A lot as THC exerts nearly all of its psychoactive results via the CB1 cannabinoid receptor, the “traditional” psychedelics – LSD, psilocybin, mescaline, and dimethyltryptamine (DMT) – are outlined by activation of the serotonin 5-HT2A receptor.
Extensively distributed all through the central nervous system, 5-HT2A receptors mediate a lot of necessary processes together with studying and reminiscence, notion, irritation, hormone regulation, and naturally hallucination.
Given the position of the endocannabinoid system (ECS) as a “grasp regulator” of many of those features and extra, maybe we shouldn’t be stunned that 5-HT2A seemingly manifests a few of its downstream results by altering the discharge and signaling of endocannabinoids.
Serotonin ECS Crosstalk
A 2006 examine,1 coauthored by esteemed psychedelic scientist David Nichols, paperwork a spike within the endocannabinoid 2-AG, however not in anandamide, the opposite main endocannabinoid, following stimulation with serotonin of 5-HT2A receptors in rat mind cells. The paper concludes that “neurotransmitters reminiscent of serotonin could act as regulators of endocannabinoid tone.”
One other examine2 two years later goes a step additional by demonstrating that activation of 5-HT2A in rat neurons by serotonin impacts not solely the discharge of endocannabinoids but additionally the expression of the CB1 receptor. A goal of 2-AG, anandamide, and THC alike, this cannabinoid receptor is vital to the psychoactivity of hashish and performs a job in lots of cognitive and physiological processes. “These findings set up a hyperlink between serotonin signaling and endocannabinoid signaling,” the authors write. “It appears seemingly that this mechanism might mediate most of the actions of 5-HT2Rs all through the mind.”
Right this moment, some 15 years on, two new research from two separate analysis teams discover this hyperlink in human topics following a psychedelic dose of ayahuasca, a fancy brew containing DMT, a 5-HT2A agonist and potent psychedelic, in addition to different plant compounds that will work together with the endocannabinoid system in much less direct methods.
Whether or not or not any clear conclusions can but be drawn, this analysis represents a notable step ahead within the investigation of crosstalk between these two important neurotransmitter methods and of the physiological cascade concerned within the psychedelic expertise.
Ayahuasca, Endocannabinoids, and Social Nervousness Dysfunction
Partially knowledgeable and impressed by these two preliminary research, a staff of researchers primarily based in Brazil, the place ayahuasca, the potent hallucinogenic plant concoction, has a protracted historical past of shamanic use, sought to reply a decidedly fashionable scientific query: How does ayahuasca administration have an effect on endocannabinoid ranges in wholesome volunteers versus these recognized with social nervousness dysfunction?
To study extra, the staff carried out two small pilot, proof-of-concept randomized and placebo-controlled trials. Within the first, 20 wholesome people ingested a single dose of ayahuasca or placebo. Within the second, 17 people with social nervousness dysfunction additionally obtained a placebo or a single (although roughly half-as-potent) serving of ayahuasca. Blood attracts at baseline and 90 and 240 minutes after administration had been subsequently used to research ranges of anandamide and 2-AG.
The outcomes, revealed within the journal Human Psychopharmacology in February 2022,3 point out excessive variability in each trials, with biphasic results noticed in some instances (often a rise adopted by a lower, although generally the alternative), and in others regular will increase or decreases. Few findings had been statistically vital; takeaways are exhausting to come back by.
“Contemplating the outcomes of each exams collectively, evidently in social nervousness dysfunction sufferers, ayahuasca elevated [anandamide] ranges from baseline to 90 minutes after its consumption, decreasing them under baseline ranges on the 240-minute time-point,” the authors summarize, including: “The examine could have been underpowered because of the small pattern, and it’s doable that statistically vital variations could possibly be noticed if the pattern was bigger.”
Curiously, not solely had been the outcomes combined and unaligned with preclinical findings, however they had been additionally inconsistent with earlier findings from the identical staff. In a brief case report revealed as a letter to the editor within the Journal of Medical Psychopharmacology in 2018,4 the researchers describe measuring endocannabinoid ranges within the blood of a single wholesome, 34-year-old male each earlier than and 90 and 240 minutes after ayahuasca consumption. The consequence? For anandamide, a gentle decline under baseline; for 2-AG, a slight lower adopted by a sharper enhance.
Extra on Ayahuasca’s Molecular Pathways
For these counting alongside – that’s 4 completely different research drawing 4 completely different conclusions. And here’s a fifth: one other examine, revealed within the Could 2022 situation of Biomedicine and Pharmacotherapy,5 wherein plasma samples had been collected from 23 wholesome common customers of ayahuasca within the Netherlands earlier than and after consumption.
The scope of this examine was far broader than these mentioned above, because the Spain-based researchers measured ranges of a protracted checklist of metabolic markers together with amino acids, hormones, neurotransmitters, and a dozen endocannabinoids together with anandamide, 2-AG, and lesser-known compounds like DHEA, OEA, 2-OG, 2-LG, LEA, and DEA. However so far as the 2 main endocannabinoids go, the researchers noticed that ayahuasca consumption elevated ranges of anandamide and decreased ranges of 2-AG.
Whereas that is basically the precise reverse of what was noticed within the Brazilian staff’s 2018 case examine, it doesn’t make a lot sense to check the 2 given their completely different designs. Nor does it actually make sense to try to stack any of the human research up towards the early preclinical work due to the exponentially larger complexity concerned in administering a fancy botanical brew to people versus straight serotonin to rat mind cells in vitro.
What we will glean thus removed from all of the conflicting information is that this: The endocannabinoid system is modified via activation of the identical cell receptor focused by traditional psychedelics, and the ECS is one way or the other concerned in mediating the physiological results of those highly effective medicine. And that feels like an avenue price exploring extra.
Nate Seltenrich, an unbiased science journalist primarily based 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.
Footnotes
