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Last Updated: 21.06.23

The Science of MDMA & Its Therapeutic Uses: Benefits & Risks

Huberman dives deep into the fascinating world of MDMA, examining its impact on emotional processing, addiction treatment, and PTSD therapy. Covering neuronal mechanisms, neurotoxicity debates, legal considerations, and more, this episode offers valuable insights into neuropharmacology, mental health, and the therapeutic potential of MDMA.

Key Takeaways

High level takeaways from the episode.

MDMA Synthesized by Merck in the early 1900s

  • No initial clinical use or exploration

MDMA is a synthetic compound, not found in nature

  • Unique and exciting for clinical treatment due to its distinct effects

Produces powerful increases in dopamine and serotonin

  • Acts as an empathogen, increasing social connectedness and empathy

Ongoing exploration of MDMA’s potential toxicity and long-​​term effects

  • Possible neurotoxicity, but ways to use therapeutically that avoid toxicity

MDMA is currently granted breakthrough status, allowing scientists and clinicians to study it with authorization

  • Still a Schedule 1 drug and illegal to possess without permission
  • On the cusp of becoming legal for medical use

MDMA: 3,4‑methylenedioxymethamphetamine

  • Methamphetamine component: blocks the reuptake of dopamine from neurons after dopamine is released 
    • Increases dopamine levels
  • Methylene dioxymethamphetamine component: increases serotonin levels 
    • Blocks reuptake of serotonin and increases serotonin release

Increases in serotonin are 3–8 times greater than the increases in dopamine

  • Unique combination of increased dopamine and serotonin levels leads to mood elevation, stimulation, and pro-​​social effects

Dopamine increase: stimulant effect

  • Alertness, increased talking, excitement, positive motivation

Serotonin increase: pro-​​social effect

  • Feeling more socially connected, rating fearful faces as less fearful, rating happy faces as more positive

Combination of dopamine and serotonin increase: empathogen effect

  • Empathy for others and oneself, including past experiences
  • Potential benefits for the treatment of PTSD

MDMA is different from classic psychedelics like psilocybin and LSD

  • MDMA is more of a mood-​​impacting drug than mystical

MDMA can augment or boost the effects of talk therapy for PTSD

  • Does not cure PTSD on its own

Short-​​term effects: Increases in trust, pleasure, energy, and emotional warmth.

Long-​​term effects: Potential neuroplastic or rewiring changes

  • Can be beneficial or not beneficial, depending on the context and individual

Dosage Range: 0.75 to 1.5 milligrams per kilogram of body weight

  • Clinical studies may include a “booster” dose later in the session
  • Toxicity of MDMA scales with dosage and frequency of use

MDMA does not produce long-​​lasting increases in lateral connectivity between brain networks like psilocybin and LSD

  • However, it does change resting state functional connectivity within limbic structures (e.g., amygdala)

Studies show that MDMA reduces blood flow to the amygdala and hippocampus, leading to decreased threat detection and increased positive mood

  • These changes persist even after the drug has worn off

MDMA also increases oxytocin release

  • Oxytocin: neurohormone involved in bonding (parent-​​child, friends, lovers, etc.)

SSRIs (e.g., Prozac, Zoloft): increase serotonin but do not create the same effects as MDMA

  • Giving an SSRI prior to MDMA can block the pro-​​social and empathogenic effects of MDMA
  • This is due to the complexity of polypharmacology and the activation of specific serotonin receptors in specific brain areas

Recreational use of MDMA often contaminated with dangerous substances like fentanyl.

Neurotoxicity: MDMA increases dopamine and serotonin, which can promote electrical activity in neurons

  • High levels of dopamine can be neurotoxic
  • Methamphetamine: known to cause neurotoxicity and brain degeneration

A 2002 study in Science claimed severe dopaminergic neurotoxicity in primates after recreational doses of MDMA

  • Study was later retracted due to issues with labeling and mislabeling of MDMA and methamphetamine
  • No clear data on neurotoxicity in humans or non-​​human primates at clinically relevant doses of pure MDMA
  • Pure MDMA in controlled clinical settings may have a lower risk of neurotoxicity than popularly believed

    • Risk increases with higher doses, frequent use, and consumption of other drugs
  • Risk also increases in settings where blood pressure or body temperature can be greatly increased, as MDMA is a psychostimulant that increases blood pressure, heart rate, and body temperature
  • MDMA taken with caffeine or in high-​​temperature environments can increase neurotoxicity.

    Crash/​​comedown: drop in mood, increase in lethargy, and lack of motivation after taking MDMA

    • Commonly believed to be due to depletion of serotonin or dopamine, or death of serotonergic and dopaminergic neurons
  • Prolactin: hormone that increases after MDMA ingestion, potentially causing the crash
  • P5P (a metabolite of vitamin B6) may suppress prolactin and help with the crash, but more research is needed
  • Taking amino acid precursors to serotonin (L‑tryptophan) or dopamine (L‑tyrosine) to prevent crash is not supported by evidence and may be detrimental.

    MDMA can reduce the levels of activity in the hippocampal-​​amygdala-​​insula circuitry, potentially providing relief for PTSD sufferers.

    Overall rate for clinically effective response to MDMA-​​assisted therapy is 88% vs. 60% for the placebo and therapy alone

    • No other known treatment for a psychiatric disorder with such a high success rate

    MDMA-​​assisted therapy also helped resolve alcohol use disorder and other substance use disorders in many cases.

    MDMA being explored for treatment of depression, alcohol use disorder, and eating disorders as well.

    MDMA seems to enhance the effectiveness of talk therapy within a limited number of sessions.


    We recommend using this distillation as a supplemental resource to the source material.

    • The Science of MDMA & Its Therapeutic Uses: Benefits & Risks

      Huberman Lab

      In this episode, Huberman explores MDMA’s effects on emotions, addiction, and PTSD treatment, as well as neurotoxicity debates.

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