Combining Psychoactive Substances, Alcohol and Other Sedatives

Urgent help first

Call 911 in the US for trouble breathing, unresponsiveness, seizures, a very high body temperature, chest pain, or confusion that is worsening. For a possible poisoning or overdose, US Poison Help is 1-800-222-1222 (other countries: poison help by country). In the US, 988 is the Suicide & Crisis Lifeline. This page describes risks. It does not advise how to combine substances, and it does not tell anyone to start, stop or change a medicine.

The basic picture

Most sources look at one substance at a time. Real-world use is often different. NIDA says that using psychedelic and dissociative drugs that contain contaminants, or using them in combination with other substances, may produce effects not associated with using these drugs alone. [1] NIDA also reports that evidence to date shows fatal overdoses involving these substances are typically associated with very high doses or with using combinations of drugs, particularly combining them with alcohol. [1]

Evidence labels used: approved medicine (for label statements), established, mixed, insufficient evidence, evidence of harm. See how we label evidence. Combining substances is not a single topic: each pairing has its own risks, and for many pairings no evidence exists.

How common is combining?

A survey of 98 active MDMA and hallucinogen users in Denmark found simultaneous use of several substances was prevalent among MDMA, LSD and psilocybin users, in particular with alcohol and cannabis. Alcohol and cannabis were typically used before, during and after these drugs. [2] This shows what people report doing, not what is safe. The sample was small and recruited through advertisements and word of mouth.

Alcohol

MDMA and alcohol. A 2021 systematic review concluded that alcohol adds to the existing risk of MDMA-induced hyperthermia (overheating), dehydration and low sodium (hyponatremia). It reported that alcohol interacts with several drivers of these problems, including exposure to high ambient temperatures, heavy exercise such as vigorous dancing, and delayed sweating. The authors concluded that recreational and clinical MDMA users should refrain from drinking alcohol to reduce the risk of health incidents. [3] Label: evidence of harm (systematic review). MDMA is not a classic psychedelic; see MDMA versus classic psychedelics.

Classic psychedelics and alcohol. Proper evidence not found for controlled human studies of alcohol combined with psilocybin or LSD. We checked PubMed searches for alcohol with psilocybin and LSD and found reports of co-use, not interaction trials. NIDA's statement that deaths are associated with combinations, particularly with alcohol, is general. [1]

Prescription MAOIs and alcohol. The US label for the MAOI antidepressant phenelzine says it should not be used with central nervous system depressants such as alcohol and certain narcotics. [4] For MAO-inhibiting preparations, see MAO-inhibiting preparations and interactions.

Benzodiazepines and other sedatives

Benzodiazepines are prescription sedatives used for anxiety, sleep and seizures. The US label for the benzodiazepine lorazepam carries a boxed warning that using it with opioids may result in profound sedation, respiratory depression, coma and death. It also says abuse and misuse of benzodiazepines commonly involve concomitant use of other medicines, alcohol or illicit substances, which is associated with more frequent serious adverse outcomes. [5] The label also warns that abrupt discontinuation after continued use may precipitate life-threatening withdrawal reactions, which is why changes belong with a prescriber. [5] Label: approved medicine (lorazepam; US FDA).

Research settings sometimes use sedatives under medical supervision. A systematic review noted that GABAergic agents such as benzodiazepines have been advocated as an intervention to mitigate acute psychological or physiological adverse effects of psychedelics. [6] That is a clinician's tool in a monitored setting. It is not a recommendation for self-treatment, and it does not tell anyone that sedatives are safe alongside psychedelics.

For HPPD, one systematic review found benzodiazepines ineffective when LSD was the trigger. [7] See persistent perceptual symptoms.

Proper evidence not found for quantified risks of combining classic psychedelics with benzodiazepines or opioids outside the label statements above.

Stimulants, cannabis, dextromethorphan and others

• Serotonin-active medicines and drugs. MedlinePlus says street drugs including amphetamines, cocaine, opiates, ecstasy and LSD have been associated with serotonin syndrome, and that MAOIs can cause it with dextromethorphan, meperidine and fentanyl. [8] See serotonergic medicines.
• A case report. A 2026 case described severe serotonin syndrome with respiratory failure after ayahuasca, then over-the-counter dextromethorphan and diphenhydramine. [9]
• Cannabis. Co-use with psychedelics is common in surveys. [2] Proper evidence not found for interaction data on this pairing in this session's sources. See cannabis and CBD interactions.
• Hidden ingredients. NIDA says more research is needed on whether certain psychedelic and dissociative drugs are mixed with contaminants such as fentanyl. [1] See contamination and adulteration.

Who is at higher risk

People with heart, liver or kidney disease, mental health conditions, or those taking prescribed medicines should talk with a clinician before any substance use, because the sources above do not cover individual situations. See existing conditions and talking with a health professional.

What the evidence cannot say

• Which combinations are "safe". No source here supports a safe pairing.
• How risk changes with different amounts or products; the sources do not give reliable personal-use information, and this page deliberately does not.
• How common serious problems from combinations are in the general population.

For other pages see psychedelic drug interactions and toxicology and substance use support and urgent help.