A lot as THC exerts the vast majority of its psychoactive results by way of 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 quite a few essential processes together with studying and reminiscence, notion, irritation, hormone regulation, and naturally hallucination.
Given the function 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 possible manifests a few of its downstream results by altering the discharge and signaling of endocannabinoids.
Serotonin ECS Crosstalk
A 2006 research,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 akin to serotonin could act as regulators of endocannabinoid tone.”
One other study2 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 essential 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 possible that this mechanism may mediate most of the actions of 5-HT2Rs all through the mind.”
Serotonin could act as a regulator of endocannabinoid tone.
At this time, 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 posh 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 essential neurotransmitter methods and of the physiological cascade concerned within the psychedelic expertise.
Ayahuasca, Endocannabinoids, and Social Anxiousness Dysfunction
Partially knowledgeable and impressed by these two preliminary research, a group of researchers primarily based in Brazil, the place ayahuasca, the potent hallucinogenic plant concoction, has an extended 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 group 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 ECS is concerned in mediating the physiological results of psychedelic medication.
The outcomes, printed within the journal Human Psychopharmacology in February 2022,3 point out excessive variability in each trials, with biphasic results noticed in some circumstances (normally a rise adopted by a lower, although generally the other), and in others regular will increase or decreases. Few findings had been statistically important; takeaways are arduous 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, lowering them beneath baseline ranges on the 240-minute time-point,” the authors summarize, including: “The research could have been underpowered as a result of small pattern, and it’s attainable that statistically important variations might be noticed if the pattern was bigger.”
Curiously, not solely had been the outcomes blended and unaligned with preclinical findings, however they had been additionally inconsistent with earlier findings from the identical group. In a brief case report printed as a letter to the editor within the Journal of Scientific 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 end result? For anandamide, a gradual decline beneath baseline; for 2-AG, a slight lower adopted by a sharper improve.
Extra on Ayahuasca’s Molecular Pathways
For these counting alongside – that’s 4 totally different research drawing 4 totally different conclusions. And here’s a fifth: one other research, printed within the Could 2022 situation of Biomedicine and Pharmacotherapy,5 during which plasma samples had been collected from 23 wholesome common customers of ayahuasca within the Netherlands earlier than and after consumption.
The scope of this research was far broader than these mentioned above, because the Spain-based researchers measured ranges of an extended 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 major endocannabinoids go, the researchers noticed that ayahuasca consumption elevated ranges of anandamide and decreased ranges of 2-AG.
Whereas that is primarily the precise reverse of what was noticed within the Brazilian group’s 2018 case research, it doesn’t make a lot sense to check the 2 given their totally 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 better complexity concerned in administering a posh botanical brew to people versus straight serotonin to rat mind cells in vitro.
What we are able to glean thus removed from all of the conflicting information is that this: The endocannabinoid system is modified by way of 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 medication. And that appears 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. Will not be reprinted with out permission.