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Although still criminalized in most of the US, psilocybin—the active ingredient in magic mushrooms—has shown promise as a treatment for depression, addiction, and other mental health conditions. But while it’s largely safe, psilocybin can interact badly with other drugs, especially stimulants and other hallucinogens, and with the medication often prescribed for those mental health conditions.

Is mixing magic mushrooms with other substances dangerous?

Taken on their own, magic mushrooms have the lowest risk profile of any recreational drug, with just 0.2% of 12,000 surveyed users needing emergency medical treatment.[1] There are no credible reports of lethal overdoses, and the greatest risk is thought to be “bad trips”—time-limited experiences of anxiety and paranoia.

However, magic mushrooms are significantly more dangerous when taken alongside other substances, both illicit and prescribed. Sometimes this mixing is unintentional: powdered “shrooms” may be cut with other drugs like PCP and MDMA

Psilocybin interacts particularly badly with stimulants, as both can increase heart rate and blood pressure. Combining magic mushrooms and depressants like alcohol and opioids can increase the risk of accidents and injuries.

Magic mushrooms also shouldn’t be taken alongside any other substance that acts on serotonin, such as other hallucinogens and antidepressants, as the combination could lead to serotonin syndrome, which can be fatal.

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Psilocybin and alcohol

Little research has been conducted into the effects of mixing psilocybin and alcohol. According to some reports, psilocybin may reduce the perceived effects of alcohol, potentially leading the individual to drink too much.[2] Other anecdotal reports claim that consuming alcohol increases the likelihood of a bad trip on mushrooms.

Additionally, both alcohol and mushrooms that contain psilocybin can cause nausea and vomiting. Combining the two, especially in high quantities, can make you feel sick. You may also experience disorientation and confusion and become dehydrated.[3]

Large amounts of alcohol cause a loss of coordination and lowering of inhibitions. This, combined with psychedelics’ distortion of perception, can increase the risk of injuries and accidents.[4]

Psilocybin has also been investigated as a treatment for alcoholism. In clinical trials, two doses taken over eight weeks reduced heavy drinking days for people with alcohol use disorder.[5]

Psilocybin and marijuana

Psilocybin and marijuana are a common combination. One study of poly-substance users found that nearly 60% of university students who had recently taken magic mushrooms consumed cannabis at the same time.[6] Anecdotal evidence suggests people use cannabis to manage nausea and anxiety mushrooms can cause or simply because they're daily cannabis users. They also report that cannabis can intensify the effects of psilocybin, especially the visual and audio hallucinations. But that intensity might be overwhelming and frightening for psychedelic novices.[7]

Psilocybin and stimulants

Stimulants, which include cocaine, amphetamines, and MDMA, increase blood pressure and heart rate. Psilocybin also has this effect and the combination can create potentially dangerous hypertension and tachycardia. In extreme circumstances, psilocybin and stimulants can cause heart attacks or seizures.[8]

Psilocybin and other hallucinogens

All hallucinogens, including psilocybin, LSD, and DMT, work in broadly similar ways by binding to serotonin receptors. This leads to cross-tolerance: regular or recent use of another psychedelic may mean the user feels only muted effects from psilocybin.

But simultaneous use can be hazardous. Combining two or more serotonergic drugs, such as psilocybin and another hallucinogen, can sometimes lead to dangerously high levels of serotonin, a dangerous condition known as serotonin syndrome. 

Mild cases of serotonin syndrome feature high blood pressure, elevated heart rate, shivering, sweating, jerking or twitching, and dilated pupils. More severe cases of serotonin also feature hyperactive bowel sounds and a temperature as high as 104 °F. In some cases, it can lead to shock, cardiac arrest, seizures, coma, and death.[9]

Psilocybin and antidepressants

Psilocybin has been investigated as a treatment for depression, with clinical trials showing that just two doses can cause improvement or even remission in some people for weeks.[10] The effect is so powerful that a letter from the US government’s Substance Abuse and Mental Health Services Administration (SAMHSA) suggests that psilocybin could gain FDA approval to treat depression as early as 2024.[11]

However, psilocybin may interact badly with traditional antidepressants that people are already taking.

Most modern antidepressants, such as SSRIs sertraline (Zoloft) and fluoxetine (Prozac) and SNRIs such as duloxetine (Cymbalta), primarily work by increasing levels of serotonin in the brain. Psilocybin acts similarly, binding to some of the same serotonin receptors. That leads to cross-tolerance: people on antidepressants may experience only minor psychedelic effects from psilocybin. 

Additionally, combining two serotonergic agents can cause serotonin syndrome, which in serious cases can be fatal. Antidepressant users who have taken more magic mushrooms because they initially didn't have much effect are at particular risk of serotonin syndrome.

Psilocybin and depressants (opioids)

There has been little research into the interaction of psilocybin and opioids. But it’s thought that psilocybin could increase opioids’ depressing effect on the central nervous system (CNS). In mild cases, this could mean loss of coordination, confusion, and drowsiness, More dangerously, it could mean the user's breathing and heart slow or even stop.

Psilocybin, when safely taken, may reduce drug use and cravings in people with opioid use disorder. A recent self-selecting survey examined the experiences of more than 150 people who had used psychedelics such as LSD (39%) and psilocybin (28%) and subsequently experienced a reduction or cessation in their opioid use.[12]

Psilocybin and benzos

Some people report using benzodiazepines like Valium to prevent bad trips when taking psilocybin and other hallucinogens such as LSD. They may also take benzodiazepines to dull some of the comedown symptoms from a psychedelic trip.

When psychedelic users seek medical treatment for bad trips, they’ll typically be given benzodiazepines. However, people should avoid self-medicating. The CNS depressant effects of benzodiazepines could, when paired with the perceptual distortion of psilocybin, lead to accidents and injuries. It may also be difficult to get the dosage right and people on psilocybin are at risk of accidentally taking excessively high doses of benzodiazepines, which could lead to respiratory depression, coma, and death.