Contraindications and Concomitant Medications and Supplements

MDMA is likely to interact with many psychiatric medications (MAPS, 2021); however, MDMA may be used safely with some previously approved medications for post-traumatic stress disorder (PTSD), such as paroxetine (an SSRI antidepressant), though it may cause attenuation or reversion of certain subjective effects associated with MDMA administration (Segura et al., 2005).

Health professionals should be mindful of possible interactions and consult a physician or pharmacist on the possibility of interactions. Any change in medication should be overseen by a licensed medical provider. Use of psychedelic medicines other than ketamine in a clinical setting is very new and, has for many years, been limited to highly controlled clinical trials. Not all concomitant medications have been studied.

Contraindications

The following are contraindications for MDMA administration.

  • Ongoing use of a medication that has a potential interaction with MDMA, including most types of psychiatric medications, where the medication cannot be tapered (see concomitant medications).

  • Present suicide risk that makes MDMA-assisted psychotherapy unsafe (though history of suicide attempts may not be an exclusion).

  • Current substance use disorder (screening physician should evaluate on a case-by-case basis).

  • Current eating disorder with active purging.

  • Unwillingness to abstain from use of psychoactive substances 24 hours prior to treatment.

  • First-degree relatives with any psychotic disorders or bipolar disorders.

  • History of (or a current) primary psychotic or mental health disorder, which may include bipolar affective disorder type 1, major depressive disorder with psychotic features, or current dissociative identity disorder.

  • Have a history of ventricular arrhythmias at any time (other than occasional premature ventricular contractions in the absence of ischemic heart disease within past 12 months.

  • Have Wolff-Parkinson-White syndrome or any other accessory pathway that has not been successfully eliminated by ablation.

  • Have a marked baseline prolongation of QT/QTc interval or additional risk factors for Torsade de pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).

  • Have a diagnosis of uncontrolled essential hypertension (blood pressure values ≥135/85mmHg on three separate occasions).

  • Have a history of significant hyponatremia or hyperthermia.

  • Any additional medical condition that could make receiving a stimulant medication harmful because of increases in blood pressure, heart rate, or other concerns, such as liver, heart, or kidney disease, or uncontrolled hypertension (to be determined by the screening physician).

  • Clients who are pregnant, breastfeeding, or planning/attempting to become pregnant during treatment period and are not practising an effective means of contraception.

  • Breastfeeding clients are encouraged to abstain from breastfeeding for a minimum of 48 hours (and up to 96 hours) following treatment (~4-5 half-lives though this is an estimate based on a half-life of ~7-8 hours. Depending on the acidity of a mother’s urine, elimination can be delayed substantially.

Note

While it is believed that MDMA doesn’t cause psychosis, mania, bipolar disorder, or borderline personality disorder, more research is needed to determine whether MDMA causes or triggers an earlier onset of these conditions.

Additional Scenarios

In addition to the contraindications, if the client meets any of the following criteria, MDMA-assisted therapy is not recommended.

  • Are not able to give adequate informed consent.

  • Lack of fluency in the language of the treating health professionals.

  • Lack of stable living situation or lack of supportive family/network.

  • Have any current problem which, in the opinion of the health professionals or supervising physicians, might interfere with participation in treatment.

Concomitant Medications and Supplements

There are myriad more potential drug interactions between MDMA and other substances. The following are selected based upon commonality or potential for severe risks in combination.

Please ensure that you read through all items before proceeding by selecting each title.

Drug Interaction
Lithium

Increased risks of seizures have been reported when using MDMA in combination with lithium (Nayak et al., 2021).
CYP inhibitors (e.g. ritonavir/cobicistat)

Increased risks of serotonin syndrome in combination with MDMA. Fatalities reported in literature (Antoniou & Tseung, 2002).
Monoamine Oxidase Inhibitors

Increased risks of serotonin syndrome in combination with MDMA. Fatalities reported in literature, use in combination is an absolute contraindication (Pilgrim et al., 2012; Davies et al., 2018; Vuori et al., 2003; Cohen et al., 2021).
SSRI/SNRI antidepressants

Diminished effects of MDMA when in combination and for a period after antidepressants have been continue. Use in combination a relative contraindication due to lowered benefits of MDMA assisted therapy (Feduccia, 2020).
Stimulants

Increased cardiovascular risks in combination with MDMA. Co-ingestion of stimulants have been associated with increased neurotoxicity (Mohamed et al., 2011).
Bupropion

Increased concentration of MDMA and prolongs duration of experience. May increase risks of seizures in combination (Schmid, 2015).

In collaboration with the treatment physician, prescribed psychiatric medications will be tapered by the referring physician and discontinued at least five half-lives before MDMA administration if considered safe and reasonable to do so. These medications include, but are not limited to:

  • Tricyclic antidepressants

  • Lithium

  • Selective Serotonin Reuptake Inhibitors (SSRIs)

  • Serotonin-Norepinephrine Reuptake Inhibitor (SNRIs)

  • Monoamine Oxidase Inhibitors (MAOIs)

  • St. John’s Wort

  • First and second-generation antipsychotic medications

  • Mood stabilizers including valproic acid, carbamazepine, topiramate

  • Stimulant medications including amphetamines

  • Any other medications viewed by the treatment physician as having potential serotonin activity

  • Opioid medications outside of a client’s opioid agonist therapy that is deemed by the treatment physician to present a safety risk or preclude successful participation in treatment

Health Professional Tip

How should you talk to your clients about relative and absolute contraindications when it comes to MDMA-assisted therapy?

Because this is a new treatment, cautions must be taken to ensure there are no underlying mental or physical vulnerabilities that may put the client at a greater risk of adverse side effects or potential harms. Current standard contraindications draw from conditions that have been excluded due to potential for risk in research that has been done to validate the treatment. Since MDMA increases blood pressure and heart rate, individuals with certain cardiovascular concerns must be evaluated for risks of this exposure. Also, because MDMA has psychoactive properties that cause a significant alteration in mood, thought, and behaviour during the acute effects, it’s important for individuals with mental health concerns to be evaluated for risk and appropriateness.

A relative contraindication is like an orange light/caution suggesting further evaluation and careful decision making weighing potential risks and benefits through informed consent.

An absolute contraindication is like a red light, meaning that this treatment is currently not recommend for someone with this particular condition.

As more research is done, inclusion and exclusion criteria typically broaden so that treatments can be proven safe enough for a broader range of people with a greater variety of underlying mental and physical health conditions.

References

Antoniou, T. and A.L. Tseng, Interactions between recreational drugs and antiretroviral agents. Ann Pharmacotherapy, 2002. 36(10): p. 1598-613.

Pilgrim, J.L., et al., Serotonin toxicity involving MDMA (ecstasy) and moclobemide. Forensic Sci Int, 2012. 215(1-3): p. 184-8.

Davies, N., W. English, and J. Grundlingh, MDMA toxicity: management of acute and lifethreatening presentations. Br J Nurs, 2018. 27(11): p. 616-622.

Vuori, E., et al., Death following ingestion of MDMA (ecstasy) and moclobemide. Addiction, 2003. 98(3): p. 365-8.

Cohen, I.V., Makunts, T., Abagyan, R. et al. Concomitant drugs associated with increased mortality for MDMA users reported in a drug safety surveillance database. Sci Rep 11, 5997 (2021). https://doi.org/10.1038/s41598-021-85389-x

Feduccia, A.A., et al., Discontinuation of medications classified as reuptake inhibitors affects treatment response of MDMA-assisted psychotherapy. Psychopharmacology, 2020.

MAPS. (2021). Multidisciplinary Association for Psychedelic Studies Investigator's Brochure. In (13 ed.). San Jose: MAPS.

Mohamed, W.M., et al., MDMA: interactions with other psychoactive drugs. Pharmacol Biochem Behav, 2011. 99(4): p. 759-74.

Nayak, S. M., Gukasyan, N., Barrett, F. S., Erowid, E., Erowid, F., Griffiths, R. R. (2021). Classic Psychedelic Coadministration with Lithium, but Not Lamotrigine, is Associated with Seizures: An Analysis of Online Psychedelic Experience Reports. Physicians Weekly. https://www.physiciansweekly.com/classic-psychedelic-coadministration-with-lithium-but-not-lamotrigine-is-associated-with-seizures-an-analysis-of-online-psychedelic-experience-reports

Schmid, Y., et al., Interactions between bupropion and 3,4-methylenedioxymethamphetamine in healthy subjects. J Pharmacol Exp Ther, 2015. 353(1): p. 102-11.

Segura, M., Farré, M., Pichini, S., Peiró, A. M., Roset, P. N., Ramírez, A., . . . de la Torre, R. (2005). Contribution of cytochrome P450 2D6 to 3,4-methylenedioxymethamphetamine disposition in humans: use of paroxetine as a metabolic inhibitor probe. Clin Pharmacokinet, 44(6), 649-660. https://doi.org/10.2165/00003088-200544060-00006