MDMA Safety Check: Exploring Drug Interactions

Overview: MDMA (ecstasy, Molly) can have dangerous interactions with other medications, supplements, and even some foods. These interactions can change how MDMA works in your body, potentially leading to weaker effects, worsened side effects, or even serious health risks like serotonin syndrome. Adrenergic drugs (e.g., pindolol) may reduce some MDMA’s effects like heart rate increase but may not affect others. More research is needed. Antipsychotics (e.g., haloperidol) can completely change MDMA’s effects, making it unpleasant instead of euphoric. Bupropion (Wellbutrin) may prolong MDMA’s positive effects but also increase its levels in the body, potentially leading to higher risks, and serious interactions have been reported. Stimulants (e.g., methylphenidate) may delay MDMA’s effects, increase heart rate/blood pressure, and worsen negative side effects. SSRIs (e.g., fluoxetine) significantly weaken both the positive and negative effects of MDMA.  Serious interactions are unlikely but have been reported. Similar to SSRIs, SNRIs (e.g., duloxetine) weaken MDMA’s effects and may reduce some physiological changes. MDMA and MAOIs (e.g., phenelzine) is an extremely dangerous combination that can lead to life-threatening serotonin syndrome. Reboxetine weakens both positive and negative effects of MDMA but increases its levels in the body. Ritonavir (HIV medication) may significantly alter MDMA’s metabolism, potentially increasing its toxicity.

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MDMA and Other Drugs: Exploring Potential Interactions

MDMA, also known as ecstasy or Molly, can have significant interactions with other medications. A drug interaction occurs when the effects of one drug are altered by the presence of another drug, food, beverage, or supplement.

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These interactions can lead to changes in the way drugs are metabolized, absorbed, distributed, or eliminated from the body, which can result in either increased or decreased drug efficacy or potential side effects.

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Drug interactions are an important factor to consider when considering the use of MDMA. There are two main types of drug interactions:

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• Pharmacokinetic Interactions: These interactions affect the absorption, distribution, metabolism, or excretion of drugs in the body. For example, one drug may inhibit (block) or increase the activity of the enzymes responsible for metabolizing another drug, leading to altered blood levels of the affected drug. In the context of medications, some enzymes play a crucial role in metabolizing (breaking down) drugs. This breakdown process helps the body eliminate the drug and prevents it from staying in your system for too long.

• Pharmacodynamic Interactions: These interactions occur when drugs with similar or opposing mechanisms of action (how a drug produces its effect in the body) are taken together, leading to additive, synergistic, or antagonistic effects. For example, combining two drugs that both lower blood pressure can lead to a greater decrease in blood pressure than when each drug is used alone.

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It's important for healthcare professionals and individuals taking medications to be aware of potential drug interactions to minimize the risk of adverse effects and ensure optimal therapeutic outcomes. This often involves thorough medication reconciliation, patient education, and close monitoring for signs of interactions or adverse effects.

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Researchers recently conducted a systematic review, which allowed them to evaluate the existing evidence, synthesize findings, and provide valuable insights into the interactions between psychiatric medications and MDMA. 

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MDMA and Adrenergic Drugs 

Adrenergic drugs are medications that affect the function of the sympathetic nervous system, typically by mimicking or blocking the action of the neurotransmitter epinephrine (adrenaline) or norepinephrine (noradrenaline). Neurotransmitters are chemical messengers in the brain and nervous system that facilitate communication between nerve cells, or neurons.

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The researchers identified 4 randomized controlled trials (RCTs) — a type of study design in medical research where participants are randomly assigned to receive different interventions —  that combined MDMA with four different adrenergic drugs: pindolol, carvedilol, clonidine, and doxazosin. These studies were included as medications from this class are occasionally used to treat PTSD. 

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Here are the findings from the studies combining MDMA with different adrenergic drugs:

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Pindolol: 

• When given one hour before MDMA (1.6 mg/kg orally), Pindolol (20 mg orally), slightly affected some aspects of the emotional experience induced by MDMA, such as reducing “positive basic mood,” “mania-like experience,” and “dreaminess.”

• Pindolol pretreatment reduced the increase in peak heart rate caused by MDMA but did not affect changes in mean arterial pressure, body temperature, or adverse effects significantly.  (Hysek et al. 2010).

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‍Carvedilol:

• When combined with MDMA (125 mg orally), carvedilol (50 mg orally) significantly reduced MDMA's stimulatory effects on the heart and body temperature.

• Despite this reduction, there was still a significant increase in circulating epinephrine and norepinephrine levels.

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Clonidine:

• When given one hour before MDMA (125 mg orally), clonidine (150 μg orally) reduced the increase in circulating norepinephrine and blood pressure caused by MDMA.

• However, blood pressure decreased similarly to that of clonidine alone. 

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Doxazosin:

• When administered approximately 16 hours before MDMA, doxazosin (8 mg orally) reduced the increase in mean arterial pressure induced by MDMA, despite increasing norepinephrine and heart rate. 

• Doxazosin pretreatment also weakened the heightened mood and body temperature effects of MDMA.

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These findings suggest that combining MDMA with certain adrenergic drugs can modulate its physiological and subjective effects, potentially influencing its therapeutic efficacy and safety in the treatment of conditions like PTSD.

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Although combining MDMA with adrenergic drugs can influence its effects, it's uncertain whether these effects are simply added together or if there's a more complex interaction between the drugs. Further research is needed to clarify how adrenergic agents interact with MDMA

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MDMA and Antipsychotics

Antipsychotics are a class of medications primarily used to treat psychosis, a symptom of some mental health conditions such as schizophrenia and bipolar disorder. They work by altering the levels of certain neurotransmitters in the brain, particularly dopamine, to alleviate symptoms.

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In a 2000 study, a combination of MDMA with an antipsychotic, haloperidol (administered intravenously at 1.4 mg), was examined. The MDMA dosage was 1.5 mg/kg orally. The results revealed a significant alteration in the psychological profile typically associated with MDMA use.

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This combination led to a reduction in well-being, an increase in anxiety, and a diminished sense of “oceanic boundlessness.” Oceanic boundlessness is a term often used in the context of psychedelic experiences to describe a profound sense of interconnectedness, unity, and expansiveness.

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These findings suggest a notable shift from MDMA’s usual pleasurable effects to a dysphoric state when paired with haloperidol.

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MDMA and Bupropion 

Bupropion, also sold under the brand name Wellbutrin, is a medication primarily used as an antidepressant to treat major depressive disorder in adults. It works differently from most antidepressants by affecting the levels of dopamine and norepinephrine. 

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In a 2015 study, researchers investigated the effects of combining bupropion XR (extended-release) with MDMA. The study involved titrating bupropion XR to 300 mg orally over a span of 7 days. On the seventh day, MDMA was administered concurrently with bupropion XR at a dose of 125 mg orally.

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The findings of the study revealed several noteworthy interactions between bupropion and MDMA:

• Bupropion pretreatment resulted in a moderate reduction in norepinephrine levels and reduced the elevation of heart rate typically associated with MDMA use.

• Bupropion significantly prolonged the positive mood effects induced by MDMA.

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The study also observed alterations in MDMA (changes in how MDMA was processed in the body) metabolism due to the presence of bupropion. Specifically, the concentration of MDMA in the body was higher and a reduction in its primary metabolites, DHMA (3,4-dihydroxymethamphetamine) and HMMA (3-hydroxy-4-methoxy-methamphetamine). Metabolites are substances produced when the body breaks down a drug

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This suggests inhibition of the CYP2D6 enzyme by bupropion. Enzymes are proteins in the body that help break down drugs and CYP2D6 is one such enzyme involved in metabolizing both MDMA and bupropion. Bupropion may have inhibited the activity of the CYP2D6 enzyme, leading to higher levels of MDMA and lower levels of its metabolites. 

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In addition, there was a decrease in MDA (3,4-methylenedioxyamphetamine) levels, another metabolite of MDMA, when bupropion was present. This finding suggests that bupropion may have inhibited the activity of the CYP2B6 enzyme (another enzyme involved in the metabolism of bupropion) by bupropion leading to lower levels of MDA.

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Interestingly, co-administration of MDMA also led to increased levels of bupropion in the body, attributed to MDMA’s ability to inhibit the CYP2D6 enzyme.

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While clinical trials have not reported serious adverse effects from combining bupropion and MDMA, there are notable risks, particularly when used outside controlled settings. A study which analyzed data from the FDA’s Adverse Event Reporting Systems (FAERS), examined co-ingestion of MDMA with medications in non-clinical settings and found that several combinations of antidepressants with MDMA increased mortality rates, with bupropion exhibiting the highest odds ratio for death among all antidepressants.

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Additionally, research suggests that combining bupropion and MDMA may heighten the risk of seizures, stimulant toxicity, or a severe and potentially fatal condition called serotonin syndrome. Serotonin syndrome is a serious condition that occurs when there’s too much serotonin in the body. Symptoms of serotonin syndrome include agitation, confusion, fever, high blood pressure, muscle twitching, and seizures. In extreme cases, it can be fatal.  

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Both MDMA and bupropion act as stimulants capable of lowering seizure thresholds, and they increase each other’s blood concentrations when taken together. Consequently, caution is warranted when considering simultaneous use of bupropion and MDMA, especially in uncontrolled environments.

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MDMA and Stimulants

Stimulants are a class of drugs that rev up the central nervous system and body. This can lead to a variety of effects, including:

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• Increased alertness and focus

• Enhanced energy levels

• Elevated mood

• Improved cognitive function (in some cases)

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Stimulants work by increasing the levels or activity of certain neurotransmitters, like dopamine and norepinephrine.

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In a study combining MDMA with methylphenidate (e.g. Ritalin, Concerta) — a medication for conditions like attention deficit hyperactivity disorder (ADHD) — researchers observed that methylphenidate delayed the time it took for MDMA to reach its maximum concentration in the body. This delay suggested that methylphenidate might reduce the absorption of MDMA. 

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Additionally, the combination of MDMA and methylphenidate resulted in increased circulating epinephrine levels, heart rate, and rate pressure product. These changes indicated heightened cardiovascular activity associated with the combination.

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When individuals are under the influence of MDMA alone, it typically enhances mood and emotional empathy, making it easier to recognize and experience positive emotions, including happiness. However, methylphenidate reduced the ability to feel and recognize feelings of happiness or joy compared to taking MDMA alone, while increasing mental concentration. 

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Furthermore, participants reported experiencing more acute (short-term) and subacute (between acute and chronic) subjective complaints or negative effects compared to when they took MDMA alone. This suggests that the combination of MDMA and methylphenidate may worsen adverse effects, indicating potential increased risks or discomfort when using both substances together.

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MDMA and Selective Serotonin Reuptake Inhibitors (SSRIs)

Selective Serotonin Reuptake Inhibitors (SSRIs) are a type of antidepressant medication commonly prescribed to treat depression and other mental health conditions. Normally, after serotonin transmits a signal between brain cells, it gets reabsorbed by the sending cell. SSRIs selectively inhibit (block) this reuptake process. This allows more serotonin to stay active in the space between brain cells, potentially leading to improved mood regulation.

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As both MDMA and SSRIs both increase serotonin levels in similar ways, there is potential for both pharmacodynamic and pharmacokinetic interactions.

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Several SSRIs, such as citalopram (e.g. Celexa and Lexapro), fluoxetine (Prozac), and paroxetine (e.g. Paxil and Seroxat), have been studied in combination with MDMA. These studies have consistently shown that SSRIs weaken the subjective effects of MDMA by approximately 30% to 80% and weaken physiological effects by about 6% to 14% (except paroxetine, which weakened physiological effects by 40% to 60%).

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Both fluoxetine and paroxetine, strong inhibitors of the CYP2D6 enzyme, increase plasma concentrations of MDMA despite weakening its effects.

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Additionally, exploratory studies suggest that paroxetine may interact with multiple cytochrome P450 enzymes involved in MDMA metabolism and blunt MDMA-induced immunosuppression, particularly cytokine release. 

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Another study investigated duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI), in combination with MDMA and found that duloxetine:

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• Reduced circulating norepinephrine levels

• Weakened MDMA-induced increases in heart rate and blood pressure

• Reduced MDMA-induced elevations in copeptin levels, particularly in females.

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Subjectively, duloxetine significantly reduced many of MDMA’s effects on mood and alterations in consciousness (such as well-being, extroversion, closeness, and openness) despite increased MDMA levels due to CYP2D6 inhibition by duloxetine. These findings suggest that pharmacokinetics are not solely responsible for the weakening effects of duloxetine on MDMA.

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There is growing concern about the potential for serotonin syndrome when combining SSRIs and MDMA, believed to be due to increased serotonin levels in the brain. However, studies suggest that the physiological effects of MDMA are weakened when taken with SSRIs, which might lower the risk of serotonin syndrome, at least with short-term SSRI use.

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Additionally, a review of scientific literature indicates that SSRIs, SNRIs, and Tricyclic Antidepressants are unlikely to cause dangerously high serotonin levels when used alongside MDMA. Nevertheless, as mentioned earlier regarding bupropion, while clinical trials haven't reported serious problems with combining SSRIs and MDMA, data from the FDA’s Adverse Event Reporting Systems (FAERS) suggests that several combinations of antidepressants with MDMA have led to increased mortality rates.

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MDMA and Monoamine Oxidase Inhibitors (MAOIs)

MDMA acts as both a serotonin releaser and reuptake inhibitor. This means it increases the amount of serotonin flooding your brain and prevents your body from reabsorbing it as quickly. Monoamine oxidase inhibitors (MAOIs) are a type of antidepressant that prevent the breakdown of certain brain chemicals, including serotonin.

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When combining MDMA with an MAOI, you essentially have a double whammy effect on serotonin levels. This can lead to serotonin syndrome. Many documented deaths associated with MDMA use involve individuals also taking MAOIs. 

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The effects of MAOIs can last for a significant time in the body, even after you stop taking them. So, it’s crucial to wait an appropriate amount of time before using MDMA after taking an MAOI.

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Important Note: The psychedelic brew ayahuasca contains naturally-occurring MAOIs. This allows the psychoactive compound DMT, present in ayahuasca, to enter the bloodstream and produce its effects. Therefore, If you’ve recently consumed ayahuasca, it’s essential to wait a significant amount of time before considering MDMA use due to the lingering presence of MAOIs in the body.

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MDMA and Reboxetine 

Reboxetine, also sold under the brand name Edronax, is a medication belonging to a class called norepinephrine reuptake inhibitors (NRIs). Reboxetine is primarily used as an antidepressant to treat major depressive disorder in adults. Unlike SSRIs that target serotonin, reboxetine works by inhibiting the reuptake of norepinephrine

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In a study exploring how the reboxetine (8 mg orally) affects the MDMA experience (125 mg orally), researchers noted reductions in circulating norepinephrine levels and weakened cardiovascular and simulant effects of MDMA.

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Interestingly, reboxetine weakened the positive subjective effects typically associated with MDMA use, such as feelings of bliss, closeness, and boundlessness, but it also reduced negative effects or adverse symptoms induced by MDMA, such as tremors and restlessness.

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This suggests that reboxetine had an overall dampening effect on the subjective experience of MDMA, both in terms of its positive and negative aspects. These effects occurred despite increased plasma levels of MDMA, likely due to reboxetine inhibiting the activity of CYP2D6.

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MDMA and Ritonavir

Ritonavir is a medication used in the treatment of HIV (human immunodeficiency virus) infection. It belongs to a class of drugs known as protease inhibitors.

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As mentioned, MDMA undergoes metabolism involving several P450 enzymes. These complex pharmacokinetics mean that MDMA is vulnerable to drug-drug interactions with drugs that inhibit a broad range of P450 enzymes like ritonavir.

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Ritonavir’s inhibitory effects on multiple CYP450 enzymes can significantly impact the metabolism of MDMA, potentially leading to alterations in its levels in the body and increased risk of toxicity

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Important Note

This is not a complete list, and MDMA can interact with many other substances. Always consult a healthcare professional before using MDMA, especially if you are taking any medications.