Scientists investigate the relationship between serotonin and cannabinoid signaling. The following article will give you a picture regarding the relationship between the endocannabinoid system and Ayahuasca.

THC produces most of its psychoactive effects through the CB1 cannabinoid receptor, whereas the “classic” psychedelics – LSD, psilocybin, mescaline, and dimethyltryptamine (DMT) – are characterized by activation of the serotonin 5-HT2A receptor.

5-HT2A receptors, which are widely distributed throughout the central nervous system, mediate a variety of essential activities, including learning and memory, perception, inflammation, hormone regulation, and of course hallucination.

Given the significance of the endocannabinoid system (ECS) as a “master regulator” of many of these processes and others, it is not surprising that 5-HT2A likely exerts some of its downstream effects via modulating the release and signaling of endogenous cannabinoids.


In rat brain cells stimulated with serotonin at 5-HT2A receptors, a 2006 study co-authored by renowned psychedelic scientist David Nichols reveals a rise in the endocannabinoid 2-AG, but not in anandamide, the other major endocannabinoid. Help us to understand more about the relationships between the endocannabinoid system and Ayahuasca. The conclusion of the study is that neurotransmitters such as serotonin may regulate endocannabinoid tone.

Two years later, another study demonstrates that the stimulation of 5-HT2A in rat neurons by serotonin not only impacts the production of endogenous cannabinoids, but also the expression of the CB1 receptor. This cannabinoid receptor, which is the target of 2-AG, anandamide, and THC, is essential to the psychoactivity of cannabis and is involved in numerous cognitive and physiological processes. The authors write, “These findings show a connection between serotonin signaling and endocannabinoid signaling.” This pathway may mediate a number of 5-HT2R effects across the brain.

Today, some 15 years later, two new studies from two separate research groups explore this link in human subjects after a psychedelic dose of ayahuasca, a complex brew containing DMT, a 5-HT2A agonist and potent psychedelic, as well as other plant compounds that may interact with the endocannabinoid system in a less direct manner.

Whether or not definitive conclusions can be taken at this time, this research represents a significant advance in the examination of crosstalk between these two essential neurotransmitter systems and the physiological cascade involved in the psychedelic experience.


A team of Brazilian researchers, where ayahuasca, the potent hallucinogenic plant concoction, has a long history of shamanic use, sought to answer a decidedly modern scientific question: how does ayahuasca administration affect endocannabinoid levels in healthy volunteers as opposed to those diagnosed with social anxiety disorder?

To understand more about the endocannabinoid system and Ayahuasca, the researchers conducted two small pilot randomized and placebo-controlled proof-of-concept experiments. Twenty healthy participants were given a single dose of ayahuasca or a placebo in the first study. In the second study, 17 participants with social anxiety disorder got either a placebo or a single dose of ayahuasca that was nearly half as strong. Blood samples taken at baseline and 90 and 240 minutes after injection were later analyzed for anandamide and 2-AG concentrations.

The results, which were published in the journal Human Psychopharmacology in February 2022, indicate substantial variability in both trials, with biphasic effects reported in some cases (often an increase followed by a reduction, but sometimes the opposite) and continuous increases or decreases in others. Few results were statistically significant; conclusions are scarce.

“Considering the results of both tests together, it appears that in social anxiety disorder patients, ayahuasca increased [anandamide] levels from baseline to 90 minutes after its intake, and then reduced them below baseline levels at the 240-minute time-point,” the authors write, adding: “The study may have been underpowered due to the small sample size, and it is possible that statistically significant differences could have been observed with a larger sample size.”

Not only were the results contradictory and misaligned with preclinical studies, but they also contradicted earlier findings by the same research. In a 2018 letter to the editor published in the Journal of Clinical Psychopharmacology, researchers describe testing endocannabinoid levels in the blood of a single healthy 34-year-old guy before, 90 minutes after, and 240 minutes after ayahuasca consumption. The outcome? For anandamide, a consistent reduction below baseline; for 2-AG, a small decrease followed by a sharper rise.


For those keeping track about the endocannabinoid system and Ayahuasca, that’s four distinct studies with four distinct findings. In a fifth study, published in the May 2022 issue of Biomedicine and Pharmacotherapy, plasma samples were taken from 23 healthy frequent Dutch users of ayahuasca before and after intake.

The researchers from Spain evaluated a long variety of metabolic markers, including amino acids, hormones, neurotransmitters, and a dozen endocannabinoids, such as anandamide, 2-AG, and lesser-known substances such as DHEA, OEA, 2-OG, 2-LG, and DEA. Regarding the two principal endocannabinoids, however, the researchers noticed that ayahuasca use increased anandamide levels and lowered 2-AG levels.

Despite the fact that this is practically the exact reverse of what was discovered in the Brazilian team’s 2018 case study, it makes little sense to compare the two systems. Due to the considerably increased intricacy involved in providing a complex botanical concoction to humans as opposed to administering pure serotonin to rat brain cells in vitro, it makes little sense to compare human studies to early preclinical research.

The endocannabinoid system is altered by activation of the same cell receptor targeted by classic psychedelics, and the ECS is implicated in mediating the physiological effects of these potent medications. And that appears to be a path worthy of further investigation.

We hope you enjoyed our article regarding the endocannabinoid system and Ayahuasca. Now, in the next article, we intend to shed light on the topic of how CBD really is related to psychedelics. Enjoy reading and stay healthy and wealthy. ?

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