Immunological Effects of Ayahuasca in Humans

Ayahuasca is a botanical hallucinogen traditionally used by indigenous groups in the northwestern Amazon and more recently adopted therapeutically by Mestizo populations and as a sacrament in Brazilian syncretic religions. The brew is typically made from Banisteriopsis caapi, which contains β-carbolines (harmine, tetrahydroharmine (THH), harmaline), combined with Psychotria viridis or Diplopterys cabrerana, which supply the tryptamine dimethyltryptamine (DMT). β-carbolines inhibit monoamine oxidase-A, permitting orally ingested DMT to reach the central nervous system where it acts at serotonergic 5-HT1A/2A/2C receptors and may engage glutamatergic mechanisms implicated in hallucinogenic effects. Given the growing use of ayahuasca worldwide and interest in its therapeutic potential, Guimarães and colleagues noted a gap in knowledge about its immunological effects in humans. The present article therefore aims to review the available human data on how ayahuasca ingestion affects immune parameters, summarising controlled acute studies and any identified long-term observational data.

The investigators performed electronic searches in PubMed using the terms “ayahuasca”, “dimethyltryptamine”, “harmine”, or “harmaline” combined with “immunity” or “immune”, and included all studies published up to September 2014 with no language restriction. Searches of specialised books, book chapters and doctoral theses were also undertaken. Inclusion criteria were: (1) double‑blind, placebo‑controlled clinical trials of acute ayahuasca administration and (2) studies of long‑term ayahuasca consumption. Excluded were in‑vitro and animal studies. The search returned four published papers, of which two met the inclusion criteria; the other two were an in‑vitro study and a review and were excluded. Both included acute human trials were double‑blind, randomised, crossover clinical studies conducted by the study team using freeze‑dried ayahuasca imported from Brazil and prepared from B. caapi and P. viridis. The freeze‑dried material was analysed and reported to contain 8.33 mg DMT, 14.13 mg harmine, 0.96 mg harmaline and 11.36 mg THH per gram. In the first acute trial, 10 healthy volunteers received encapsulated freeze‑dried ayahuasca at 1.0 mg DMT/kg body weight, placebo and an active control (20 mg d‑amphetamine) in a double‑blind, randomised, crossover design; subjective, neurophysiological, autonomic, neuroendocrine and immunological measures were taken before and at regular intervals up to 12 hours post‑dose. The second acute trial used a similar double‑blind, randomised, crossover design to assess tolerance or sensitisation after two consecutive oral ayahuasca doses of 0.75 mg DMT/kg each, with the same measurement schedule up to 12 hours after the first dose. The extracted text does not clearly report the sample size for the second trial. For long‑term effects, the reviewers located a clinical evaluation reported in a book chapter that compared 15 long‑term church members (≥10 years use) with 15 matched controls; immunity data were collected before ayahuasca ingestion and the primary reported measure was total leucocyte counts.

Of the four items identified by the search, two acute human trials met the inclusion criteria and were analysed; the other two identified items were excluded (an in‑vitro study and a review). In the first acute trial (n=10), ayahuasca produced a significant decrease in total lymphocyte percentages compared with placebo and with d‑amphetamine. Both ayahuasca and amphetamine produced significant reductions in CD3 and CD4 lymphocyte levels versus placebo. CD19 (B‑cell) levels showed no change in the overall analysis, although a time‑course analysis revealed a significant decrease at two hours after ayahuasca. Natural killer (NK) cell levels were significantly increased after ayahuasca and amphetamine versus placebo. No differences between treatments were evident at 24 hours, indicating the effects were transient. The second acute trial reported a similar pattern—decreases in CD3 and CD4 lymphocytes and increases in NK cells after ayahuasca—and found no evidence of tolerance or sensitisation for the measured immunological variables following two consecutive doses. The freeze‑dried ayahuasca used in both trials had the same alkaloid concentrations as reported above. The only long‑term human data located came from a clinical evaluation of 15 long‑term church members who consume ayahuasca regularly (typically twice monthly, sometimes several times per week) compared with 15 matched controls. That study reported no significant differences in total leucocyte counts between long‑term ayahuasca consumers and controls. The extracted text does not provide additional immunophenotyping details for the long‑term cohort.

Guimarães and colleagues interpret the acute human findings as a transient lymphocyte redistribution characterised by reductions in CD3 and CD4 T‑cell percentages and concurrent increases in NK cells; the long‑term data showed no difference in total leucocyte counts between frequent ritual users and matched controls. The authors discuss two broad mechanistic possibilities. First, DMT and related hallucinogens may act directly on immune cells through serotonergic receptors: 5‑HT2A receptors are expressed on central and peripheral immune cells and animal studies with 5‑HT2A agonists (for example DOI) have produced changes in T‑cell subsets and anti‑inflammatory effects that were reversed by 5‑HT2A antagonists. Thus, DMT could alter leukocyte differentiation, function or cytokine secretion via direct 5‑HT receptor activation. Second, a nonspecific neuroendocrine stress response could account for lymphocyte changes. Acute ayahuasca increases cortisol and urinary normetanephrine, suggesting activation of the hypothalamic‑pituitary‑adrenal axis and the sympathetic nervous system; such responses are known to redistribute lymphocytes in acute stress and resemble immune profiles produced by psychostimulants such as d‑amphetamine and MDMA. The authors also review in‑vitro and animal evidence that DMT can modulate immune function via the sigma‑1 receptor and that β‑carbolines can suppress certain lymphocyte functions in vitro. These diverse mechanisms could contribute to the observed immunological signals. With respect to clinical significance, the investigators note that decreases in CD3 and CD4 are conventionally viewed as potentially detrimental because these cells regulate cytotoxic T cells and B‑cell responses; however, in the reported acute studies the changes were transient and not clearly pathological. The absence of differences in total leucocytes among long‑term ritual users may reflect infrequent dosing schedules (commonly bimonthly) allowing recovery between ingestions, but the authors caution that the long‑term data are limited. The authors acknowledge important limitations: small sample sizes in the acute trials, multiple statistical comparisons, lack of reported sample size for one trial in the extracted text, and in the long‑term study lack of dose control and reliance on total leucocyte counts as the sole immunological parameter. They conclude that, given ayahuasca’s growing popularity and its ritual pharmacology, the potential impact of regular ayahuasca use on human immunity warrants further, more detailed investigation.