Mechanistically, 3,4-methylenedioxymethamphetamine (MDMA) is described as an amphetamine derivative, operating in 2 different mechanisms to increase the central nervous system's serotonin concentration. At a typical dose of 1.7 mg/kg, MDMA promotes serotonin neuronal efflux by altering the chemical gradient that moves serotonin away from the intercellular space and influences the same reuptake transporter used by serotonin reuptake inhibitors (SSRIs). Additionally, MDMA is metabolized by and can inhibit CYP2D6 which allows some SSRIs to have the potential to inhibit MDMA metabolism. However, there is a lack of data investigating the drug-drug interaction (DDI) between SSRIs and MDMA given the potential of both drugs to raise synaptic cleft serotonin levels and the potential pharmacokinetic interaction if the SSRI is a potent CYP450 2D6 inhibitor. It has been proposed that many of the symptoms of MDMA toxicity may overlap with serotonin syndrome. This may result in some cases of serotonin syndrome being missed, and subsequently underrepresented, warranting caution in prescribing SSRIs to MDMA users. [1]
A 2022 systematic review investigated DDIs between MDMA, psilocybin, and psychiatric medications, including adrenergic agents, antipsychotics, anxiolytics, mood stabilizers, NMDA antagonists, psychostimulants, and various antidepressants. Data were evaluated from 40 studies, including 26 randomized controlled trials and 11 case reports. MDMA exerts its effect via the reversal of monoamine transporters, including serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT), resulting in increased concentrations of intrasynaptic monoamines; the effects primarily impact serotonin (5-HT), followed by norepinephrine, and lastly dopamine. Similarly, psilocybin and LSD impact serotonin neurotransmission via 5-HT2a agonism, suggesting both psychedelic agents confer potential for DDI with many classes of antidepressant and antipsychotic medications. Interactions may result in an increased risk of serotonin syndrome or attenuation of MDMA’s effects. All studies, however, included relatively small sample sizes of healthy adult patients. Only one study was included that studied concurrent use of MDMA and an antipsychotic, haloperidol, finding the combination resulted in reduced well-being, higher rate of state anxiety, and reduced perception of a sensation denoted as “oceanic boundlessness.” Some studies assessing interactions between MDMA and individual antidepressants were also evaluated, generally noting attenuation of some of MDMA’s effects when taken with bupropion and serotonin reuptake inhibitors (e.g., bupropion, citalopram, paroxetine, fluoxetine, and duloxetine). [2]
Studies comparing combination use with psilocybin, however, demonstrated more mixed results. For example, chlorpromazine attenuated psilocybin-induced mydriasis and visual perceptual changes, while haloperidol had no effects on psilocybin-induced perceptual changes, although it did increase a parameter denoted as “dread of ego dissolution.” Risperidone resulted in attenuation of psilocybin-induced alterations in consciousness, including a reduction in dread of ego dissolution. One study investigated combination use of a serotonin reuptake inhibitor (escitalopram) and psilocybin, finding escitalopram pretreatment did not significantly attenuate ratings of altered states of consciousness due to psilocybin but did result in significant reductions in several other subjective ratings. Generalizability of this data is limited, as all the included studies were based on younger, healthy adult patients receiving limited duration of psychiatric medications, generally only once. [2]
Another comprehensive overview of DDIs was conducted more recently between classic psychedelics and other drugs in humans, deriving results from 52 studies (32 lysergic acid diethylamide [LSD] studies; 10 psilocybin; 4 mescaline; 3 dimethyltryptamine [DMT]; 2 5-MeO-DMT; 1 ayahuasca). DDIs discussed antidepressants, antipsychotics, and mood stabilizers. Potent 5-HT2a antagonists (i.e., risperidone, olanzapine, pipamperone, mirtazapine, mianserin, etoperidone) are anticipated to diminish psychedelic effects. Risperidone and chlorpromazine were effective in attenuating the effects of LSD and psilocybin, with risperidone’s effect being dose-dependent. Buspirone, a 5-HT1a receptor agonist, reduced psilocybin-induced visual hallucinations, which was not seen with ergotamine. This effect may be due to the more effective inhibitory impact of buspirone over psilocybin on pyramidal neurons. Dopamine receptor antagonists, such as haloperidol, displayed no impact on psilocybin-induced hallucinations and increased anxiety but diminished the feelings of oceanic boundlessness and derealisation. Serotonin reuptake inhibitors, such as fluoxetine, sertraline, and paroxetine, showed reduced effects of LSD in one study. Fluoxetine also delayed LSD onset in half of the participants, showing decreased LSD sensitivity. As certain SSRIs, like fluoxetine, are potent inhibitors of CYP2D6 enzymes, the expectation is a stronger, prolonged LSD effect. However, due to various molecular actions, the opposite is true. Alternatively, escitalopram only reduced ego disintegration and anxiety, with no effect on psilocybin-induced positive mood or mind-altering effects. [3]
Trazodone, a serotonin receptor antagonist and reuptake inhibitor (SARI), was shown to reduce the psychological and hallucinogenic effects of LSD and potentially desensitize 5-HT2a receptors, reducing the cell’s psychedelic response. While one small study showed no serious treatment-emergent adverse events with concomitant synthetic psilocybin and SSRI treatment (i.e., sertraline, escitalopram, fluoxetine, vilazodone, paroxetine, citalopram), another reported weakened psilocybin effects with SSRI/ serotonin-norepinephrine reuptake inhibitor (SNRI) concomitant use, suggesting 5-HT2a receptor downregulation. Monoamine oxidase inhibitors (MAOIs; i.e., phenelzine, isocarboxazide) showed attenuated or locked effects of LSD. In contrast, tricyclic antidepressants (TCAs; i.e., desipramine, imipramine, clomipramine) showed increased psychological effects of LSD, potentially due to noradrenaline and serotonin reuptake mechanisms. Chronic administration of TCAs, such as desipramine, can increase neuron sensitivity to LSD, suggesting a postsynaptic serotonin receipt sensitization to LSD. Findings may be affected by the inclusion of trials from 1950-1970 providing limited or incomplete data. In addition, DDIs were specific to other drugs’s effects on psychedelics but did not mention the effects these psychedelics may have on antidepressant or antipsychotic therapies. [3]
An older review from 2007 provided a hierarchy of risk for serotonin syndrome; substances that inhibit serotonin reuptake are at the least amount of risk to increase serotonin to life-threatening levels when combined with ecstasy, while agents at high risk of serotonin syndrome may lead to serious increases in serotonin when combined with ecstasy. Some agents, like herbal supplements or agents with uncertain mechanisms of action, provide an unknown amount of risk when combined with ecstasy. See Table 1 for a summary of agents with risk when combined with MDMA. [4]