Within the first half of this collection, we reviewed latest analysis into the function of the CB2 cannabinoid receptor in most cancers proliferation. This week we flip our consideration to a different fascinating facet of CB2 perform: its affect on psychiatric and temper problems regardless of not being concentrated within the central nervous system (CNS).
In spite of everything, the CNS is the area of its sibling, the CB1 cannabinoid receptor — the first goal of THC and the mediator of hashish’ intoxicating results. CB2, against this, is extra prominently expressed within the peripheral nervous system, the place it regulates irritation, ache, and neuroprotection. CB2 is discovered to a a lot lesser extent within the mind, the place it modulates dopamine signaling, neuroinflammation, and neurogenesis.
The CB2 receptor was of explicit curiosity to visionary cannabinoid scientist Raphael Mechoulam. Within the 12 months previous to his latest passing at age 92, Mechoulam was nonetheless actively concerned in analysis investigating CB2 in a wide range of illness fashions. Right here we take a look at a few his last papers on CB2 and psychological well being, in addition to two associated evaluations printed in the identical timeframe.
CB2 & Schizophrenia
First comes a paper on CB2’s function in schizophrenia, a situation associated to psychosis whose signs embrace hallucinations, delusions, disorganized pondering, social withdrawal, decreased emotional expression, and apathy. Coauthored by Brazilian scientists affiliated with the College of São Paulo, it appeared within the journal Progress in Neuro-Psychopharmacology & Organic Psychiatry1 in July 2022.
“The CB2 receptor modulates dopaminergic neurotransmission, which is abnormally enhanced in schizophrenia sufferers,” the authors clarify. That a lot is evident. Given this, they wished to know, how may “HU-910,” an artificial analysis compound that selectively prompts the CB2 receptor, have an effect on habits in a rodent mannequin of the illness?
By way of a collection of exams, they discovered that HU-910 administration did certainly produce an anti-psychotic-like impact via the CB2 receptor. The authors recommend that these outcomes “assist additional analysis on the potential therapeutic properties of this compound to deal with schizophrenia.”
However their conclusion that HU-910 might function a drug warrants some warning. Cannabinoid receptors don’t perform merely as on/off switches. As Venture CBD has addressed prior to now relative to proposed therapies for bone illness, Alzheimer’s Illness, and autoimmune dysfunction, selective CB2 agonists to date have been disappointing within the medical context as a result of unintended penalties and different unwelcome outcomes ensuing from the receptor’s large attain within the physique.
CB2 & Despair
The final paper bearing Mechoulam’s title earlier than his demise — amongst a physique of labor encompassing 379 whole articles listed at Pubmed — considerations the function of the CB2 receptor in mediating the antidepressive impact of cannabidiolic acid-methyl ester (CBDA-ME). Titled “Cannabinoid Receptor 2 Blockade Prevents Anti-Depressive-like Impact of Cannabidiol Acid Methyl Ester in Feminine WKY Rats,” it appeared within the February 2023 particular problem of the Worldwide Journal of Molecular Sciences,2 which explored the organic mechanisms of cannabinoids in psychological well being.
CBDA-ME is a steady artificial analogue of cannabidiolic acid (CBDA), the uncooked, unheated model of CBD current in hashish flower. (The truth that CBDA turns into CBD within the presence of daylight or warmth makes it tough to check, therefore the necessity for a extra steady CBDA-related compound.) First described in 19693 by Mechoulam and a coauthor, CBDA-ME has in recent times been proven to exert anxiolytic,4 anti-hyperalgesic,5 and anti-depressive6 results in male rodents at low doses.
The Israel-based authors assessed the antidepressant impact of CBDA-ME in mice via a standard laboratory mannequin often called the “compelled swim check.” Among the many authors’ findings, one stands out (and makes its method into the paper’s title): an artificial CB2 antagonist referred to as “AM-630” blocked CBDA-ME’s anti-depressive impact in feminine rats, however not in males, indicating that the CB2 receptor is concerned in mediating the compound’s impact.
Does this recommend that CB2 activation — maybe not directly triggered by CBD or CBDA in addition to CBDA-ME — might assist combat despair, not less than in ladies? Probably, the authors conclude, however “the cumulative knowledge point out that these pathways are nonetheless ambiguous and require future analysis with the intention to totally perceive the mechanisms of motion of acute CBDA-ME in relieving the signs of despair.”
Concentrating on CB2 in CNS Problems
Two different evaluations from 2022 present a broader perspective on CB2’s function in a number of emotional, cognitive, and psychiatric problems — from habit and anxiousness to Huntington’s and Parkinson’s ailments.
A report printed within the Worldwide Journal of Molecular Sciences, coauthored by Emmanuel Onaivi at William Patterson College in New Jersey and a workforce of Japanese scientists, concludes that CB2 receptors “are extremely expressed in neuropsychiatric and neurodegenerative problems, and that selective CB2 ligands have promising results on the symptomatic administration of those problems.”
Nonetheless, given the potential for such medicine to have vital unwanted effects, the authors additionally advocate additional examine of cannabis-derived compounds to focus on CB2 in tandem with CB1, in addition to much less immediately via the broader endocannabinoid system.
Subsequent, an April 2022 assessment in Frontiers in Psychiatry7 notes that latest findings of CB2’s presence in a number of mind areas and totally different mind cell varieties, together with neurons and glia, point out that “CB2 could carefully relate the immune system and the mind circuits regulating irritation, temper, and cognitive features.” This receptor is especially implicated in neuropsychiatric ailments related to neuroinflammation, in accordance with the European scientists, who conclude that future analysis ought to proceed to zero in on the vital hyperlink between CB2, irritation, and psychiatric problems.
Learn half 1 of this 2-part collection: Most cancers & the CB2 Receptor
Nate Seltenrich, an unbiased science journalist based mostly within the San Francisco Bay Space, covers a variety of topics together with environmental well being, neuroscience, and pharmacology. Copyright, Venture CBD. Is probably not reprinted with out permission.
Cortez, Isadora Lopes et al. “HU-910, a CB2 receptor agonist, reverses behavioral modifications in pharmacological rodent fashions for schizophrenia.” Progress in neuro-psychopharmacology & organic psychiatry vol. 117 (2022): 110553. doi:10.1016/j.pnpbp.2022.110553
Hen-Shoval, Danielle et al. “Cannabinoid Receptor 2 Blockade Prevents Anti-Depressive-like Impact of Cannabidiol Acid Methyl Ester in Feminine WKY Rats.” Worldwide journal of molecular sciences vol. 24,4 3828. 14 Feb. 2023, doi:10.3390/ijms24043828
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
Pertwee, Roger G et al. “Cannabidiolic acid methyl ester, a steady artificial analogue of cannabidiolic acid, can produce 5-HT1A receptor-mediated suppression of nausea and anxiousness in rats.” British journal of pharmacology vol. 175,1 (2018): 100-112. doi:10.1111/bph.14073
Zhu, Yong Fang et al. “An analysis of the anti-hyperalgesic results of cannabidiolic acid-methyl ester in a preclinical mannequin of peripheral neuropathic ache.” British journal of pharmacology vol. 177,12 (2020): 2712-2725. doi:10.1111/bph.14997
Hen-Shoval, D et al. “Acute oral cannabidiolic acid methyl ester reduces depression-like habits in two genetic animal fashions of despair.” Behavioural mind analysis vol. 351 (2018): 1-3. doi:10.1016/j.bbr.2018.05.027
Kibret, Berhanu Geresu et al. “New Insights and Potential Therapeutic Concentrating on of CB2 Cannabinoid Receptors in CNS Problems.” Worldwide journal of molecular sciences vol. 23,2 975. 17 Jan. 2022, doi:10.3390/ijms23020975
Morcuende, Alvaro et al. “Immunomodulatory Function of CB2 Receptors in Emotional and Cognitive Problems.” Frontiers in psychiatry vol. 13 866052. 15 Apr. 2022, doi:10.3389/fpsyt.2022.866052