According to Hirokawa and Takeda (1998):
"Axonal caliber is a principal determinant of the conduction velocity at which nerve impulses are propagated along the axon (Gasser and Grundfest, 1939). Because NFs fill most of the space in large myelinated axons, it is natural to assume that a primary function of NFs is to determine axonal caliber. This hypothesis was supported by the analysis of a recessive mutant (Quv) in a Japanese quail that lacks NFs in axons (Yamasaki, 1991; Ohara et al., 1993) and of Peterson's mice expressing an NF-H–β galactosidase fusion protein, which completely inhibits neurofilament transport into axons (Eyer and Peterson, 1994). Loss of axonal NFs results in the failure of radial growth of axons. Recently, many studies have been conducted to determine the role of each of the NF component proteins in NF formation and in determination of the axonal caliber."
https://pmc.ncbi.nlm.nih.gov/articles/PMC2132816/ [4718]
Norgren et al in 2003 measured "Elevated neurofilament levels in neurological diseases":
"Neurofilaments, a major cytoskeletal constituent of neuronal cells, can be released into the cerebrospinal fluid during several neurodegenerative diseases. By means of a new sensitive ELISA capable of measuring 60 ng/l of neurofilament light, significant elevations were observed for different neurological disorders. Cerebral infarction presented levels of 19800+/-9100 ng/l, amyothropic lateral sclerosis 3600+/-1200 ng/l, 'relapsing-remitting' MS 2500+/-1500 ng/l, extrapyramidal symptoms 1100+/-300 ng/l, late onset AD 300+/-100 ng/l and vascular dementia 1400+/-800 ng/l. In patients with no signs of neurological diseases the upper normal level and cut-off values was determined to be below 100 ng/l. NF-L determinations will be a valuable complement in identifying neuronal degradation and can be used clinically for diagnostic and monitoring purposes."
https://pubmed.ncbi.nlm.nih.gov/14499942/ [4719]
Mechoulam et al in "Endocannabinoids and Neuroprotection" say:
"Traumatic brain injury (TBI) releases harmful mediators that lead to secondary damage. On the other hand, neuroprotective mediators are also released, and the balance between these classes of mediators determines the final outcome after injury. Recently, it was shown that the endogenous brain cannabinoids anandamide and 2-Arachidonoyl glycerol (2-AG) are also formed after TBI in rat and mouse respectively, and when administered after TBI, they reduce brain damage. In the case of 2-AG, better results are seen when it is administered together with related fatty acid glycerol esters. Significant reduction of brain edema, better clinical recovery, and reduced infarct volume and hippocampal cell death are noted. This new neuroprotective mechanism may involve inhibition of transmitter release and of inflammatory response. 2-AG is also a potent modulator of vascular tone, and counteracts the endothelin (ET-1)-induced vasoconstriction that aggravates brain damage; it may thus help to restore blood supply to the injured brain."
https://www.science.org/doi/abs/10.1126/stke.2002.129.re5 [504]
In "Beneficial Effects of Cannabis on Blood–Brain Barrier Function in Human Immunodeficiency Virus" (2021) Ellis et al in California note:
"Among persons with human immunodeficiency virus, more frequent use of cannabis was associated with better blood–brain barrier (BBB) indices. Better BBB indices were associated with lower neurofilament light in cerebrospinal fluid, suggesting that cannabis may have a beneficial impact on HIV-associated BBB injury."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246839/ [4392]
J Sebastian Eichter et al at Strasbourg University present a mixed picture in "A Systematic Review of the Complex Effects of Cannabinoids on Cerebral and Peripheral Circulation in Animal Models" (2018) - human ones are relatively uncommon.
Some highlights...
"Cannabinoids have been proven to exert vasodilation independent of the endothelium or vanilloid- and cannabinoid-receptors (Breyne et al., 2006; Ho and Gardiner, 2009; Mair et al., 2010).vanilloid- and cannabinoid-receptors (Breyne et al., 2006; Ho and Gardiner, 2009; Mair et al., 2010)."
"The CB1 receptor has otherwise been suspected to inhibit sympathetic neurogenic vasoconstrictor responses (Pakdeechote et al., 2007) and mostly shown vasodilative effects (Iring et al., 2013; Al Suleimani et al., 2015; Baranowska-Kuczko et al., 2016)."
"In an experiment on isolated cerebral arteries of the cat, vasodilation was identified specifically as a result of regulation of Ca2+-currents by increase of CB1 receptor activity through AEA (Gebremedhin et al., 1999). This showed the receptor's role in the increase of regional cerebral blood flow."
"In the perfused rabbit ear artery, Δ9-THC induced vasoconstriction (Barbosa et al., 1981). Conversely, a vasodilative effect of Δ9-THC and AEA could be shown in isolated cerebral rabbit arteries, involving the metabolism of arachidonic acid and lower doses of the molecules (Ellis et al., 1995). Vasodilatation was induced in rabbit mesenteric arteries by AEA (cyclo-oxygenase-(COX)-dependent) and Δ9-THC (COX-independent) but not in carotid arteries of rabbits (Fleming et al., 1999)."
"Vasodilation decreases peripheral resistance and increases blood flow. In the cerebral territory, this may be a protective mechanism and increase oxygen supply in case of a cerebral insult. Depending on the time-point at which vasodilation is activated, this protection may be beneficial in early stages of ischemia. If it occurs at a later stage, it might accelerate the recuperation of cerebral function."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986896/ [1643]
If I had felt cannabis was causing vasoconstriction in my head I would have stopped, wouldn't I?
In Poland, Kotańska et al (2021) show vasodilatory effects of a THC analogue via GPR18, and state that (agonist)
"...compound PSB-KD-107 demonstrated antioxidant activity at a level of 60–80% of that of ascorbic acid."
and
"did not significantly affect the ECG recording in terms of duration of the PQ interval, the QRS complex, and the QT interval."
https://www.mdpi.com/1424-8247/14/8/799 [2184]
Morales et al (2020) explain about GPR18:
"GPR18 is a G protein-coupled receptor that belongs to the orphan class A family. Even though it shares low sequence homology with the cannabinoid receptors, CB1R and CB2R, a growing body of research suggests its relationship with the endocannabinoid system, not only because it is able to recognize cannabinoid ligands, but also because of its expression and ability to heteromerize with CBRs."
GPR18 has therapeutic potential:
"Modulation of GPR18 has been associated with physiopathological processes including pain, sperm physiology, immunomodulation, intraocular pressure, metabolism or cancer."
...
"In addition, GPR18 activation by NAGly35 or (−)Δ9-tetrahydrocannabinol (Δ9-THC) has been shown to lower intraocular pressure in male mice during the day, providing a new potential therapeutic target for glaucoma. It is worth mentioning that Δ9-THC exhibits this effect through a combined action at CB1R and GPR18."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949482/ [2185]
Only eight years too late, Singh and Neary (2020) in "Neuroprotection Following Concussion: The Potential Role for Cannabidiol" announced
Concussions can result in many physiological consequences, potentially resulting in post-concussion syndrome. While impairments in cerebrovascular and cardiovascular physiology following concussion have been shown, there is unfortunately still no single treatment available to enhance recovery. CBD has been shown to influence the blood brain barrier, brain-derived neurotrophic factors, cognitive capacity, the cerebrovasculature, cardiovascular physiology, and neurogenesis, all of which have been shown to be altered by concussion. CBD can therefore potentially provide treatment to enhance neuroprotection by reducing inflammation, regulating cerebral blood flow, enhancing neurogenesis, and protecting the brain against reactive oxygen species."
And
"It is thought that when CBD is administered alongside other phytocannabinoids, such as tetrahydrocannabinol (THC or Δ9-THC), there is an entourage effect that elevates the therapeutic properties of both CBD and THC."
https://www.cambridge.org/core/journals/canadian-journal-of-neurological-sciences/article/neuroprotection-following-concussion-the-potential-role-for-cannabidiol/3D24F8E3BB6C2403B9027A183FF2B4A7 [1644]
"Cannabidiol inhibits neuronal endoplasmic reticulum stress and apoptosis in rats with multiple concussions by regulating the PERK-eIF2α-ATF4-CHOP pathway" say Yang et al (2025):
"Compared with the sham-operated rats, the rat models of MCC [multiple concussions] showed significantly increased mRNA expressions of PERK, eIF2α and CHOP and protein expressions of PERK, eIF2α, ATF4, CHOP, TRIB3, p-AKT and pro-caspase-3 in the cerebral cortex. CBD treatment, especially at the high dose, obviously increased the expression of p-Akt and lowered the expression levels of the other factors tested in the rat models. Network pharmacology analysis indicated interactions of the core targets of CBD with the factors related to endoplasmic reticulum stress and TBI, and molecular docking study showed a high binding energy of CBD with multiple factors pertaining to endoplasmic reticulum stress and apoptosis.
"Conclusions: MCC induce endoplasmic reticulum stress and apoptosis in rat brain tissues, for which CBD, especially at a high dose, provides neuroprotective effects by inhibiting endoplasmic reticulum stress and cell apoptosis."
https://pubmed.ncbi.nlm.nih.gov/40579137/ [5132]
"Cannabidiol Improves Cognitive Impairment after Traumatic Brain Injury by Attenuating Neuronal Oxidative Stress and Apoptosis via the SET/PP2A/Akt Signaling Axis" report Gao et al (2026).
"Cannabidiol alleviates cognitive impairment after traumatic brain injury in mice.
"Cannabidiol activates Akt signaling via a PI3K-independent mechanism to exert neuroprotective effects.
"SET identified as a direct CBD target modulating PP2A activity and Akt signaling.
"CBD masks the nuclear localization signal of SET, thereby promoting its cytoplasmic retention, inhibiting PP2A activity, and sustained Akt activation."
They say
"CBD can inhibit neuronal oxidative stress and apoptosis both in vivo and in vitro. Mechanistically, we identify a novel SET/PP2A/Akt signaling axis, in which CBD directly bound to SET, induced conformational changes in its nuclear localization signal and promoted its retention in the cytoplasm. Elevated cytoplasmic SET suppresses PP2A activity, activates Akt signaling pathway, and inhibits oxidative stress and pro-apoptotic cascades, promoting neuronal survival."
https://www.sciencedirect.com/science/article/abs/pii/S0944711326000061?via%3Dihub [5821]
"One of the first descriptions of this so-called “entourage effect” was proffered by Karniol and Carlini who discovered that CBD potentiated the analgesic capacity of delta-9-tetrahydrocannabinol (∆ 9 -THC) in the hot plate test."
In tests on the terpene myrcene.
"The greatest effect of myrcene occurred at the 120 min timepoint where the 1 mg/kg dose improved nociception by 211.0 ± 17.93% and the 5 mg/kg dose 269.3 ± 63.27% (Figure 1A). Focusing on the 120 min timepoint Int. J. Mol. Sci. 2022, 23, 7891 3 of 15 (Figure 1B), the analgesic effect of myrcene was blocked by pre-treatment with either the CB1-receptor antagonist AM281 (p < 0.001 one factor RMANOVA with Bonferroni’s post hoc test; n = 8 animals/group) or the CB2-receptor antagonist AM630 (p < 0.0001). Neither antagonist alone had any effect on joint pain."
However in this instance, no synergistic effect with CBD was found:
"In these experiments, a low dose of CBD, which in itself had no effect on pain and inflammation, was chosen to see if it could synergize with myrcene to augment antinociception and anti-inflammation. While myrcene alone reduced secondary allodynia and leukocyte rolling, the addition of CBD had no additional effect on these parameters (p > 0.05, Figure 3A,B)."
Of course there is nothing stopping you administering myrcene by smoking cannabis.
https://www.mdpi.com/1422-0067/23/14/7891/pdf?version=1658401613 [1666]
In "Administration of Δ9-Tetrahydrocannabinol Following Controlled Cortical Impact Restores Hippocampal-Dependent Working Memory and Locomotor Function" Song, Kong, Wang and Sanchez-Ramos tested the hypothesis that
"...administration of the phytocannabinoid Δ9-THC promotes significant functional recovery from traumatic brain injury (TBI) in the realms of working memory and locomotor function. This beneficial effect is associated with upregulation of brain 2-AG, G-CSF, BDNF, and GDNF. The latter three neurotrophic factors have been previously shown to mediate brain self-repair following TBI and stroke."
"Δ9-THC-treated mice exhibited marked improvement in performance on the Y-maze indicating that treatment with the phytocannabinoid could reverse the deficit in working memory caused by the CCI. Δ9-THC-treated mice ran on the rotarod longer than vehicle-treated mice and recovered to normal rotarod performance levels at 2 weeks. Δ9-THC-treated mice, compared with vehicle-treated animals, exhibited significant upregulation of G-CSF as well as BDNF and GDNF in the cerebral cortex, striatum, and HP. Levels of 2-AG were also increased in the Δ9-THC-treated mice."
And the experiment, which involved a reproducible brain injury known as a controlled cortical impact (CCI), showed:
"Administration of the phytocannabinoid Δ9-THC promotes significant functional recovery from traumatic brain injury (TBI) in the realms of working memory and locomotor function. This beneficial effect is associated with upregulation of brain 2-AG, G-CSF, BDNF, and GDNF. The latter three neurotrophic factors have been previously shown to mediate brain self-repair following TBI and stroke."
The authors' reference 13 reminds us also of the discovery a decade earlier by Hegde et all, that cannabinoid receptor activation leads to massive mobilization of myeloid-derived suppressor cells with potent immunosuppressive properties. [811]
https://www.liebertpub.com/doi/10.1089/can.2021.0053?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed [1523]
"THC caused induction of Myeloid-Derived Suppressor Cells (MDSCs). THC acted through CB2 receptor as pharmacological inhibitor of CB2 receptors blocked the anti-inflammatory effects. THC-treated mice showed significant alterations in the expression of miRNA (miRs) in the lung-infiltrated mononuclear cells (MNCs). Specifically, THC caused downregulation of let7a-5p which targeted SOCS1 and downregulation of miR-34-5p which caused increased expression of FoxP3, NOS1, and CSF1R. Together, these data suggested that THC-mediated alterations in miR expression in the lungs may play a critical role in the induction of immunosuppressive Tregs and MDSCs as well as suppression of cytokine storm leading to attenuation of SEB-mediated lung injury."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308536/ [1543]
"Promotion of recovery from Traumatic Brain Injury (TBI) by Granulocyte Colony-Stimulating Factor (G-CSF) treatment requires cannabinoid receptor type 2 activity" say Song et al (2025):
"Granulocyte colony-stimulating factor (G-CSF) has the capacity to enhance brain repair following various injuries to brain. G-CSF treatment after TBI in rodents has been reported to promote brain repair, hippocampal neurogenesis, and behavioral recovery. Delta9-THC treatment also enhances brain repair after TBI, and triggers upregulation of G-CSF in brain, raising the question as to whether G-CSF mediates recovery via the eCBs. A recent report revealed that pharmacological blockade of CB1 and CB2 receptors did not impede recovery from CCI. Given that pharmacological blockade of receptors has limitations, studies were conducted in mice with ablated or “knocked out” CB2R (CB2R KO mice). The hypothesis to be tested is that G-CSF enhancement of brain repair does not require activity of CB2 receptors.
"Results and discussion G-CSF administration for 3 days after CCI did not enhance recovery of balance and coordination measured on the rotometer in CB2R KO mice, unlike the beneficial effects of G-CSF treatment observed in normal control mice. Even before CCI, the CB2R mice were markedly impaired on the rotometer, suggesting that activity of CB2R is important for normal function of neural networks that mediate balance and coordination. Expression of CB2R was increased by G-CSF treatment in normal mice 3 days after CCI but not in CB2R KO mice. Interestingly, the CB1R in the CB2R KO mice was upregulated by G-CSF treatment indicating that “knocking-out” or lowering expression of CB2R did not impact expression of CB1R. Expression of the neurotrophic factors BDNF and GDNF did not change with G-CSF treatment in CB2R KO mice. Levels of the endogenous cannabinoid ligand, 2-AG, were shown to be increased by G-CSF treatment in the CB2R KO mice, but upregulation of 2-AG does not appear to promote recovery of balance and coordination. Additional studies will be required of other components of the eCBs.
"Conclusion The hypothesis that G-CSF enhancement of brain repair does not require activity of CB2 receptors is disproven by data in this report. The eCBs, in particular activity of the CB2R, is critical for G-CSF promotion of recovery of balance and coordination impaired by CCI."
https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-025-00305-8 [5313]
This is good news for anyone who has, in the course of his Slovene practice dring that decade, made a joke about Ptuj's Town Smell, and as a result been whacked in the sphenoid by a jealous coked-up sporty boy, as part of Ptuj's language-teaching scheme, and who has, as a result, suffered a stroke.
Various researchers have tried to find an association between cannabis use and stroke. But nearly all were unable to eliminate tobacco as a confounding factor. National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press" found only one that did, by Stephen Sidney:
"The relative risk associated with cannabis use was assessed by Cox proportional hazards model with adjustments for age, race, education, BMI, history of hypertension, smoking, and alcohol use. The relative risk for stroke in current users was 1.0 (95% CI = 0.5–1.9) for men and 0.7 (95% CI = 0.3–2.2) for women; in former users it was 0.8 (95% CI = 0.4–1.8) for men and 1.5 (95% CI = 0.7–3.5) for women. Both current cannabis use and former cannabis use were not associated with increased risk of stroke."
So the only tobacco-adjusted study says, in plain language, that women cannabis users will get 30% fewer strokes, men will get neither more nor fewer, and men who stop will get 20% fewer and women who stop will get 50% more. Thus NECUD is a danger to women and female former users in particular. Discussing the studies and their limitations, the NAS authors note:
"With the exception of the Sidney (2002) study, none of the studies have data on the temporal relation between the cannabis or tobacco use and the stroke. A general problem was the analytic treatment of tobacco use."
Even without this important confounder the odds ratios were modest.
https://nap.nationalacademies.org/read/24625/chapter/8#169 [1642]
But if you are unlucky and do have a stroke - let us recall the Defendant was hit on the head by a jealous coked-up sporty boy for practising his Slovene on the Town Smell - cannabis will see you through. According to de Souza Stork et al (2025), writing in Inflammopharmacology:
"Male Wistar rats were subjected to 60-min middle cerebral artery occlusion (MCAO) or sham surgery, and received FSC (15 or 30 mg/kg) or coconut oil by gavage at different time points post-MCAO. After 72 h, neurological score, infarct volume, blood cell count, thymus, spleen and adrenal gland size and weight, serum corticosterone, intestinal permeability, oxidative stress, and inflammatory cytokines in peripheral organs were assessed.
"Key findings: The results show a significant improvement in neurological deficits, suggesting the therapeutic potential of FSC in post-stroke recovery. Additionally, a reduction in body mass, a decrease in blood cells related to the immune response, and atrophy of lymphoid organs, lower corticosterone levels, and reduced intestinal permeability were observed. FSC treatment also demonstrated a crucial role in protecting against oxidative stress and post-stroke lung inflammation.
"Significance: The discovery of the positive impacts of FSC in this study represents an entry point for new explorations and perspectives within this field. With latent potential, these findings have the power to shape clinical research, especially in the realm of neurodegenerative diseases and innovative therapies. Therefore, the results highlight the promising role of FSC, paving the way for more effective and transformative clinical interventions."
https://pubmed.ncbi.nlm.nih.gov/40389682/ [5189]
"Cannabigerol Attenuates Memory Impairments, Neurodegeneration, and Neuroinflammation Caused by Transient Global Cerebral Ischemia in Mice" report Kohara et al (2025):
"This study investigated the neuroprotective mechanisms of CBG in mitigating memory impairments caused by transient global cerebral ischemia in C57BL/6 mice using the bilateral common carotid artery occlusion (BCCAO) model. Mice underwent sham or BCCAO surgeries and received intraperitoneal (i.p.) injections of either a vehicle or CBG (1, 5, or 10 mg/Kg), starting 1 h post-surgery and continuing daily for 7 days. Spatial memory performance and depression-like behaviors were assessed using the object location test (OLT) and tail suspension test (TST), respectively. Additional analyses examined neuronal degeneration, neuroinflammation, and neuronal plasticity markers in the hippocampus. CBG attenuated ischemia-induced memory deficits, reduced neuronal loss in the hippocampus, and enhanced neuronal plasticity. These findings suggest that CBG’s neuroprotective effects against BCCAO-induced memory impairments may be mediated by reductions in neuroinflammation and modifications in neuroplasticity within the hippocampus."
https://www.mdpi.com/1422-0067/26/16/8056 [5354]
In the giveaway-titled "Efficacy of Inhaled Cannabis on Painful Diabetic Neuropathy" Wallace et al at UC reveal
"The prevalence of diabetic peripheral neuropathy (DPN) appears to be increasing so that it now effects an estimated 366 million individuals worldwide. DPN occurs in approximately 50% of patients with diabetes with about 15% being painful. DPN can present in several forms ranging from mononeuropathy to distal polyneuropathy. Patients often complain of pain and hyperalgesia in their feet, usually worse at night. Other symptoms include numbness, paresthesia, sensitivity to touch, unsteadiness and weakness." [1634]
Strokes can arise from atherosclerosis or external injury, mine is in the TBI category. My neuropathy arose rather suddenly after that, so isn't redolent of the diabetic. As I was excluded from, or made a second-class non-citizen of, the health insurance system, and especially unable to argue the details with whomever didn't know what was going on, because Slovenia refuses to teach foreigners its language, until December 2020 I had no HbA1c test in Slovenia or other investigation.
So here we have a medication that could help at least 27.3 Slovenias - 55 million people globally, to take Wallace et al's estimate.
And it's illegal because an Egyptian doctor blackmailed the western powers in 1925?
It's illegal because an about-to-be out-of-work Volstead Act employee wanted to put Charlie Parker, Louis Armstrong and Thelonious Monk behind bars, and thought jazz and cannabis equalled insanity. Those are some of the reasons it's illegal?
Denying self-medication in the absence of the availability of any other medical intervention (because it's Slovenia and you don't even speak Slovene) would be a violation of the right to such treatment. So why not make it even worse for yourselves by putting a person on trial for being attacked and injured?
For depression. If you want fun, the law says, you should drink alcohol. Alcohol is an addiction-forming depressant. Even its most ardent supporters would not claim they drink because of an alcohol deficiency, or because it rectifies a chemical imbalance.
At the same time, the existence of an endocannabinoid deficiency is taboo. But there are more cannabinoid receptors in the brain than there are for all of the neurotransmitters put together. However there is no time to teach the ECS in medical schools, their curricula are too full already. https://www.leafly.com/news/science-tech/cannabis-endocannabinoid-system-in-medical-school. [505]
MDMA is very obviously a useful treatment for PTSD. Serious suicidal ideation (a score of 4 or 5 on the C-SSRS) was minimal during the study and occurred almost entirely in the placebo arm.
https://www.nature.com/articles/s41591-021-01336-3 [506]
https://cssrs.columbia.edu/wp-content/uploads/C-SSRS_Pediatric-SLC_11.14.16.pdf [3022]
In all of this, it is of tantamount importance to psychiatry and the law is that fun and health are not to be connected. Apparently, the important message to keep front and centre is the one about depression, not the one about happiness.
The safety of illegal drugs used in happiness, or amelioration of unwanted states, is not determined by their legality. They do not become safer when they are decriminalised, or less effective when outlawed. When, in 1992, the Vatican decided to admit Galileo was right, the solar system did not abandon a geocentric arrangement and reposition itself into a new legal format. In the event of future legislative changes, a return to geocentricism can be guaranteed
Cannabis has been a medicine for thousands of years [507] and the scourge of humanity for a hundred. Psychedelics have played a part in the development of civilisation, Richard Nixon and the American war effort somewhat less so.
Suicidologists in Quebec found that the devil in the weed was in the detail:
In longitudinal cross-lagged analyses, weekly cannabis use at age 15 was associated with greater odds (OR=2.19, 95% CI=1.04-4.58) of suicidal ideation two years later. However, other substance use (alcohol, tobacco, other drugs) fully explained this association.
https://www.sciencedirect.com/science/article/abs/pii/S0165032720309344?via%3Dihub [508]
"Suicidal Ideation in Medicinal Cannabis Patients: A 12-Month Prospective Study" by Lynskey et al (2024) found the kind of effect you might expect on suicidal ideas from a substance noted for its levity-promoting effects, even for users trapped in a psychiatric model:
"Observational data were available for 3781 patients at entry to treatment, 2112 at three months and 777 for 12 months. Self-reported depressed mood and SI were assessed using items from the PHQ-9. Additional data included sociodemographic characteristics and self-reported well-being.
"Results
25% of the sample reported SI at treatment entry and those with SI had higher levels of depressed mood (mean = 17.4 vs. 11.3; F(1,3533) = 716.5, p < .001) and disturbed sleep (mean = 13.8 vs. 12.2, F(1,3533) = 125.9, p < .001), poorer general health (mean = 43.6 vs. 52.2, F(1,3533) = 118.3, p < .001) and lower quality of life (mean = 0.44 vs. 0.56 (F(1,3533) = 118.3, p < .001). The prevalence of SI reduced from 23.6% to 17.6% (z = 6.5, p < .001) at 3 months. Twelve-month follow-up indicated a substantial reduction in depressed mood with this reduction being more pronounced in those reporting SI (mean (baseline) = 17.7 vs. mean (12 months) = 10.3) than in other patients (mean (baseline) = 11.1 vs. mean (12 months) = 7.0).
Thus the researchers again discovered what any fool knows:
"Treatment with CBMPs reduced the prevalence and intensity of suicidal ideation."
https://www.tandfonline.com/doi/abs/10.1080/13811118.2024.2356615 [3288]
Meanwhile, in "Matrix Metalloproteinase-9 as an Important Contributor to the Pathophysiology of Depression" Hongmin Li et al at The Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
"Among MMP members, the most important may be MMP−9. It is implicated in the remodeling and stabilization of dendritic spines, pre and post-synaptic receptor dynamics, consolidation of long term potentiation, synaptic pruning and myelin formation. MMP-9 is also involved in the sprouting, pathfinding and regeneration of axons."
As for depression:
"The role of MMP-9 in the pathology of depression. MMP-9 is elevated in endothelial cells and neutrophils during inflammation. (A) Excessive MMP-9 is thought to be involved in demyelination associated with depression. (B) MMP-9 disrupts BBB through tight junction proteins or basement membrane degradation, which increases neuroinflammation and may be linked to depression or bipolar disorders with cognitive decline. (C) Activated MMP-9 localizes in part to synapses and is involved in synaptic pruning essential for longterm potentiation (LTP), and attenuation of cortical synaptic LTP-like plasticity; collectively, these are thought to contribute to depression. (D) MMP-9 remodels perineuronal nets that participate in synaptic stabilization and limit synaptic plasticity. Depression may occur when perineuronal net signaling is aberrant."
"Domenici et al. reported that MMP-9 in serum was significantly higher in patients with major depressive disorders (n = 245) vs. controls. Rybakowski et al. performed a study on 54 in-patients with bipolar mood disorder and 29 control subjects. An increase of serum MMP-9 at the early stages of bipolar illness is found to accompany only the depressive episodes and not manic ones."
Among the human highlights
"Alaiyed et al. reported that MMP-9 levels were elevated in prefrontal cortex of antidepressant-treated patients with major depressive disorders."
and
"MMP-9 inhibitors possess potential therapeutic effects for depression."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8971905/ [1640]
"As bipolar disorder and marijuana use are individually associated with cognitive impairment, it also remains unclear whether there is an additive effect on cognition when bipolar patients use marijuana. The current study aimed to determine the impact of marijuana on mood in bipolar patients and to examine whether marijuana confers an additional negative impact on cognitive function. Twelve patients with bipolar disorder who smoke marijuana (MJBP), 18 bipolar patients who do not smoke (BP), 23 marijuana smokers without other Axis 1 pathology (MJ), and 21 healthy controls (HC) completed a neuropsychological battery. Further, using ecological momentary assessment, participants rated their mood three times daily as well as after each instance of marijuana use over a four-week period. Results revealed that although the MJ, BP, and MJBP groups each exhibited some degree of cognitive impairment relative to HCs, no significant differences between the BP and MJBP groups were apparent, providing no evidence of an additive negative impact of BPD and MJ use on cognition. Additionally, ecological momentary assessment analyses indicated alleviation of mood symptoms in the MJBP group after marijuana use; MJBP participants experienced a substantial decrease in a composite measure of mood symptoms. Findings suggest that for some bipolar patients, marijuana may result in partial alleviation of clinical symptoms. Moreover, this improvement is not at the expense of additional cognitive impairment."
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157060 [2448]
In astonishing news, science has now discovered that cannabis makes you happy, describing this in the Yale Journal of Biological Medicine (2020) as a "positive side effect".
Li et al (2020) examined "The Effectiveness of Cannabis Flower for Immediate Relief from Symptoms of Depression":
"We observed 1,819 people who completed 5,876 cannabis self-administration sessions using the ReleafApp™ between 06/07/2016 and 07/08/2019, with the goal of measuring real-time effects of consuming Cannabis flower for treating symptoms of depression. Results: On average, 95.8% of users experienced symptom relief following consumption with an average symptom intensity reduction of –3.76 points on a 0-10 visual analogue scale (SD = 2.64, d = 1.71, p <.001). Symptom relief did not differ by labeled plant phenotypes (“C. indica,” “C. sativa,” or “hybrid”) or combustion method. Across cannabinoid levels, tetrahydrocannabinol (THC) levels were the strongest independent predictors of symptom relief, while cannabidiol (CBD) levels, instead, were generally unrelated to real-time changes in symptom intensity levels. Cannabis use was associated with some negative side effects that correspond to increased depression (e.g. feeling unmotivated) in up to 20% of users, as well as positive side effects that correspond to decreased depression (e.g. feeling happy, optimistic, peaceful, or relaxed) in up to 64% of users. Conclusions: The findings suggest that, at least in the short term, the vast majority of patients that use cannabis experience antidepressant effects, although the magnitude of the effect and extent of side effect experiences vary with chemotypic properties of the plant."
and
"One of the most clinically relevant findings from this study was the widely experienced relief from depression within 2 hours or less. Because traditional antidepressants have times-to-effect in weeks, short-term Cannabis use might be a solution to these delays in treatment or could be used to treat acute episodes associated with suicidal behavior and other forms of violence."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309674/ [2447]
In 2024, Specka et al made the same discovery again, in a retrospective longitudinal 18 week study of 59 outpatients with MDD who had previously tried antidepressants - in "Effectiveness of Medical Cannabis for the Treatment of Depression: A Naturalistic Outpatient Study":
"Patients were 20-54 years old; 72.9% were male; one third reported times of regular cannabis consumption within the previous five years. Drop-out rate was 22% after 18 weeks. Mean severity of depression decreased from 6.9 points (SD 1.5) at entry to 3.8 points (2.7) at week 18 (baseline observation carried forward; 95% CI for the mean difference: 2.4 to 3.8; p<0.001). A treatment response (>50% reduction of the initial score) was seen in 50.8% at week 18. One third of patients complained about side effects, none was considered as severe. Concomitant antidepressant medication (31% of patients) was not associated with outcome."
https://pubmed.ncbi.nlm.nih.gov/38211630/ [4366]
And in fact this discovery reoccurs every now and then. In 2009 the Laboratory of Neuroendocrinology, The Rockefeller University, New York researchers Hill et al considered "The therapeutic potential of the endocannabinoid system for the development of a novel class of antidepressants", stating:
"Substantial evidence has accumulated implicating a deficit in endocannabinoid in the etiology of depression; accordingly, pharmacological augmentation of endocannabinoid signaling could be a novel target for the pharmacotherapy of depression. Within preclinical models, facilitation of endocannabinoid neurotransmission evokes both antidepressant and anxiolytic effects. Similar to the actions of conventional antidepressants, enhancement of endocannabinoid signaling can enhance serotonergic and noradrenergic transmission; increase cellular plasticity and neurotrophin expression within the hippocampus; and dampen activity within the neuroendocrine stress axis. Furthermore, limbic endocannabinoid activity is increased by both pharmacological and somatic treatments for depression, and, in turn, appears to contribute to some of the neuroadaptive alterations elicited by these treatments. These preclinical findings support the rationale for the clinical development of agents which inhibit the cellular uptake and/or metabolism of endocannabinoids in the treatment of mood disorders."
https://pubmed.ncbi.nlm.nih.gov/19732971/ [4385]
We await those clinical agents with some skepticism and trepidation and we'll just be ok with weed, thanks.
In a 2023-published longitudinal comparison of mortality rates in bipolar disorder with common causes of mortality Yocum et al at the University of Michigan began by examining deaths and associated variables among 1,128 participants who had volunteered for the program's long-term study of individuals with and without bipolar disorder."
They discovered that the 847 study participants with bipolar disorder accounted for all but two of the 56 fatalities that have occurred since the study's start in 2006. Their analysis, adjusting for statistical differences, reveals that a person with a diagnosis of bipolar disorder was six times more likely to die over a 10-year period than participants in the same study without a bipolar disorder diagnosis.
To see if they could discover the same effect, the researchers then looked to another data source. More than 18,000 patients who receive primary care from Michigan Medicine, the academic medical centre at the University of Michigan, had years' worth of anonymous patient records examined by the researchers. Those in this group who had a history of bipolar disorder had a four-fold higher risk of passing away during the study period than those who did not.
High blood pressure was the only factor in this group of individuals linked to an even higher risk of passing away during the study period. Regardless of bipolar disorder, the risk of death was five times higher for those with hypertension than for those with normal blood pressure. In contrast, regardless of bipolar status, smokers were twice as likely to die in this sample as never-smokers, and those over 60 were three times more likely to die. McInnis, a psychiatry professor at the University of Michigan Medical School, stated, "To our major surprise, in both samples we found that having bipolar disorder is far more of a risk for premature death than smoking."
https://economictimes.indiatimes.com/industry/healthcare/biotech/healthcare/bipolar-disorder-can-make-you-die-early-says-study-key-findings/bipolar-disorder-and-death/slideshow/106638965.cms [4323]
https://www.sciencedirect.com/science/article/abs/pii/S0165178123005516?via%3Dihub [4324]
It is fairly simple - the Defence hopes not simplistic - to infer that the benefits reported in [2448] will ameliorate the tendency to die reported in [4324] via positive effects on both mood and cardiometabolic stress.
It's almost as if, faced with some personal life-stress situation, Ptuj people could wait to find a doctor, then wait for a doctor's appointment, then wait for some antidepressants based on a no longer credible serotonin hypothesis to take effect.
Those seeking a more convenient route through the system could go to the pub, where they will at the very least lose some dignity, and at worst kill somebody.
Alternatively they could go and get some cannabis, which according to Li et al [2447] works immediately, altering their perception of the situation by raising their hedonic tone.
But if you insist on banning the one thing that will help without anyone getting their face smashed in, and if you insist on banning something which is impossible to ban - so drunk people in Ptuj can pick and choose enemies upon whom they can unleash their rage - ban depressed people. Not cannabis and psychedelics.
In 2022, Miranda et al found cannabis had "uniquely beneficial effects" in bipolar patients:
"Cannabis use is highly prevalent in people with bipolar disorder (BD), with many reporting using cannabis to ameliorate symptoms. These symptoms include deficits in goal-directed behaviors (i.e., decision-making and hyper-motivation) and cognitive function (i.e., attention and learning). However, chronic cannabis use is also associated with cognitive impairment, thus it is unclear to what degree cannabis is useful in ameliorating symptoms of BD. Here, we determined the effects of chronic cannabis use on goal-directed behavior and cognition that are impaired in people with BD. We recruited BD+ and BD- participants that were either cannabis users (C+) or non-users (C-). We performed a 2X2 ANOVA on interim data using BD and cannabis use as between-subjects factors on the 4 diagnostic groups: BD-/C- (n=25), BD-/C+(n-21), BD+/C- (n=8) and BD+/C+ (n=12). Participants were tested with a cognitive battery measuring risky decision-making (Iowa Gambling Task; IGT), motivation (Progressive Ratio Breakpoint Ratio Task; PRBT), reward learning (Probabilistic Learning Task; PLT) and sustained attention (5-C CPT). Overall, cannabis users were younger than non-users. Using age as a covariate, we observed BD x cannabis interaction effects on the IGT and PRBT. BD+/C+ participants showed less risk-prone behaviors on the IGT (F (1,63), p=.015, ES=.09) and normalized motivation on the PRBT (F (1,61), p=.045, ES=.065). We observed moderate effects of cannabis on punishment sensitivity (F (1,63), p=0.059, ES=0.055) and sustained attention (F (1,48), p=0.056, ES=0.074). Chronic cannabis use was associated with a modest improvement in some cognitive functions. Cannabis use was also associated with a normalization of risky decision making and effortful motivation in people with BD, but not healthy participants. Thus, chronic cannabis use may have uniquely beneficial effects in people with BD. Previous studies suggest that some people with BD have increased dopaminergic activity due to a reduced dopamine transporter expression. Chronic cannabis use has been shown to reduce dopamine release, thus chronic cannabis use may result in a return to dopamine homeostasis in people with BD and consequently normalizing their deficits in goal directed behaviors. We are engaged in additional studies that explore this potential dopaminergic/endocannabinoid mechanism."
https://www.abstractsonline.com/pp8/#!/10619/presentation/84925 [2445]
"To pin down the effects of cannabis on those with bipolar, researchers recruited people with and without the disorder, along with cannabis users and non-users in each group, analyzing each combination. Participants were tested on cognitive battery measuring risky decision-making, reward-learning, and sustained attention.
"Ultimately, researchers confirmed that cannabis indeed could hold some special benefits for those with bipolar, specifically in helping to reduce risky decision-making. Researchers also suggested that cannabis reduces the dopaminergic activity in the brain, which helps suppress symptoms, and found that cannabis had moderate effects on punishment sensitivity and sustained attention.
"'Chronic cannabis use was associated with a modest improvement in some cognitive functions,' authors noted. 'Cannabis use was also associated with a normalization of risky decision making and effortful motivation in people with [bipolar disorder], but not healthy participants. Thus, chronic cannabis use may have uniquely beneficial effects in people with [bipolar disorder].'"
https://hightimes.com/health/study-cannabis-has-uniquely-beneficial-effects-on-people-with-bipolar-disorder/ [2446]
This aligns with the metabolic overdrive hypothesis of bipolar: hyperglycolysis and
glutaminolysis in bipolar mania. According to Campbell and Campbell (2024):
"Evidence from diverse areas of research including chronobiology, metabolomics and magnetic resonance spectroscopy indicate that energy dysregulation is a central feature of bipolar disorder pathophysiology. In this paper, we propose that mania represents a condition of heightened cerebral energy metabolism facilitated by hyperglycolysis and glutaminolysis. When oxidative glucose metabolism becomes impaired in the brain, neurons can utilize glutamate as an alternative substrate to generate energy through oxidative phosphorylation. Glycolysis in astrocytes fuels the formation of denovo glutamate, which can be used as a mitochondrial fuel source in neurons via transamination to alpha-ketoglutarate and subsequent reductive carboxylation to replenish tricarboxylic acid cycle intermediates. Upregulation of glycolysis and glutaminolysis in this manner causes the brain to enter a state of heightened metabolism and excitatory activity which we propose to underlie the subjective experience of mania. Under normal conditions, this mechanism serves an adaptive function to transiently upregulate brain metabolism in response to acute energy demand. However, when recruited in the long term to counteract impaired oxidative metabolism it may become a pathological process."
https://www.openread.academy/en/paper/reading?corpusId=503098553 [4761]
"A limited number of studies consistently support the evidence for altered brain glutamate levels as measured by proton magnetic resonance spectroscopy (1H-MRS) in otherwise healthy chronic cannabis users, with all but one of the five studies indicating reduced levels of glutamate-derived metabolites Glutamate (Glu) or Glutamate + Glutamine (Glx) in both cortical and subcortical brain areas."
https://www.nature.com/articles/s41380-019-0374-8 [4760]
In a sample of 297 with a mean age below 30, Beaton et al (2016) found the illegal weed users were more sensible than the legal nicotine addicts:
"Post-hoc comparisons showed that the Control and Marijuana groups were less impulsive than the Marijuana+Nicotine, Nicotine, and Overeating groups (Table 3)."
"Impulsive Sensation Seeking (ImpSS) and Barratt's Impulsivity scales (BIS) Scales were analyzed with a non-parametric factor analytic technique (discriminant correspondence analysis) to identify group-specific traits on 297 individuals from five groups: Marijuana (n = 88), Nicotine (n = 82), Overeaters (n = 27), Marijuauna + Nicotine (n = 63), and CONTROLs (n = 37).
"Results: A significant overall factor structure revealed three components of impulsivity that explained respectively 50.19% (pperm < 0.0005), 24.18% (pperm < 0.0005), and 15.98% (pperm < 0.0005) of the variance. All groups were significantly different from one another. When analyzed together, the BIS and ImpSS produce a multi-factorial structure that identified the impulsivity traits specific to these groups. The group specific traits are (1) CONTROL: low impulse, avoids thrill-seeking behaviors; (2) Marijuana: seeks mild sensation, is focused and attentive; (3) Marijuana + Nicotine: pursues thrill-seeking, lacks focus and attention; (4) Nicotine: lacks focus and planning; (5) Overeating: lacks focus, but plans (short and long term).
"Conclusions: Our results reveal impulsivity traits specific to each group."
https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC4318510&blobtype=pdf [3922]
In similar attention to the same detail, Round et al (2020) found:
"Trait impulsivity was significantly higher in cigarette smokers than non-smokers, irrespective of cannabis use, except for motor impulsivity, where cigarette smoking was only associated with elevated trait impulsivity in non-smokers of cannabis. Dimensions of trait impulsivity were significantly positively related to cigarette smoking frequency and nicotine dependence, but not to cannabis smoking frequency or dependence. Smoking cigarettes or cannabis was associated with significantly impaired reflection impulsivity relative to not smoking either substance. However, no additional increases in reflection impulsivity were observed in those who smoked both cigarettes and cannabis. No group differences in response inhibition were detected."
Trait impulsivity in detail:
"There were significant main effects for cigarette smoking status on BIS-11 total scores (F(1, 220) = 32.76, p < .001, ηp 2 = .13), along with the attention (F(1, 220) = 15.63, p < .001, ηp 2 = .07) and non-planning subscales (F(1, 220) = 27.95, p < .001, ηp 2 = .11), such that individuals who smoked cigarettes scored significantly higher than those who did not smoke cigarettes (Figure 1(a) to (c)). No significant effects of cannabis smoking or interactions were found (all F(1, 220) < 2.27, p ⩾ .101, ηp 2 ⩽ .01). For the BIS-11 motor impulsivity subscale, there was again no significant main effect of cannabis (F < 1, p = .773, ηp 2 < .001), but a significant main effect of cigarette smoking (F(1, 220) = 19.14, p < .001, ηp 2 = .08), this time qualified by a significant cigarette smoking × cannabis smoking interaction (F(1, 220) = 5.92, p = .016, ηp 2 = .03; see Figure 1d). Cigarette smoking was again associated with higher levels of impulsivity, but simple effects analyses showed that this effect was seen in NS (p<.001), but not smokers (p = .178) of cannabis. Motor impulsivity did not differ as a function of cannabis smoking in either cigarette smokers (p = .095) or non-cigarette smokers (p=.078)."
https://journals.sagepub.com/doi/pdf/10.1177/0269881120926674?download=true [3923]
"A Naturalistic Examination of the Acute Effects of High-Potency Cannabis on Emotion Regulation Among Young Adults: A Pilot Study" by Cavalli et al (2024) made the horrifying finding that:
"Participants reported a more positive mood and decreases in anxiety while intoxicated. There was no evidence that acute high-potency cannabis affected participants' implicit or explicit emotion regulation task performance."
https://onlinelibrary.wiley.com/doi/10.1002/hup.2915 [5194]
"Potentiation of GABA by either CBD or 2-AG is selective for the α2 subunit" report Bakas et al (2017).
https://www.sciencedirect.com/science/article/abs/pii/S1043661816311392?via%3Dihub [3926]
Adolescent cannabis users showed lower GABA in a small study of just 39 subjects by Subramaniam et al in Salt Lake City, where sales of tea and coffee are presumably quite low. But:
"Assessment of impulsive behavior demonstrated no significant between-group differences in motor, non-planning, attention, and total impulsivity scores. Additionally, impulsivity measures and tissue-corrected GABA+ or Glx levels were not significantly correlated in either group."
https://www.sciencedirect.com/science/article/abs/pii/S0376871622000631 [3923]
The University of Utah is not affiliated with the LDS, but Mormon attendance is reckoned at 25-50%. Given this venue, it may be that the Mormons are increasing their impulsivity and denying themselves a good night's sleep. Tea accumulates GABA and a special process has been devised to produce high-GABA tea.
https://en.wikipedia.org/wiki/GABA_tea [3924]
Although there has been a debate about whether oral GABA can even cross the blood-brain barrier, collected studies using tea, coffee, rice and other dietary sources, a review by Hepsomali et al (2020) - based in various non-Mormon places from Nottingham to Hokkaido - found mildly convincing evidence for benefits upon stress and sleep.
https://pmc.ncbi.nlm.nih.gov/articles/PMC7527439/ [3925]
Cannabis is not the only influence on GABA. The Defendant wonders on what superstitious or empirical basis cannabis could be held responsible for legal transgressions when alcohol would not.
Psychedelics and depression. Compass Pathways plc published results in 2021.
"In the randomised, controlled, double-blind trial, a single dose of investigational COMP360 psilocybin was given to 233 patients in conjunction with psychological support from specially trained therapists. All patients discontinued antidepressants prior to participation. The trial was powered to compare two active doses of COMP360, 25mg and 10mg, against a comparator 1mg dose. The 25mg group vs the 1mg group showed a -6.6 difference on the MADRS* depression scale at week 3 (p<0.001). The 25mg group demonstrated statistical significance on the MADRS efficacy endpoint on the day after the COMP360 psilocybin administration (p=0.002). The 10mg vs 1mg dose did not show a statistically significant difference at week 3. The MADRS was assessed by independent raters who were remote from the trial site, and blind to intervention and study design, effectively creating a triple blind.
"At least twice the number of patients in the 25mg group showed response and remission* at week 3 and week 12, compared with the 1mg group. The protocol-defined sustained response* up to week 12 was double, with 20.3% of patients in the 25mg group vs 10.1% in the 1mg group. Using a definition of sustained response* that is consistent with other TRD studies, the difference was more than double, with 24.1% of patients in the 25mg group vs 10.1% in the 1mg group."
https://ir.compasspathways.com/news-releases/news-release-details/compass-pathways-announces-positive-topline-results [4310]
Another report that year by Carhart-Harris et al compared psilocybin and escitalopram. Psilocybin worked better. The subjects were tested using the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16; scores range from 0 to 27, with higher scores indicating greater depression.
"A total of 59 patients were enrolled; 30 were assigned to the psilocybin group and 29 to the escitalopram group. The mean scores on the QIDS-SR-16 at baseline were 14.5 in the psilocybin group and 16.4 in the escitalopram group. The mean (±SE) changes in the scores from baseline to week 6 were −8.0±1.0 points in the psilocybin group and −6.0±1.0 in the escitalopram group, for a between-group difference of 2.0 points (95% confidence interval [CI], −5.0 to 0.9) (P=0.17). A QIDS-SR-16 response occurred in 70% of the patients in the psilocybin group and in 48% of those in the escitalopram group, for a between-group difference of 22 percentage points (95% CI, −3 to 48); QIDS-SR-16 remission occurred in 57% and 28%, respectively, for a between-group difference of 28 percentage points (95% CI, 2 to 54). Other secondary outcomes generally favored psilocybin over escitalopram, but the analyses were not corrected for multiple comparisons. The incidence of adverse events was similar in the trial groups."
https://www.nejm.org/doi/full/10.1056/NEJMoa2032994 [4311]
"The Montgomery–Åsberg Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes in patients with mood disorders. It was designed in 1979 by British and Swedish researchers (Marie Åsberg) as an adjunct to the Hamilton Rating Scale for Depression (HAMD) which would be more sensitive to the changes brought on by antidepressants and other forms of treatment than the Hamilton Scale was. There is, however, a high degree of statistical correlation between scores on the two measures.
and
"The questionnaire includes questions on ten symptoms:
"Apparent sadness
Reported sadness
Inner tension
Reduced sleep
Reduced appetite
Concentration difficulties
Lassitude
Inability to feel
Pessimistic thoughts
Suicidal thoughts
"Each item yields a score of 0 to 6; the overall score thus ranges from 0 to 60. Higher MADRS score indicates more severe depression. Usual cutoff points are:
"0 to 6: normal/symptom absent
7 to 19: mild depression
20 to 34: moderate depression
35 to 60: severe depression."
https://en.wikipedia.org/wiki/Montgomery%E2%80%93%C3%85sberg_Depression_Rating_Scale [4257]
In 2021 Aaronson et al embarked upon "Single-Dose Synthetic Psilocybin With Psychotherapy for Treatment-Resistant Bipolar Type II Major Depressive Episodes. A Nonrandomized Controlled Trial" (2023)...
"Bipolar II disorder (BDII) is a lifelong condition characterized by recurrent hypomanic and depressive episodes with a lifetime prevalence of at least 0.4% among adults. It causes a level of functional impairment and disability comparable to bipolar I disorder (BDI) Despite treatment, patients with BDII are typically symptomaticmost of the time, primarily experiencing protracted and difficult-to-treat periods of depression. Bipolar disorder has high mortality, as 30% of affected individuals attempt and 5% to 15% commit suicide. Historically, BDII was viewed as the lesser of the bipolar disorders due to the absence of florid mania. However, recent studies document that functional impact and risk of suicide are similar in BDI and BDII."
and
"INTERVENTIONS A single dose of synthetic psilocybin, 25 mg, was administered. Psychotropic medications were discontinued at least 2 weeks prior to dosing. Therapists met with patients for 3 sessions during pretreatment, during the 8-hour dosing day, and for 3 integration sessions posttreatment.
"MAIN OUTCOMES AND MEASURES The primary outcome measure was change in Montgomery-Åsberg Depression Rating scale (MADRS) at 3 weeks posttreatment. Secondary measures included MADRS scores 12 weeks posttreatment, the self-rated Quick Inventory of Depression Symptoms-Self Rating (QIDS-SR), and the self-rated Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF), each completed at baseline and all subsequent visits. Safety measures included the Columbia Suicide Severity Rating Scale (CSSRS) and the Young Mania Rating Scale (YMRS) completed at each visit. "RESULTS Of the 15 participants in this study (6 male and 9 female; mean [SD] age, 37.8 [11.6] years), all had lower scores at week 3, with a mean (SD) change of −24.00 (9.23) points on the MADRS, (Cohen d = 4.08; 95% CI, −29.11 to −18.89; P < .001). Repeat measures analysis of variance showed lower MADRS scores at all tested posttreatment time points, including the end point (Cohen d = 3.39; 95% CI, −33.19 to −16.95; adjusted P < .001). At week 3, 12 participants met the response criterion (50% decrease in MADRS), and 11 met remission criterion (MADRS score 10). At the study end point, 12 patients met both response and remission criteria. QIDS-SR scores and Q-LES-Q-SF scores demonstrated similar improvements. YMRS and CSSRS scores did not change significantly at posttreatment compared to baseline."
https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2812443 [4256]
Full article saved: psilocybin bipolar 4256
The upheaval continued with a 2023 reanalysis of the data that made Prozac great.
"Back in 2003, the NIMH-sponsored Treatment for Adolescents with Depression Study (TADS) included 439 adolescents aged 12-17 who met DSM-IV criteria for depression. There were four treatment arms, including fluoxetine (Prozac) only; cognitive-behavioral therapy (CBT) only; fluoxetine and CBT; and placebo. The psychotherapy groups were not able to be blinded. The randomized trial lasted for 12 weeks, and participants were asked which group they believed they were in at both 6 weeks and 12 weeks. Improvement in depression was measured with the Children’s Depression Rating Scale–Revised (CDRS-R).
"The TADS study is commonly cited as evidence for Prozac’s effectiveness in depression treatment, because the combined drug and CBT group did slightly better than the placebo group. However, the drug group alone did no better than the placebo group in the TADS analysis of the CDRS-R.
"The current analysis was conducted as part of the Restoring Invisible and Abandoned Trials (RIAT) initiative, which allowed the researchers access to the raw data from the TADS study. They obtained information on the fluoxetine group (109 participants) and the placebo group (111 participants), since those were the two blinded groups, in order to directly compare the effects of unblinding.
"In all the groups, more than 60% of the participants and raters correctly guessed whether they received the drug or placebo (a perfectly blinded study would result in 50% guessing correctly).
"The researchers found that the placebo effect was stronger than the actual treatment itself. Those who guessed that they received the treatment were more likely to improve than those who guessed they received the placebo—even if their guess was incorrect. That is, on average, those who believed they received the drug improved, even if they actually received the placebo. Likewise, those who believed they received the placebo were less likely to improve, even if they actually received the drug.
"Those who believed they received the drug, on average, improved by 10 points more on the CDRS-R than those who believed they received the placebo. Those who believed they received the drug improved by 26.98 points, on average. Those who believed they received the placebo improved by 16.65 points, on average.
"Amazingly, the group that did the best was those who believed they received the drug, but actually received the placebo. These patients did better than those who received the drug and knew it!
"'Adolescents who guessed they were on fluoxetine, but were actually allocated to placebo, demonstrated the largest improvement in CDRS-R,' the researchers write.
"Finally, the researchers confirmed the initial finding of TADS: after accounting for the placebo effect (treatment guess), the researchers found that taking Prozac did not improve depression.
"The researchers write, 'Treatment guess had a substantial and statistically significant effect on outcome (Children’s Depression Rating Scale-Revised change mean difference 9.12, p < 0.001), but actual treatment arm did not (1.53, p = 0.489).”='
"The researchers conclude that unblinding, which amplifies the placebo effect, may be the reason antidepressants typically beat placebo by a slight margin in clinical trials. They add that future studies need to make sure to assess unblinding in order to provide accurate data on drug efficacy.
"'Our analysis suggests that the effects that are demonstrated in placebo-controlled trials of antidepressants may represent amplified placebo effects that are a result of the differential distribution of expectancy effects caused by unblinding. Since the expectancy effects are substantial, even a small degree of unblinding might produce an apparent difference between an active drug and a placebo. For future research, there is a clear need for more stringent study designs that systematically record and analyse treatment guesses and assess blindness, and do so early on and repeatedly,' they write.
"Moreover, since clinical practice guidelines are based on evidence from studies like TADS, the researchers argue that guideline authors need to reassess the evidence base for their recommendations. Recommending antidepressants on the basis of studies like TADS is poor science."
https://www.madinamerica.com/2023/12/placebo-effect-not-antidepressants-responsible-for-depression-improvement/ [4297]
A successful outcome often follows a placebo treatment, and these should be made much more expensive. When Bschor et al compared "Differential Outcomes of Placebo Treatment Across 9 Psychiatric Disorders" (2024):
"This systematic review and meta-analysis of 90 high-quality RCTs with 9985 participants found significant improvement under placebo treatment for all 9 disorders, but the degree of improvement varied significantly among diagnoses. Patients with major depressive disorder experienced the greatest improvement, followed by those with generalized anxiety disorder, panic disorder, attention-deficit/hyperactivity disorder, posttraumatic stress disorder, social phobia, mania, and OCD, while patients with schizophrenia benefited the least."
Specifically, the strength of the placebo effect by indication showed:
"Symptom severity improved with placebo in all diagnoses. Pooled pre-post placebo effect sizes differed across diagnoses (Q = 88.5; df = 8; P < .001), with major depressive disorder (dav = 1.40; 95% CI, 1.24-1.56) and generalized anxiety disorder (dav = 1.23; 95% CI, 1.06-1.41) exhibiting the largest dav. Panic disorder, attention-deficit/hyperactivity disorder, posttraumatic stress disorder, social phobia, and mania showed dav between 0.68 and 0.92, followed by OCD (dav = 0.65; 95% CI, 0.51-0.78) and schizophrenia (dav = 0.59; 95% CI, 0.41-0.76)."
https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2818945 [4685]
More about pooled effect sizes (dav):
https://www.statsdirect.com/help/meta_analysis/effect_size.htm [4686]
And heterogeneity in meta-analysis and the Q-test:
https://www.statsdirect.com/help/#meta_analysis/heterogeneity.htm [4687]
MADRS was back in 2024 with a new acronym: Psilocybin Assisted Psychotherapy (PAP) in the first such trial in Canada, and the findings of Rosenblat et al were:
"Psilocybin had antidepressant effects with adequate safety, comparable to previous trials
Major depressive disorder and bipolar II disorder with complex presentations were included
Repeated doses of psilocybin were associated with greater antidepressant effects
Feasibility in patients with complex presentations support further study in this group"
and
"Participants were randomized to immediate treatment (n = 16) or delayed treatment (n = 14). 29/30 were retained to the week-2 primary endpoint. Adverse events were transient, with no serious adverse events. Greater reductions in depression severity as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) were observed in the immediate treatment arm compared to the waitlist period arm with a large hedge’s g effect size of 1.07 (p < 0.01). Repeated doses were associated with further reductions in MADRS scores compared to baseline."
https://www.sciencedirect.com/science/article/pii/S2666634024000357?dgcid=coauthor [4431]
In "Examining the potential of psilocybin and 5-MeO-DMT as therapeutics for traumatic brain injury" (2025) Plummer et al declare:
"Traumatic brain injury (TBI) is a significant global health challenge, with limited effective treatments for its acute and chronic consequences. TBI is characterized by neuroinflammation, oxidative stress, impaired neuroplasticity, imbalances in neurotransmission, and cell death - factors that contribute to the development of neurological and psychiatric disorders. Emerging evidence suggests that serotonergic psychedelics psilocybin and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) may hold promise as treatments for TBI. These compounds promote neuroplasticity, exert anti-inflammatory and neuroprotective effects, and have shown efficacy in treating psychiatric conditions that share pathophysiological features with TBI. 5-HT1A and 5-HT2A receptors are implicated in their effects, but psilocybin also targets neurotrophic TrkB receptors, whereas 5-MeO-DMT targets sigma-1 receptors, known to have neuroprotective properties. This review integrates current preclinical and clinical research, highlighting both the shared and distinct mechanistic pathways through which psilocybin and 5-MeO-DMT may alleviate TBI-related impairments, such as cognitive and affective dysfunction and neuroinflammation. Additionally, the safety profiles, dosing paradigms, and clinical challenges of these psychedelics are critically examined. By bridging insights from psychedelic science and neurotrauma research, this review underscores the innovative potential of psilocybin and 5-MeO-DMT as adjunctive treatments for TBI, paving the way for novel interventions in neurorehabilitation."
https://pubmed.ncbi.nlm.nih.gov/40669813/ [5163]
In "Psilocybin as a Treatment for Repetitive Mild Head Injury: Evidence from Neuroradiology and Molecular Biology" Brengel et al (2025) report:
"Repetitive mild head injuries incurred while playing organized sports, during car accidents and falls, or in active military service are a major health problem. These head injuries induce cognitive, motor, and behavioral deficits that can last for months and even years with an increased risk of dementia, Parkinson’s disease, and chronic traumatic encephalopathy. There is no approved medical treatment for these types of head injuries. To this end, we tested the healing effects of the psychedelic psilocybin, as it is known to reduce neuroinflammation and enhance neuroplasticity. Using a model of mild repetitive head injury in adult female rats, we provide unprecedented data that psilocybin can reduce vasogenic edema, restore normal vascular reactivity and functional connectivity, reduce phosphorylated tau buildup, enhance levels of brain-derived neurotrophic factor and its receptor TrkB, and modulate lipid signaling molecules."
https://pmc.ncbi.nlm.nih.gov/articles/PMC11838531/ [5190]
According to Palmer et al (2025) in "The Potential Role of Psilocybin in Traumatic Brain Injury Recovery: A Narrative Review" (of 45 articles):
"Assisted psilocybin use may have benefits in TBI by reducing inflammation, promoting neuroplasticity and neuroregeneration, and alleviating associated mood disorders. Positive findings in related fields, like treatment for depression and addiction, highlight the necessity for more extensive clinical trials on psilocybin’s role in TBI recovery."
https://www.mdpi.com/2076-3425/15/6/572 [5062]
It follows that taking psilocybin away increases inflammation, inhibits neuroplasticity and neurodegeneration, and worsens associated mood disorders.