Psychedelics like MDMA have shown great promise in treating psychiatric disorders like PTSD. People with PTSD are often prescribed antidepressants in the selective serotonin reuptake inhibitor (SSRI) class. Individuals interested in using MDMA often ask about interactions with their antidepressants, which is an excellent question in terms of harm reduction.
Author’s note: This article is written in the spirit of harm reduction and does not constitute medical advice. Consult your doctor before combining any medication with psychedelics.
Psychedelics like MDMA have shown great promise in treating psychiatric disorders like PTSD, which is being studied in clinical trials sponsored by MAPS. People with PTSD are often prescribed antidepressants in the selective serotonin reuptake inhibitor (SSRI) class, which include fluoxetine (Prozac), sertraline (Zoloft), escitalopram (Lexapro), citalopram (Celexa) and paroxetine (Paxil). Individuals interested in using MDMA often ask about interactions with their antidepressants, which is an excellent question in terms of harm reduction.
SSRIs decrease the psychological effects of MDMA by up to 80%, meaning that euphoria and feelings of connectedness may be significantly reduced in those taking SSRIs1. This leads some people to take much higher doses of MDMA to overcome this blunting effect. However, SSRIs decrease the physical effects of MDMA (elevated blood pressure, heart rate and temperature) by only about 10%, meaning that higher doses of MDMA can cause overheating, abnormal heart rhythms and seizures. When taking MDMA and an SSRI together, it’s safest to stay within the therapeutic range of 75-125mg used in most studies, even if the positive effects are somewhat reduced.
MDMA releases large quantities of serotonin from neurons in the brain, while SSRIs prevent neurons from reabsorbing serotonin in the space between cells. For this reason, another major concern about taking these drugs together is serotonin syndrome, which occurs when the body enters a state of “serotonin overload.” Symptoms of serotonin syndrome include elevated temperature, instability of heart rate and blood pressure, agitation, muscle rigidity, confusion, seizures, coma and death. But does MDMA actually increase the risk of serotonin syndrome in people taking SSRIs? Multiple studies have suggested that the risk of serotonin syndrome is minimal, possibly due to the competition of MDMA and SSRIs at specific serotonin receptors in the brain2. There may still be a relationship between MDMA and serotonin syndrome, but it has not been shown in studies yet. Other medications like MAOI antidepressants and certain antibiotics have been strongly associated with serotonin syndrome in those taking MDMA, so be sure to avoid these altogether.
SSRIs should never be stopped abruptly. Doing so can cause a “discontinuation syndrome” of flu-like symptoms, insomnia, nausea and anxiety. If you want to stop taking an SSRI for any reason, it should be done slowly and under the supervision of your doctor.
What about bupropion (Wellbutrin), another commonly prescribed antidepressant? Unlike SSRIs, bupropion may actually prolong the positive mood effects of MDMA. Bupropion does not interact meaningfully with the serotonin system, effectively reducing the risk of serotonin syndrome to near-zero. This doesn’t mean that combining bupropion with MDMA is 100% safe, however. Bupropion is well-known for lowering the seizure threshold, especially when combined with stimulants like amphetamines, cocaine, and MDMA. If you are prone to seizures or take higher doses of bupropion, talk to your doctor about how to proceed safely.
Setspire is an advocate for safe, intentional and legal use of psychedelic medicines.
1Sarparast et al. Drug-drug interactions between psychiatric medications and MDMA or psilocybin: a systematic review. Psychopharmacology, 2022.
2Silins E, Copeland J, Dillon P. Qualitative review of serotonin syndrome, ecstasy (MDMA) and the use of other serotonergic substances: hierarchy of risk. Aust N Z J Psychiatry. 2007 Aug;41(8):649-55. doi: 10.1080/00048670701449237. PMID: 17620161.
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