Psychedelics by Substance: MDMA

ecstasy enactogen mdma phenethylamine psychedelic Apr 22, 2021

Substance Objectives

  • Describe pharmacological properties and subjective effects of MDMA
  • Summarize clinical research results of MDMA-assisted psychotherapy (MDMA-AP)
  • Discuss harm reduction and the toxicity profile of MDMA
  • Outline drug interactions associated with MDMA


What is MDMA?

MDMA (3,4-methylenedioxymethamphetamine) is a psychoactive drug with both stimulant and psychedelic properties that has been known as ecstasy or molly in recreational marketplaces, although is now being used in conjunction with psychotherapy to treat mental health disorders such as post-traumatic stress disorder (PTSD). It is a prototypical synthetic phenethylamine psychedelic, although has been recognized as an entactogen (to touch within) or empathogen (generating a state of empathy) due to differences in mechanisms and effects relative to classic psychedelics (mind-manifesting) or hallucinogens (generating hallucination).


History of MDMA

MDMA was first synthesized by Merck in 1912, although was resynthesized by legendary psychedelic chemist Alexander Shulgin in the 1970s [1]. It was shared as a therapy tool both for individual, couple, and group therapies during the 1970s although euphoric, empathic, and stimulating effects led to increased use in nightlife settings, drawing the attention of drug regulators [2]. The Drug Enforcement Agency (DEA) officially made MDMA illegal schedule I substance in 1985. Shortly thereafter, the Multidisciplinary Association of Psychedelic Studies (MAPS) was founded and began the formidable process of proving MDMA had medicinal value by conducting clinical trials on an illicit substance [3]. Over the last 30 years MAPS has brought MDMA to the brink of medical approval, with the Food and Drug Administration (FDA) granting a breakthrough designation to MDMA-assisted psychotherapy (MDMA-AP) for the treatment of refractory PTSD [4]. The final stage of clinical trials (phase III trials) are ongoing with expected approval for medical use in the next few years.


Mechanism of MDMA

MDMA works via multiple mechanisms, although its effect may be summarized as a serotonergic amphetamine. 

 MDMA releases neurotransmitters, primarily serotonin, although also dopamine and norepinephrine. It releases neurotransmitters by interrupting vesicular monoamine transporter (VMAT2) packing and reversing the flow of neurotransmitters so that SERT pumps release serotonin into the synapse. This process is known as carrier-mediated release [5]. It binds with the ‘psychedelic’ serotonin 2A receptors (5HT2ARs), although does so with low affinity compared with classic tryptamine psychedelics. It interacts or blocks the serotonin reuptake pump (SERT), yet again does so weakly compared with selective serotonin reuptake inhibitors (SSRIs). MDMA also acts to release the social bonding neuropeptide oxytocin and vasopressin (anti-diuretic hormone) [6].

Subjective Effects: What Does MDMA Feel Like? 

The mechanisms of MDMA results in elevated mood, euphoria, enhancement of sensory perception (visual, auditory, tactile), lowered anxiety or fear responses, expansive emotional range, increased wakefulness, and decreased emotional reactivity. The pleasurable and stimulating effects of MDMA have led to popularity in nightlife settings amongst persons attending music and dancing events. The subjective effects of MDMA have been described as ideal for treatment of PTSD, as it allows the user to revisit painful or traumatic memories from the past and work through or emotionally process traumatic experiences to extinguish fear responses related to PTSD [7, 8]. Classic psychedelics such as psilocybin, LSD, or DMT are known for ego-dissolutive properties that can result in mystical experiences or experiences of oneness as well as intense hallucinations and interacting with spiritual entities at higher doses [9, 10]. Due to weak binding at the 5HT2A receptor and stimulant properties of MDMA, the ego remains intact with MDMA experiences, which may decrease psychological risks of ‘bad trips’ or overly challenging experiences. It tends to feel more of a return to a sense of ‘true self’ as fear responses and defensive mechanisms subside. There is an expansive perspective and empathic or ‘heart-opening’ effect.  These subjective qualities differentiate MDMA from classic psychedelics and define properties related to enactogens [11]. The subjective effects of MDMA have been reported as more intense by females compared to males, with females more likely to experience perceptual changes, anxiety, and thought disturbances or ‘hallucinogen-like’ effects [12].


Metabolism of MDMA

MDMA is best absorbed on an empty stomach or with a light meal a few hours prior to use. Food likely delays and limits absorption and could lead to reduced effects or later onset of effects. It is metabolized by the liver enzyme CYP2D6 to an active metabolite (3,4-methylenedioxyamphteramine or MDA) as well as metabolites suspected to be related to neurotoxic effects such as HHMA and HHA [13]. There is considerable genetic variability in CYP2D6 with concerns that persons who are poor CYP2D6 metabolizers may experience a more rapid onset of effects, higher intensity of effects, higher blood concentrations of MDMA and MDA as well as increased body temperature and cardiovascular responses [14]. These differences were most appreciable during the first 90 minutes after ingestion because MDMA inhibits its own metabolism by blocking CYP2D6, which tends to normalize CYP2D6 function across the population . Other liver enzymes such as CYP1A2, CYP2C19, CYP3A4, and CYP2B6 may have significant roles in metabolized MDMA to MDA and drugs capable of inhibiting several of these liver enzymes (e.g. ritonavir or cobicistat) have been reported to cause severe toxicity in combination with MDMA [14, 15].


Dosing and Kinetics of MDMA

Blood concentrations of MDMA correlative well with intensity of subjective effects, although blood concentrations peak shortly after subjective effects do. Persons strongly feel effects of MDMA after 60 minutes, experience peak effects between 60-120 minutes rapidly diminishing effects by 150-180 minutes [13]. Re-dosing of MDMA is common in recreational settings and also practiced in clinical trials. Repeated dosing of the same dose spaced four hours apart (100mg + 100mg) resulted in similar overall subjective effects with higher cardiovascular responses [16]. In MDMA-assisted psychotherapy an initial dose is given followed by a booster dose equivalent to 50% of the initial dose (e.g. 120mg + 60mg) [17]. The booster dose is given approximately 2.5 hours after the initial dose, which when considered with the kinetics of MDMA is rational: it allows the user to extend the duration at the peak intensity of subjective effects while controlling for cardiovascular risks of repeated dosing.


MDMA Assisted Psychotherapy and PTSD

MDMA assisted psychotherapy (MDMA-AP) is an experimental therapeutic treatment involving supervised use of MDMA by a dyad (two-person team) of therapists embedded within a larger framework of weekly psychotherapy sessions. Therapy sessions prior to the first use of MDMA-AP focus on understanding more about the therapy process, effects of the drug, and building trust between the person undergoing treatment and provider. Sessions in which MDMA is administered are 6-8 hours in length and therapists are encouraged to take a supportive and non-directive approach. MDMA-AP sessions are conducted in comfortable and curated environments, participants are encouraged to wear eye shades, and a carefully selected playlist of evocative music devoid of linguistic content is used [18]. MDMA-AP aims to create a safe and trusted environment for participants to undergo intense emotional openings and therapeutic breakthroughs in symptoms of PTSD. Therapy work is continued in the days and weeks after MDMA-AP sessions that aim to creating meaningful and sustained improvements as well as continued emotional support for the person’s overall process.

Results from phase II clinical trials indicated that for every three persons treated with two MDMA assisted psychotherapy sessions it can be expected that one of them will no longer meet diagnostic criteria for PTSD

Across six phase II studies with over 100 participants total, two MDMA-AP sessions spaced at least a month apart reduced symptoms to clinically insignificant levels in over half of participants (54.2% vs. 22.6% in control) [17]. It was noticed that persons that experienced three MDMA-AP sessions improved to a greater degree than persons receiving two sessions, thus phase III trials all feature three sessions for participants. While the current model of MDMA-AP is one amongst several possibilities, it may be important to understand psychedelic therapies as processes involving several sessions over a longer period opposed to a silver bullet that will work in a single administration.


Other Indications for MDMA Assisted Psychotherapy

There have been very few studies that have examined the therapeutic potential of MDMA-AP outside of PTSD, however MDMA gained a reputation as being helpful for couples’ therapies in the 1970s and is also being discussed for these purposes by therapists in the modern psychedelic era (listening to ecstasy). MDMA has pro-social effects and can increase feelings of emotional connectedness and fear responses to socialization. There is a single study with positive evidence supporting MDMA-AP in being helpful for social anxiety associated with an autistic disorder [19]. Other pilot studies of MDMA-AP for treatment of alcohol use disorder and anxiety associated with a life-threatening illness also have positive results [20, 21]. It is well known that Adverse Childhood Experiences (ACEs) or traumatic events that occur in childhood can result in increased risk of several mental health disorders, addictions, and physical illnesses. It has been hypothesized that trauma and stress are the etiological roots for several types of psychiatric illness beyond PTSD and the psychiatric diagnostic manual (DSM-V) has been criticized for its lack of recognition that trauma is often the etiologic root of mental illness. Several of the phase II studies of MDMA-AP for PTSD allowed persons that also experienced depression, anxiety, panic disorder, alcohol use, and ADHD [17]. Symptoms of other psychiatric illnesses tended to improve alongside symptoms of PTSD. It is plausible that if MDMA-AP can treat mental trauma then it could be a useful tool for a range of illnesses, however, is likely a potentially harmful modality for persons with bipolar I disorder, psychotic disorder, or disorders in which establishment of trust is difficult (e.g. personality disorders).


Safety of MDMA - Effects of MDMA in Clinical Trials in Persons with PTSD

Transient during experience - A range of physical and emotional side effects have been reported in clinical trials, with the most common being anxiety, emotional discomfort, dizziness, fatigue, headache, jaw clenching (bruxism), decreased appetite, and nausea [17].

Following MDMA experience - In the week after their MDMA-AP sessions, some participants noticed anxiety insomnia, irritability, difficulty concentrating, low mood, and fatigue. There have been no significant changes in neurocognitive function found by researchers associated with MDMA-AP, however longer-term deleterious changes to neurocognitive function and mood regulation has been documented with heavy ecstasy use. One participant in trials experienced suicidal ideation after a session in which a 30mg dose of MDMA (active control, low-dose) was given [17].

Cardiovascular effects - MDMA is known to increase blood pressure and heart rates with average increases of 28 beats per minute for heart rate, 25mmHg for systolic blood pressure, and 12mmHg for diastolic blood pressure [17]. Persons with uncontrolled high blood pressure (>140/90mmHg) or advanced cardiovascular conditions were excluded from clinical trials. One participant had extra heart beats (ventricular extrasystoles) that took 125mgHg, although was not a significant type of arrhythmia. Sympathetic antagonists such as clonidine and carvedilol have been demonstrated to attenuate cardiovascular responses without interfering with subjective effects [22, 23].


Toxicology of Ecstasy

Severe adverse effects associated with MDMA have been reported in recreational settings and there are many reasons for this. Populations in studies are carefully screened, environmental safety is optimized, and there is psychological support for the use of MDMA.

Seizures - In nightlife settings persons may exert themselves physically to the point of exhaustion, mix MDMA with other drugs or alcohol, experience dehydration, or prolonged exposure to hot and crowded environments. MDMA raises core body temperature ~0.4C in clinical studies and can increase body temperature >1C in hot environments. The excitatory stimulant effects, hyperthermia, stimulation in the environment (e.g. strobe lights), and lowered body sodium due to vasopressin release (SIADH) can lead to seizures [24].

Overdose – In high doses or in combination with drugs with strong interaction potential such as monoamine oxidase inhibitors (MAOIs) or pan CYP inhibitors (ritonavir/cobicistat) MDMA has been reported to cause signs and symptoms consistent with severe serotonin and stimulant toxicities including death. Other complications may include seizures, muscle breakdown (rhabdomyolysis), organ failure, and cardiovascular events (e.g. stroke) [25-28].

Impurity – What is bought on the recreational market as Ecstasy or Molly may not really be MDMA or it could contain MDMA mixed with other drugs such as methamphetamine, caffeine, dextromethorphan, or strong opioids like fentanyl. Use of ‘Ecstasy’ can be risky in this regard and substance testing for confirmation of MDMA and absence of other drugs can be life-saving harm reduction measures.

Neurotoxicity – MDMA is known to have neurotoxic effects that result in long-term decreases in cognitive functioning, lowered mood, higher anxiety, and increased difficulty regulating mood overall. Just how neurotoxic MDMA is has been a subject of intense controversy in medical literature and portrayed as highly neurotoxic in erroneous fashion through the media [29]. Long-term problems are associated with mixing drugs, frequent ecstasy use, and higher doses whereas clinical trials of moderate, intermittent, and limited administrations in clinical trials have not resulted in detectable changes in neurocognitive function. See ‘Is MDMA Neurotoxic?’ for a deep dive into this subject.

Addictive Potential – MDMA produces highly likeable and pleasurable subjective effects for many. It is also capable of releasing dopamine, which is a core feature of most drugs that are considered to have addictive potential. However, MDMA does not have as much dopamine release as regular amphetamine (d-amph) and is less well known to result in the binge and crash cycles of other stimulant use disorders. Addiction to MDMA has not occurred in supervised settings of clinical trials and is not a highly addictive substance, however can result in unhealthy patterns of administration (e.g. every weekend) or stimulant use disorders.


Drug Interactions with MDMA

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.

  • SSRI/SNRI antidepressants – Diminish effects of MDMA when in combination and for a period after antidepressants have been discontinued. Use in combination a relative contraindication due to lowered benefits of MDMA assisted therapy [30].
  • Stimulants – Increase cardiovascular risks in combination with MDMA. Co-ingestion of stimulants have been associated with increased neurotoxicity [31].
  • Monoamine Oxidase Inhibitors – Increase risks of serotonin syndrome in combination with MDMA. Fatalities reported in literature, use in combination is an absolute contraindication [26, 28].
  • Bupropion – Increases concentration of MDMA and prolongs duration of experience. May increase risks of seizures in combination [32].
  • CYP inhibitors (e.g. ritonavir/cobicistat) – Increase risks of serotonin syndrome in combination with MDMA. Fatalities reported in literature, use in combination is covered in detail [25].


Pregnancy and Lactation with MDMA

MDMA and related amphetamines can cross placental barriers as well as concentrate in breast milk. Amphetamines are also known to be harmful for developing fetus and newborns. There are no clinical studies of effects of MDMA in pregnancy or breastfeeding. In heavy ecstasy using pregnant mothers, newborns existed deleterious cognitive outcomes that persisted for years after birth, although persons studied used large amounts of MDMA and combined them with several other drugs that are also known to be toxic to fetuses or newborns [33]. MDMA is eliminated from the body within 2-3 days and nursing mothers that wished to undergo MDMA-AP could practice a ‘pump and dump’ method by pumping and discarding breast milk for 48-96 hours to undergo MDMA-AP [34].


High Notes of MDMA

MDMA is a serotonergic amphetamine and psychedelic that increases serotonin release. MDMA use in the form of ecstasy carries contextual and environmental risks that increase the risk of adverse effects. The adverse effect profile of MDMA that is being revealed by clinical trials demonstrates use can be safe. It appears that with selective screening, moderate dosing, supervised administration, and therapeutic support that risks of MDMA can be managed. It tends to diminish fear responses and emotional reactivity, while enhancing self-reflective and emotional processing capacities, which make it a promising tool for psychiatric illnesses such as PTSD.




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