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ICRS 2023: Report from Toronto

Toronto skyline

I counted over 175 talks and posters at the 33rd annual gathering of the International Cannabinoid Research Society (ICRS), which convened in Toronto at the end of June. In accordance with longstanding ICRS policy, all speakers presented new findings and data that had not yet been published in a peer-reviewed journal. But this year’s 4-day ICRS conference was notable not only for its cutting-edge science. It was also the first ICRS meeting since the passing of its cofounder and guiding light Raphael Mechoulam.

Several colleagues paid homage to Mechoulam in a moving memorial session that honored his many contributions to the burgeoning field of cannabinoid science, which has grown to encompass numerous academic and clinical disciplines. The wide range of topics addressed at the conference is both a reflection of the endocannabinoid system’s ubiquitous role in health and disease and a testament to the enduring mysteries of plant medicine.

CBD & THC

Cannabidiol (CBD) figured prominently in several noteworthy oral presentations and posters that explored the therapeutic potential of plant cannabinoids from various angles. A few highlights:

CBD for breast cancer recovery. Researchers from McGill University in Montreal reported a case study of a 52-yr-old breast cancer survivor who experienced significant improvement in neuropathy symptoms and quality of life following self-administration of 300 mg/day of CBD isolate for six weeks.

CBD for post-concussion syndrome. John Patrick Neary and a team of scientists in Western Canada examined CBD’s impact on 3 female patients who suffered from post-concussion syndrome. They found that cannabidiol helped restore blood pressure dynamics and improve cardiac function in patients who consumed doses as low as 50 mg/day or as high as 400 mg/day.

CBD for psychosis.Dutch scientists from Utrecht University reported that impaired functioning of the brain’s default mode network “likely contributes to psychosis vulnerability.” They found that a CBD treatment regimen of 600 mg daily for four weeks attenuated dysfunctional default mode connectivity in a study of 31 recent-onset psychosis patients.

THC better than CBD for obesity. Israeli scientists assessed the impact of chronically administered CBD and THC on obesity and related metabolic disorders. Given the appetite-arousing qualities of cannabis (“the munchies”), it seems paradoxical that the “prevalence of obesity and metabolic diseases are lower in cannabis users compared to non-users,” the Israelis noted. Experiments on mice yielded biphasic results: 10 mg/kg of purified THC stimulated weight gain and impaired glucose-tolerance in mice, but 30 mg/kg of THC had the opposite effect, leading to a reduction in weight gain and improved glucose-tolerance. While CBD treatment enhanced glucose-tolerance regardless of weight gain, THC showed greater promise as an anti-obesity compound, according to this study. The researchers concluded that “chronic oral consumption of sufficient concentrations of THC, but not CBD, ameliorates diet-induced obesity and . . . metabolic disorders.”

Sufficient concentrations of THC, but not CBD, reduces diet-induced obesity and metabolic disorders.

CBD-rich cultivars for anxiety. University of Colorado researcher L. Cinnamon Bidwell examined the effects of three cannabis chemovars with different THC:CBD ratios. Not surprisingly, the CBD-dominant chemovar with little THC was associated with significant reductions in anxiety and tension among cannabis users as compared to the THC-dominant and the mixed THC:CBD chemovars.

Cannabis and cortisol. Washington State University researchers probed the chronic and acute effects of cannabis use on human cortisol rhythms. “Stress relief is the most cited reason for habitual cannabis use,” they noted in their assessment of how cannabis consumption impacts levels of cortisol, a stress-related hormone. “We found a significant decrease in cortisol concentrations following acute cannabis use,” they concluded. “These findings corroborate cannabis users’ self-reported experience of decreased stress following cannabis use.”

CBG and CBC. Preliminary results from a “double-blind, placebo-controlled, crossover, field trial” underscored the anxiolytic, stress-relieving, and memory-enhancing potential of cannabigerol (CBG), which produced greater reductions in anxiety than placebo. Cannabicromene (CBC), another minor phytocannabinoid, was reported to exert effects through various pathways, including the CB2 cannabinoid receptor, ion channels TRPA1 and TRPA4, and the nuclear receptor PPAR-gamma.

Pain, Opioids & Addiction

Pain, opioids, and addiction comprised a major area of focus at ICRS 2023. Much of this research involved animal models and other preclinical experiments that shed light on the subtleties and inner workings of the endocannabinoid system. Medical scientists, for example, at Mount Sinai’s Department of Psychiatry and Neuroscience probed the neurobiological underpinnings of CBD’s ability to attenuate opioid relapse. Building on their previous work, which showed that CBD lessens cue-induced heroin-seeking in an animal model of relapse, the Mount Sinai lab identified “discrete biological pathways impacted by heroin” in the nucleus accumbens (NAc), the brain region that regulates motivation and reward: “Bioinformatic analysis revealed that CBD reversed a number of metabolic and cell signaling pathway alterations induced by heroin particularly in the NAc shell.”

Neuroscientists at Indiana University explored how allosteric modulation of the CB1 cannabinoid receptor affected opioid self-administration and relapse. Allosteric modulators can either enhance or weaken how a receptor signals. A negative allosteric modulator (NAM) — a synthetic research compound identified as GAT358 — reduced the reinforcing properties of morphine by altering the shape of the CB1 receptor and weakening its signal. This approach might “represent a viable therapeutic route to decrease opioid addictive behaviors and relapse,” the scientists surmised. The same lab reported that GAT358 suppressed “opioid-mediated unwanted side effects including tolerance and withdrawal” but did not block opioid analgesia.

The wide range of topics at ICRS is both a reflection of the endocannabinoid system’s ubiquitous role in health and disease and a testament to the enduring mysteries of plant medicine.

CBD, it should be noted, also acts as a negative allosteric modulator at the CB1 receptor, meaning that CBD doesn’t cause the CB1 receptor to signal (like THC does) but CBD influences how it signals. If the CB1 receptor is like a dimmer switch, then CBD turns it down a notch. It’s also possible for a positive allosteric modulator (PAM) to turn the dimmer switch up a notch and amplify CB1 signaling.

The Indiana University group led by Andrea G. Hohmann studied PAMs as well as NAMs, fine-tuning CB1 receptor signaling in both directions. They found that strengthening CB1 signaling via positive allosteric modulation “could suppress neuropathic pain without producing unwanted CNS side effects or tolerance.” Tweaking the CB1 receptor in such a manner avoided potential problems (intoxication, impairment) associated with direct activation of CB1 by THC or various synthetic cannabinoids. Mohammed Mustafa of Virginia Commonwealth University reported that positive allosteric modulation of the CB1 receptor also reduced somatic withdrawal signs of nicotine-dependent mice.

On the Shoulders of Giants

2023 saw the passing of two research pioneers who were giants in the field of cannabinoid science. Mary E. Abood, PhD, conducted groundbreaking studies on the structure and function of cannabinoid receptors. She also identified other receptor subtypes that bind to cannabinoids. A leading figure in the ICRS since its founding in the early 1990s, Abood was known for mentoring young women scientists. After her death on Feb. 19, 2023, the ICRS announced the creation of the “Mary E. Abood ICRS Women in Cannabinoid Research Fund” to support women trainees and investigators.

Mechoulam, 92, passed away three weeks after Abood died. For all his stunning achievements as a chemist, perhaps his greatest contribution was how he nurtured a robust noncompetitive spirit, an ethos of cooperation and collegiality that persists among scientists involved in cannabinoid research. This was evident at the dinner and awards ceremony at the end of conference — an ICRS tradition — as young scientists were acknowledged for their research accomplishments and recently elected ICRS officers were introduced. When ICRS president-elect Ziva Cooper, the director of UCLA’s Center for Cannabis and Cannabinoids, greeted the group, it felt like a generational hand-off had occurred, a passing-of-the-baton from the old guard to younger scientists who stand on the shoulders of giants.

Martin A. Lee is the director of Project CBD. He’s authored and edited several books, including Smoke Signals, Acid Dreams, and The Essential Guide to CBD. © Copyright, Project CBD. May not be reprinted without permission.

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CBD Enhances Glucose Metabolism via Nuclear Receptors

Cannabinoid receptors CB1 and CB2 are the definitive and best-known targets of endogenous and plant-derived cannabinoids, but they’re far from the only ones.

Several phytocannabinoids, including cannabidiol (CBD), for example, and the two primary endocannabinoids — anandamide and 2-AG — have been shown to interact with peroxisome proliferator-activated receptors, or PPARs1 (pronounced pee-parrs), which are found on the surface of the cell’s nucleus. This may help to explain how CBD, which has little affinity for either CB1 or CB2, can do so much.

Get to Know the PPARs

PPARs are a group of nuclear receptors that play important roles in regulating metabolism, inflammation, and gene expression. Triggered by hormones, endocannabinoids, and other fatty acid derivatives, and various nutritional compounds,2 PPARs are expressed in different parts of the body:

  • PPAR-a(PPAR-alpha) is found in the liver, kidney, heart, and skeletal muscle, as well as adipose (fat) tissue and the intestinal tract;
  • PPAR-b(PPAR-delta) is expressed in adipose tissue, skeletal muscle, heart, and liver; and
  • PPAR-y (PPAR-gamma), which comes in two forms, is expressed in almost all tissues of the body including the colon, the cardiovascular system, and immune cells.

The first evidence of an endocannabinoid interacting with PPARs came in 2002, when a research team in Tennessee showed that a metabolite of 2-AG activated PPAR-a.3 Since then many more breakthroughs have been made, and peroxisome proliferator-activated receptors are now viewed as an extension of the classic endocannabinoid system (ECS).

PPARs are now viewed as an extension of the classic endocannabinoid system.

Two recent papers reiterate the point that to really understand cannabinoids (especially CBD) and the ECS, it’s essential to get to know the PPARs.

CBD, Psychosis & Glucose Metabolism

A March 2023 study in the journal Frontiers in Psychiatry4 suggests that CBD may act through a PPAR receptor to enhance cerebral glucose metabolism, alterations of which are associated with a host of metabolic and cognitive disorders.5

The paper describes the case of a 19-year-old man in Germany who presented at the Cologne Early Recognition and Intervention Center with “a marked cognitive decline within [six] months, anhedonia, ambivalence, social withdrawal, poverty of speech, and brief, limited intermittent psychotic symptoms, particularly delusions and hallucinations.”

Prior to this, the man had no psychiatric history, the authors note. He had never taken anti-psychotic drugs nor received psychological treatment. And besides an uncle with bipolar disorder, he had no family history of other psychiatric or neurological diseases.

The man’s doctors — two of the paper’s four authors — knew that over the last decade-plus, CBD has begun to be recognized through animal and human studies as a novel therapeutic compound for psychosis that acts via indirect effects on the ECS.6,7 They wanted to try it.

“Due to its excellent tolerability and promising efficacy … and its innovative new mechanisms of action, we decided to offer a respective treatment with cannabidiol to [the] patient,” they write.

The prescription was 600 mg of pure CBD orally per day for 30 days. And it worked. The authors report a substantial clinical improvement in attention, visual processing, visuomotor speed, working memory, and other parameters beginning by day seven, with no adverse events or side effects. That’s quite notable in and of itself — but it’s their investigation of potential mechanisms of action that really contributes to the conversation.

Mechanisms of Action

Using brain scans and blood draws, the researchers observed that this reduction in clinical symptoms was accompanied by enhancement of cerebral glucose utilization — a critical metabolic process whose impairment is implicated in Alzheimer’s Disease, schizophrenia, diabetes, obesity, and more.8

They suggest that the underlying mechanism linking CBD intake, cerebral glucose utilization, and improved psychiatric symptoms may be none other than PPAR-y, one of the three known PPAR receptors. PPAR-y plays an essential role in regulating glucose homeostasis and neuroinflammation, and is directly activated by both CBD and the endocannabinoid anandamide (AEA). (AEA’s molecular fatty-acid cousins, PEA and OEA, activate PPAR-a.)

The activation of PPAR-γ by CBD may be one of the mechanisms relevant to the promising antipsychotic effects of cannabidiol.

The proposed link between CBD, cerebral glucose metabolism, psychiatric symptoms, and PPAR-y makes sense, even if it has yet to be proven definitively. Previous research has linked CBD’s efficacy in treating psychosis to its ability to boost AEA,9 which binds with PPAR-y. PPARs in general are recognized as a potential target for treating psychiatric disorders.10 And a 2022 study showed that CBD treatment improved both glucose metabolism and memory in a rat model of Alzheimer’s Disease.11

“The direct or indirect activation of PPAR-γ by cannabidiol may represent one of the various possible mechanisms relevant to the promising antipsychotic effects of cannabidiol,” the authors conclude. Yes, more research is needed — but what matters most to the patient is that it helps.

Cannabidiol Goes Nuclear

A review article in the journal Phytomedicine12 also published in March 2023 provides a broader look at the clinical implications of CBD’s affinity for PPAR-y. Appearing under the catchy title “Cannabidiol goes nuclear: The role of PPARy,” the paper summarizes existing research into the many ways in which interactions between the two influence human health.

Based on an examination of 78 previous articles, the Iran-based authors determined that CBD’s effects on a long list of conditions (Alzheimer’s disease and memory loss, Parkinson’s disease and movement disorders, multiple sclerosis, anxiety and depression, cardiovascular disease, immune conditions, cancer, and obesity) are mediated at least in part by PPAR-y.

The ubiquitous receptor manages this not only through glucose homeostasis, the authors write, but also by changing the expression of various genes implicated in insulin release, lipid metabolism, inflammation, and immunity. And they note that many effects of CBD can be prevented by synthetic PPAR-y antagonists, which are utilized as research tools.

Ultimately, the review underscores that PPAR-y is a key target for CBD — and argues quite convincingly that “[the receptor’s] activation by CBD should be considered in all future studies.”

Nate Seltenrich, Project CBD contributing writer, is the author of the column Bridging the Gap. He is an independent science journalist based in the San Francisco Bay Area, covering a wide range of subjects, including environmental health, neuroscience, and pharmacology. © Copyright, Project CBD. May not be reprinted without permission.

Footnotes

  1. O’Sullivan, Saoirse Elizabeth. “An update on PPAR activation by cannabinoids.” British journal of pharmacology vol. 173,12 (2016): 1899-910. doi:10.1111/bph.13497
  2. Scandiffio, Rosaria et al. “Beta-Caryophyllene Modifies Intracellular Lipid Composition in a Cell Model of Hepatic Steatosis by Acting through CB2 and PPAR Receptors.” International journal of molecular sciences vol. 24,7 6060. 23 Mar. 2023, doi:10.3390/ijms24076060
  3. Karkhanis, Anil et al. “15-Lipoxygenase Metabolism of 2-Arachidonylglycerol: Generation of a Peroxisome Proliferator-Activated Receptor α Agonist.” Journal of medicinal chemistry vol. 57,11 (2014): 4830-4840.
  4. Koethe, Dagmar et al. “Cannabidiol enhances cerebral glucose utilization and ameliorates psychopathology and cognition: A case report in a clinically high-risk mental state.” Frontiers in psychiatry vol. 14 1088459. 3 Mar. 2023, doi:10.3389/fpsyt.2023.1088459
  5. Rebelos, Eleni et al. “Brain Glucose Metabolism in Health, Obesity, and Cognitive Decline-Does Insulin Have Anything to Do with It? A Narrative Review.” Journal of clinical medicine vol. 10,7 1532. 6 Apr. 2021, doi:10.3390/jcm10071532
  6. Rohleder, Cathrin et al. “Cannabidiol as a Potential New Type of an Antipsychotic. A Critical Review of the Evidence.” Frontiers in pharmacology vol. 7 422. 8 Nov. 2016, doi:10.3389/fphar.2016.00422
  7. Davies, Cathy, and Sagnik Bhattacharyya. “Cannabidiol as a potential treatment for psychosis.” Therapeutic advances in psychopharmacology vol. 9 2045125319881916. 8 Nov. 2019, doi:10.1177/2045125319881916
  8. Rebelos, Eleni et al. “Brain Glucose Metabolism in Health, Obesity, and Cognitive Decline-Does Insulin Have Anything to Do with It? A Narrative Review.” Journal of clinical medicine vol. 10,7 1532. 6 Apr. 2021, doi:10.3390/jcm10071532
  9. Davies, Cathy, and Sagnik Bhattacharyya. “Cannabidiol as a potential treatment for psychosis.” Therapeutic advances in psychopharmacology vol. 9 2045125319881916. 8 Nov. 2019, doi:10.1177/2045125319881916
  10. Matrisciano, Francesco, and Graziano Pinna. “The Strategy of Targeting Peroxisome Proliferator-Activated Receptor (PPAR) in the Treatment of Neuropsychiatric Disorders.” Advances in experimental medicine and biology vol. 1411 (2023): 513-535. doi:10.1007/978-981-19-7376-5_22
  11. de Paula Faria, Daniele et al. “Cannabidiol Treatment Improves Glucose Metabolism and Memory in Streptozotocin-Induced Alzheimer’s Disease Rat Model: A Proof-of-Concept Study.” International journal of molecular sciences vol. 23,3 1076. 19 Jan. 2022, doi:10.3390/ijms23031076
  12. Khosropoor, Sara et al. “Cannabidiol goes nuclear: The role of PPARγ.” Phytomedicine: international journal of phytotherapy and phytopharmacology vol. 114 (2023): 154771. doi:10.1016/j.phymed.2023.154771

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Mental Health & the CB2 Receptor

In the first part of this series, we reviewed recent research into the role of the CB2 cannabinoid receptor in cancer proliferation. This week we turn our attention to another fascinating aspect of CB2 function: its impact on psychiatric and mood disorders despite not being concentrated in the central nervous system (CNS).

After all, the CNS is the domain of its sibling, the CB1 cannabinoid receptor — the primary target of THC and the mediator of cannabis’ intoxicating effects. CB2, by contrast, is more prominently expressed in the peripheral nervous system, where it regulates inflammation, pain, and neuroprotection. CB2 is found to a much lesser extent in the brain, where it modulates dopamine signaling, neuroinflammation, and neurogenesis.

The CB2 receptor was of particular interest to visionary cannabinoid scientist Raphael Mechoulam. In the year prior to his recent passing at age 92, Mechoulam was still actively involved in research investigating CB2 in a variety of disease models. Here we look at a couple of his final papers on CB2 and mental health, as well as two related reviews published in the same timeframe.

CB2 & Schizophrenia

First comes a paper on CB2’s role in schizophrenia, a condition related to psychosis whose symptoms include hallucinations, delusions, disorganized thinking, social withdrawal, decreased emotional expression, and apathy. Coauthored by Brazilian scientists affiliated with the University of São Paulo, it appeared in the journal Progress in Neuro-Psychopharmacology & Biological Psychiatry1 in July 2022.

“The CB2 receptor modulates dopaminergic neurotransmission, which is abnormally enhanced in schizophrenia patients,” the authors explain. That much is clear. Given this, they wanted to know, how might “HU-910,” a synthetic research compound that selectively activates the CB2 receptor, affect behavior in a rodent model of the disease?

Through a series of tests, they found that HU-910 administration did indeed produce an anti-psychotic-like effect through the CB2 receptor. The authors suggest that these results “support further research on the potential therapeutic properties of this compound to treat schizophrenia.”

But their conclusion that HU-910 could serve as a drug warrants some caution. Cannabinoid receptors don’t function simply as on/off switches. As Project CBD has addressed in the past relative to proposed therapies for bone disease, Alzheimer’s Disease, and autoimmune dysfunction, selective CB2 agonists thus far have been disappointing in the clinical context due to unintended consequences and other unwelcome outcomes resulting from the receptor’s wide reach in the body.

CB2 & Depression

The very last paper bearing Mechoulam’s name before his death — among a body of work encompassing 379 total articles listed at Pubmed — concerns the role of the CB2 receptor in mediating the antidepressive effect of cannabidiolic acid-methyl ester (CBDA-ME). Titled “Cannabinoid Receptor 2 Blockade Prevents Anti-Depressive-like Effect of Cannabidiol Acid Methyl Ester in Female WKY Rats,” it appeared in the February 2023 special issue of the International Journal of Molecular Sciences,2 which explored the biological mechanisms of cannabinoids in mental health.

CBDA-ME is a stable synthetic analogue of cannabidiolic acid (CBDA), the raw, unheated version of CBD present in cannabis flower. (The fact that CBDA becomes CBD in the presence of sunlight or heat makes it difficult to study, hence the need for a more stable CBDA-related compound.) First described in 19693 by Mechoulam and a coauthor, CBDA-ME has in recent years been shown to exert anxiolytic,4 anti-hyperalgesic,5 and anti-depressive6 effects in male rodents at low doses.

The Israel-based authors assessed the antidepressant effect of CBDA-ME in mice through a common laboratory model known as the “forced swim test.” Among the authors’ findings, one stands out (and makes its way into the paper’s title): a synthetic CB2 antagonist called “AM-630” blocked CBDA-ME’s anti-depressive effect in female rats, but not in males, indicating that the CB2 receptor is involved in mediating the compound’s effect.

Does this suggest that CB2 activation — perhaps indirectly triggered by CBD or CBDA as well as CBDA-ME — could help fight depression, at least in women? Possibly, the authors conclude, but “the cumulative data indicate that these pathways are still ambiguous and require future research in order to fully understand the mechanisms of action of acute CBDA-ME in relieving the symptoms of depression.”

Targeting CB2 in CNS Disorders

Two other reviews from 2022 provide a broader perspective on CB2’s role in several emotional, cognitive, and psychiatric disorders — from addiction and anxiety to Huntington’s and Parkinson’s diseases.

A report published in the International Journal of Molecular Sciences, coauthored by Emmanuel Onaivi at William Patterson University in New Jersey and a team of Japanese scientists, concludes that CB2 receptors “are highly expressed in neuropsychiatric and neurodegenerative disorders, and that selective CB2 ligands have promising effects on the symptomatic management of these disorders.”

However, given the potential for such drugs to have significant side effects, the authors also recommend further study of cannabis-derived compounds to target CB2 in tandem with CB1, as well as less directly through the broader endocannabinoid system.

Next, an April 2022 review in Frontiers in Psychiatry7 notes that recent findings of CB2’s presence in several brain areas and different brain cell types, including neurons and glia, indicate that “CB2 may closely relate the immune system and the brain circuits regulating inflammation, mood, and cognitive functions.” This receptor is particularly implicated in neuropsychiatric diseases associated with neuroinflammation, according to the European scientists, who conclude that future research should continue to zero in on the critical link between CB2, inflammation, and psychiatric disorders.

Read part 1 of this 2-part series: Cancer & the CB2 Receptor

Nate Seltenrich, an independent science journalist based in the San Francisco Bay Area, covers a wide range of subjects including environmental health, neuroscience, and pharmacology. Copyright, Project CBD. May not be reprinted without permission.

Footnotes

  1. Cortez, Isadora Lopes et al. “HU-910, a CB2 receptor agonist, reverses behavioral changes in pharmacological rodent models for schizophrenia.” Progress in neuro-psychopharmacology & biological psychiatry vol. 117 (2022): 110553. doi:10.1016/j.pnpbp.2022.110553
  2. Hen-Shoval, Danielle et al. “Cannabinoid Receptor 2 Blockade Prevents Anti-Depressive-like Effect of Cannabidiol Acid Methyl Ester in Female WKY Rats.” International journal of molecular sciences vol. 24,4 3828. 14 Feb. 2023, doi:10.3390/ijms24043828
  3. Mechoulam, R et al. “Carboxylation of resorcinols with methylmagnesium carbonate. Synthesis of cannabinoid acids.” Journal of the chemical society D: chemical communications vol. 1,7 (1969): 343-344. doi:10.1039/C29690000343
  4. Pertwee, Roger G et al. “Cannabidiolic acid methyl ester, a stable synthetic analogue of cannabidiolic acid, can produce 5-HT1A receptor-mediated suppression of nausea and anxiety in rats.” British journal of pharmacology vol. 175,1 (2018): 100-112. doi:10.1111/bph.14073
  5. Zhu, Yong Fang et al. “An evaluation of the anti-hyperalgesic effects of cannabidiolic acid-methyl ester in a preclinical model of peripheral neuropathic pain.” British journal of pharmacology vol. 177,12 (2020): 2712-2725. doi:10.1111/bph.14997
  6. Hen-Shoval, D et al. “Acute oral cannabidiolic acid methyl ester reduces depression-like behavior in two genetic animal models of depression.” Behavioural brain research vol. 351 (2018): 1-3. doi:10.1016/j.bbr.2018.05.027
  7. Kibret, Berhanu Geresu et al. “New Insights and Potential Therapeutic Targeting of CB2 Cannabinoid Receptors in CNS Disorders.” International journal of molecular sciences vol. 23,2 975. 17 Jan. 2022, doi:10.3390/ijms23020975
  8. Morcuende, Alvaro et al. “Immunomodulatory Role of CB2 Receptors in Emotional and Cognitive Disorders.” Frontiers in psychiatry vol. 13 866052. 15 Apr. 2022, doi:10.3389/fpsyt.2022.866052

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