as much THC It exerts most of its psychological effects through CB1 Cannabinoid receptors, the “classic” drug – LSDpsilocybin, mescaline, dimethyltryptamine (DMT) – defined by the activation of serotonin 5-HT2A future.
Widely distributed throughout the central nervous system, 5-HT2A The receptors mediate a number of important processes including learning and memory, cognition, inflammation, hormone regulation, and of course hallucinations.
Given the role of the endocannabinoid system (ECS) as a “master regulator” of many of these functions and more, we should perhaps not be surprised that 5-HT2A It probably shows some of its end effects by altering the release and signaling of endocannabinoids.
Serotonin ECS Crosstalk
2006 study,1 Co-authored by respected psychedelic scientist David Nichols, it documents a rise in endocannabinoid 2-AGbut not in anandamide, another major endocannabinoid, after stimulation with 5-serotonin.HT2A Receptors in rat brain cells. The research paper concluded that “neurotransmitters such as serotonin may act as regulators of endocannabinoid tone.”
Another study2 Two years later he goes a step further by proving that the activation of 5HT2A In rat neurons by serotonin affects not only the secretion of endocannabinoids but also the expression of CB1 future. goal 2-AGand anandamide and THC Equally, this cannabinoid receptor is key to cannabinoids’ psychological activity and plays a role in many cognitive and physiological processes. “These findings establish a link between serotonin and endocannabinoid signaling,” the authors wrote. “It seems likely that this mechanism could mediate many 5-actions.HT2Rthroughout the brain. ”
Today, about 15 years later, two new studies from two separate research groups have explored this link in people who have taken a psychedelic dose of ayahuasca, a complex drink containing DMTA 5-HT2A A powerful agonist and anesthetic, as well as other plant compounds that may interact with the endocannabinoid system in less direct ways.
Whether or not any clear conclusions can be drawn, this research represents a notable step forward in investigating the crosstalk between the two critical neurotransmitter systems and the physiological sequences involved in an anesthetic experience.
Ayahuasca, Endocannabinoids, and Social Anxiety Disorder
Inspired and partially inspired by these two initial studies, a team of researchers based in Brazil, where ayahuasca, a potent hallucinogenic plant, has a long history of shamanic use, sought to answer a recent scientific question: How does administration of ayahuasca affect the endocannabinoid levels of healthy volunteers versus those of healthy volunteers. Who has been diagnosed with social anxiety disorder?
To find out more, the team conducted two small, randomized, proof-of-concept, placebo-controlled trials. Initially, 20 healthy individuals took a single dose of ayahuasca or a placebo. In the placebo group, 17 people with social anxiety disorder also received a placebo or a single (although roughly half effective) dose of ayahuasca. Blood drawing at baseline and at 90 and 240 minutes after administration was used to analyze levels of anandamide and 2.AG.
The results are published in the journal human psychopharmacology In February 2022,3 They indicate significant variability in both experiments, with biphasic effects observed in some cases (usually an increase followed by a decrease, albeit sometimes the opposite), and in other cases steady increases or decreases. The results were few statistically significant; Hard to get takeaway.
Looking at the results of both tests together, it appears that in patients with social anxiety disorder, ayahuasca increased [anandamide] levels from baseline to 90 minutes after ingestion, reducing it below baseline levels at the 240-minute time point,” the authors summarize, adding: “The study is probably weak due to the small sample, and it is statistically possible that significant differences could be observed if The sample was larger.”
Interestingly, the results were not only mixed and inconsistent with preclinical findings, but were also inconsistent with previous findings from the same team. In a short case report published as a letter to the editor at Journal of Clinical Psychopharmacology in 2018,4 The researchers described measuring endocannabinoid levels in the blood of one healthy 34-year-old man before taking ayahuasca and 90 and 240 minutes after taking it. Results? For anandamide, steady decline below baseline; for 2-AGA slight decrease followed by a sharp increase.
More on the Ayahuasca Molecular Pathways
For those counting along – these are four different studies that drew four different conclusions. Here is a fifth: Another study published in the May 2022 issue of Biomedicine and pharmacotherapyAnd the5 Plasma samples were collected from 23 healthy regular users of ayahuasca in the Netherlands before and after consumption.
The scope of this study was much broader than that discussed above, in which researchers based in Spain measured levels of a long list of metabolic markers including amino acids, hormones, neurotransmitters, and dozens of endocannabinoids including anandamide, 2-AGand lesser known vehicles such as DHEAAnd the OEA2-OG2-LGAnd the LEAAnd the DEA. But as far as two primary endocannabinoids go, researchers note that ayahuasca consumption increased anandamide levels and lowered levels of 2.AG.
While this is basically the opposite of what was noted in the 2018 Brazilian team’s case study, it doesn’t make sense to compare the two given their different designs. Nor does it make sense to try to stack any of the human studies against early preclinical work due to the exponentially greater complexity involved in administering a complex plant-based drink to humans versus straightforward serotonin for rat brain cells in the lab.
What we can glean so far from all the conflicting data is: the endocannabinoid system is modulated by activation of the same cell receptor that the classic drug targets, and ECS It is somehow involved in mediating the physiological effects of these powerful drugs. This seems like a path worth further exploration.