[Solved] Is ayahuasca toxic?

The Ayhuasca brew combines the MAO-inhibiting β-carbolines from the Banisteriopsis caapi-lianes with the psychedelic N,N-dimethyltryptamine (DMT) from Psychotria viridis-leaves. Although its use is growing, questions remain regarding the toxicological risks and interactions with the immune system. Ayahuasca's toxicity is multifactorial, arising from pharmacokinetic interactions, receptor pleiotropy, and oxidative metabolites. The immunological effects show a delicate balance between anti-inflammatory action and immune activation.

Primary psychoactive components

The toxic and physiological effects of ayahuasca are intrinsically linked to its unique synergistic formula. The B. caapi provides β-carbolines such as harmine, harmaline, and tetrahydroharmine, which selectively inhibit monoamine oxidase-A (MAO-A) with IC₅₀ values between 5-50 nM. This inhibition blocks the first-pass metabolism of DMT in the intestine and liver, increasing oral bioavailability from <1% to >60%. DMT itself acts as a serotonergic agonist with high affinity for 5-HT₂A receptors ($K_i=118$ nM), but also shows interactions with σ₁-receptors and trace amine-associated receptors (TAAR6).

Secondary metabolites and potential toxins

In addition to the primary alkaloids, raw ayahuasca contains traces of:

• β-carboline derivatives with DNA-intercalating properties (e.g. harman)
• Oxidative metabolites such as harmol and harmalol, which generate free radicals via redox cycling
• Plant-specific glycoproteins that can trigger allergic reactions in sensitive individuals

These components contribute to the overall toxicological load, especially with chronic use or high dosages.

Acute toxic effects

Clinical studies report dose-dependent side effects:

These effects are mediated by:

1. Intestinal MAO inhibition: Local serotonin accumulation activates 5-HT₃ receptors in the vomiting center.

2. Sympathetic activation: DMT-induced noradrenaline release via TAAR1 receptors in the locus coeruleus.

3. Vasoconstriction: 5-HT₂B-agonistic effects on peripheral blood vessels.

Chronic toxicity

Animal studies demonstrate hepatotoxicity upon prolonged exposure to high β-carboline doses (100 mg/kg/day), with:

• Threefold increase in liver enzymes (ALT/AST)
• Histopathological signs of centrilobular necrosis
• Glutathione depletion due to CYP1A2-induced oxidative stress

In humans, however, no significant liver damage has been reported with traditional usage patterns (1-2x/month).

Innate immune response

In vitro studies reveal complex interactions:

• DMT (1-10 μM):
• ↓ LPS-induced TNF-α production in macrophages via σ₁ receptor-mediated inhibition of NF-κB
• ↑ IL-10 secretion by dendritic cells, suggesting tolerogenic immunomodulation

• Harmine (5-20 μM):
• Inhibition of NLRP3 inflammasome activation via direct binding to NEK7
• Suppression of TH17 differentiation by RORγt antagonism

Animal data suggest context-dependent effects: in a mouse model for colitis, ayahuasca (equivalent human dose) reduced histological inflammation with 62%, while in tumor models it increased macrophage infiltrate.

Adaptive immunity

Lymphocytes show sensitivity to β-carbolines:

• CD4⁺ T-cells: Harmaline (IC₅₀ = 8 μM) blocks IL-2 production via calcineurin inhibition
• B cells: DMT (10 μM) induces IgM secretion through 5-HT₂A-dependent ERK activation

Interestingly, in observational studies, ayahuasca users show 23% lower CRP levels than controls, possibly indicating systemic anti-inflammatory effects (just like with psilocybin).

Neutrophils

Acute ayahuasca exposure (1 x 200 mg DMT) induces:

• 40% reduction in CD11b expression → reduced adhesion/migration
• Increased NETosis via NADPH-oxidase-2 activation

These paradoxical effects (suppressed function but increased NET formation) suggest contextual immunomodulation.

Natural killer cells (NK)

β-carbolines modulate NK activity in a dose-dependent manner:

• Low doses (0.1-1 μM harmine): ↑ cytotoxicity due to perforin/granzyme upregulation
• High doses (>10 μM): ↓ IFN-γ production via JAK/STAT inhibition

Clinically, this may translate into improved tumor immunosurveillance with low-frequency use.

Conclusion

Based on the research, it can be concluded that ayahuasca contains a complex combination of active substances with potentially toxic properties, especially at high doses or with frequent use. Acute side effects—such as nausea, vomiting, tachycardia, and hypertension—occur dose-dependently and are primarily caused by the combination of MAO inhibition and serotonergic activation. Although animal studies associate hepatotoxicity with high doses of β-carbolins during prolonged exposure, such effects are not significantly demonstrated in humans with traditional use (1–2 times per month). Furthermore, the immunomodulatory effects indicate a context-dependent response that can have both beneficial and potentially adverse effects.

In short, ayahuasca is not inherently toxic when used in a controlled and traditional manner, but excessive or frequent use can lead to toxic effects. However, the MAO-inhibiting effects of ayahuasca must be taken into account; these, in combination with substances such as tyramine, can cause acute poisoning. Furthermore, serotonergic medication must also be considered to ensure deadly serotonin syndrome to prevent. People with liver conditions may need to be careful with frequent use of ayahuasca.

Ayahuasca is usually safe with occasional and careful use, but not without risk. It is especially important to take into account your medication use, diet, and health condition (for example, liver problems).

What makes ayahuasca potentially toxic?

The toxicity of ayahuasca arises from the complex interaction of various factors:

1. MAO inhibition: β-carbolines inhibit monoamine oxidase-A (MAO-A), which is necessary to activate DMT upon oral intake. However, this also impairs the breakdown of other substances (such as tyramine), which, with an improper diet or medication use, can lead to dangerous hypertension or even serotonin syndrome.

2. Oxidative metabolitesDuring the breakdown of ayahuasca, free radicals can be formed that can stress liver cells, especially with repeated use or high doses. Liver damage has been observed in animal studies, but with traditional use (1–2 times per month), serious side effects are usually not seen in humans.

3. Secondary substances: Certain by-products in raw ayahuasca can have DNA-intercalating properties or trigger immune responses, especially in sensitive individuals.