Psychedelic Drug Interactions and Toxicology

Urgent first

Serotonin syndrome, seizures and severe agitation are emergencies. In the US call 911; for suspected poisoning call Poison Help at 1-800-222-1222. See poisoning: what to do first. Never stop, start or change a prescribed medicine on the basis of this page; talk with the prescriber. This page is education only and gives no instructions for combining substances.

Quick answer

Interaction evidence for psychedelics is thin. It comes mostly from small human studies of LSD and MDMA, case reports and online self-reports. Two combinations stand out in the sources read: ayahuasca, which contains a monoamine oxidase inhibitor (MAOI), with other serotonergic substances (risk of serotonin syndrome); and classic psychedelics with lithium (reported seizures). Evidence labels: insufficient evidence overall; evidence of harm for the specific reports below.

What the main reviews found

• A 2024 systematic review of 52 human studies (32 on LSD, 10 on psilocybin, 4 on mescaline, 3 on DMT, 2 on 5-MeO-DMT and 1 on ayahuasca) found that combining psychedelics with other drugs, including antidepressants, antipsychotics, mood stabilizers and anxiolytics, could weaken effects, strengthen them, or change nothing. Apart from a few case reports, no serious adverse drug events were described. [1] Because most data are about LSD, they do not simply transfer to psilocybin.
• A 2022 review of 40 publications on MDMA or psilocybin with psychiatric medicines included 26 randomized studies in healthy adults, 3 epidemiologic studies and 11 case reports. [2] Many studies are small and in healthy volunteers rather than in people taking long-term medicines.

Trial protocols also show how cautious researchers are: in one large trial, people on psychotropic medicines were eligible only after a medication taper. [3] (This describes a study rule and is not advice for anyone to taper.)

SSRIs and other antidepressants

The reviews above found mixed effects (blunted, increased or unchanged) and no consistent serious events in studies, but they did not establish that combinations are safe. [1][2] Because evidence is limited and the effects vary, decisions about any medicine belong with the prescriber.

Lithium

A 2021 analysis of online experience reports found that 47% of 62 reports of classic psychedelics taken with lithium involved seizures, compared with none of 34 reports with lamotrigine. [4] These are self-reported, unverified accounts, not clinical data, so the true rate is unknown. The authors provisionally concluded psychedelic use may pose a significant seizure risk for people on lithium. [4]

MAOIs and ayahuasca

Ayahuasca is a traditional Amazonian brew that combines a plant containing a monoamine oxidase inhibitor with a plant containing DMT. Risks include psychotic episodes related to DMT and serotonin syndrome, which can be life threatening, and the consequences are uncertain because of poor quality control, unpredictability and polydrug interactions. [5] A 2026 case report described a 46-year-old man who developed severe serotonin syndrome and respiratory failure after ayahuasca followed by over-the-counter dextromethorphan and diphenhydramine; he needed intensive care and recovered. [6] The authors say the MAOI content predisposes people to serotonin toxicity when combined with other serotonergic agents. [6] For the plant itself see ayahuasca and Amazonian plants. Medicine-by-medicine lists were not available from the sources read.

Alcohol and other substances

NIDA says fatal overdoses involving some psychedelic and dissociative drugs are typically associated with very high doses or combinations, particularly with alcohol. [7]

Toxicology

• Physical toxicity. NIDA says fatal overdoses and serious adverse effects are rarely associated with typical use of commonly used psychedelics, although some substances, including ibogaine, have been linked to deaths and serious effects. [7] See iboga and ibogaine.
• Heart. Supervised studies show temporary rises in blood pressure; mean heart rhythm (QTc) effects at standard exposure are small; a valve concern from chronic exposure is biologically plausible, but clinical valve injury has not been established. [8]
• Contamination and variable content. Illicit drugs can contain colorless, odorless fentanyl. [7] Mushroom products can vary in active content by more than an order of magnitude. [8]
• Pregnancy. No eligible human pregnancy outcome studies were found for psilocybin or ayahuasca. [9]

Gaps

Proper evidence not found in the sources read for most medicine-by-medicine combinations, for herbs and supplements taken with psychedelics, or for older adults and people with kidney or liver disease. Absence of data is not evidence of safety. [9]

Next steps

Bring a full list of medicines and supplements to a clinician: how interactions work and talking with a health professional. See also adverse effects and contraindications.