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

History of MDMA

• Synthesized by Merck in the early 1900s 
  • No initial clinical use or exploration
• Rediscovered by Alexander Shulgin, a renegade drug chemist 
  • Shulgin designed drugs to understand their subjective effects on humans
  • Shared drugs with his wife, friends, therapists, and physicians
  • Initially not illegal, but later became illegal and scrutinized by the DEA
• MDMA is a synthetic compound, not found in nature 
  • Unique and exciting for clinical treatment due to its distinct effects

Chemical and Subjective Effects of MDMA

• Similar to mescaline in chemical properties and some subjective properties
• Unique compound with no other known natural or pharmaceutical equivalent
• Produces powerful increases in dopamine and serotonin 
  • Acts as an empathogen, increasing social connectedness and empathy
• Used recreationally and in clinical trials for PTSD treatment 
  • Distinct difference between recreational and therapeutic use

Clinical Trials and Therapeutic Use of MDMA

• Exciting results in treating PTSD 
  • Unprecedented success in the field of psychiatry
• Requires appropriate and safe use in conjunction with therapy sessions
• Ongoing exploration of MDMA’s potential toxicity and long-​​term effects 
  • Possible neurotoxicity, but ways to use therapeutically that avoid toxicity
• Discussion of dosages, spacing between sessions, and offsetting potential toxicity
  Peacol: A Book on MDMA
• Peacol (Phenylethylamines I Have Known and Loved) by Shogen 
  • Describes the discovery and synthesis of MDMA
  • Provides insight into the history of the pharmaceutical industry, the war on drugs, and the interaction between illegal drug exploration and clinical treatment of psychiatric challenges
• 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

What is MDMA?

• 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

Effects of MDMA

• 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
    Distinguishing MDMA from Other Psychedelics
• MDMA is different from classic psychedelics like psilocybin and LSD 
  • Psilocybin and LSD mainly increase serotonin activation in the brain
  • Ketamine is a dissociative anesthetic, used for the treatment of depression
  • MDMA is an empathogen with stimulant properties and a serotonergic component
• MDMA is more of a mood-​​impacting drug than mystical

MDMA’s Unique Effects

• Combination of big increases in dopamine and even bigger increases in serotonin 
  • Creates a situation where people have more energy and pleasure
  • Increases trust and emotional warmth towards others and oneself
• MDMA can augment or boost the effects of talk therapy for PTSD 
  • Does not cure PTSD on its own

Serotonin Receptors and MDMA

• MDMA activates the serotonin 1B receptor 
  • Creates a desire to bond, create trust, and engage in conversations
• Psilocybin and LSD activate the serotonin 2A receptor 
  • Leads to more interconnectedness between different brain areas
  • Opens neuroplasticity and rewiring of neural connections

Neural Circuits Activated and Modified by MDMA

• 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

Understanding MDMA’s Effects on the Brain

• Experiments can be done using functional Magnetic Resonance Imaging (fMRI)
  • Can examine how interconnected certain brain areas are and their activity levels
  • Helps to understand the neural circuit phenomena and potential neurotoxicity issues
    Effects of MDMA on the Brain
• Addresses the Default Mode Network (DMN)
  • Active when not attending to anything specific
  • Related to imagination, daydreaming, and self-​​referencing thoughts
• Studies on MDMA effects: 
  • fMRI scans to see brain network activation changes
  • Comparing brain images of people who have taken MDMA to those who haven’t
  • Giving different dosages of MDMA and observing responses to stimuli
• Animal studies on MDMA effects: 
  • Social activity changes in mice
  • Octopuses show increased social behavior
  • Common basis: activation of more serotonin release in brain networks

MDMA’s Impact on Perception and Emotions

• Study by Harriet De Witt (University of Chicago) 
  • Effects of MDMA on sociability and neural responses to social threat and social reward
• Findings:
  • Response to threatening faces/​​stimuli reduced (reductions in amygdala activity)
  • Respond more positively to happy faces
  • Bi-​​directional effect on perception of others’ emotions

Dosages of MDMA in Studies

• 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

Brain Areas Affected by MDMA

• Amygdala: involved in threat detection systems, fear, and other functions
• Insula: important for interoception (perception of feelings and emotional states) 
  • Heightened connectivity between amygdala and insula in PTSD patients
  • MDMA may help reduce this heightened connectivity
    Interoception and Exteroception
• Interoception: ability to focus on sensations within the body 
  • Examples: fullness of gut, emotions, tiredness/​​alertness
• Exteroception: ability to focus on things beyond the body 
  • Examples: visual attention, auditory attention, external events
• Insula: brain area critical for interoception 
  • Contains a map of the complete body surface, including internal organs
• Amygdala: involved in threat detection 
  • Has direct connections with the insula

PTSD and Brain Networks

• People with PTSD have stronger connections between the amygdala and insula 
  • Heightened input from threat detection centers to interoceptive centers
• Functional imaging studies show changes in brain connectivity between amygdala and insula in people with PTSD 
  • Reductions in connections between these areas correlate with reductions in PTSD symptoms

MDMA and Brain Connectivity

• 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, Dopamine, Serotonin, and Oxytocin

• Animal studies have explored the roles of dopamine and serotonin in the motivational and prosocial effects of MDMA 
  • Results in mice translate well to humans for these types of circuits
• Oxytocin, a hormone involved in social bonding, may also play a role in the effects of MDMA
  MDMA Effects on the Brain
• MDMA increases dopamine and serotonin 
  • Dopamine: establishes rewarding effects of an experience
  • Serotonin: increases social interaction and empathy
• Activation of serotonin 1B receptor in the nucleus accumbens leads to pro-​​social effects of MDMA 
  • Different from LSD and psilocybin, which activate serotonin 2A receptor
• MDMA also increases oxytocin release 
  • Oxytocin: neurohormone involved in bonding (parent-​​child, friends, lovers, etc.)
  • Study: plasma oxytocin concentrations increased after taking 1.5 mg/​​kg of body weight of MDMA

MDMA vs. Other Drugs

• Methamphetamine: reduces social interaction, unlike MDMA
• 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

Oxytocin and Bonding

• Oxytocin: involved in bonding between people and other creatures, as well as the breaking of those bonds
• Humans can have strong oxytocin responses to their pets, particularly dogs, and vice versa
• MDMA powerfully increases oxytocin release, which may contribute to its pro-​​social and empathogenic effects
  Oxytocin and MDMA
• Oxytocin: hormone involved in bonding and social behavior 
• MDMA increases oxytocin levels by nearly fivefold
• Study: compared oxytocin levels in people given MDMA, placebo, or oxytocin nasal spray 
  • Measured subjective feelings of connectedness, sociability, and other factors
• Results: MDMA-​​induced oxytocin increase does not appear to be the source of prosocial effects 
  • Animal studies: blocking oxytocin receptor in mice given MDMA did not change sociability
  • Humans: oxytocin nasal spray increased oxytocin levels but did not increase sociability
• Some people have a different version of the oxytocin receptor gene that may affect MDMA’s prosocial effects 
  • Bulk of data points to serotonin and dopamine increases as main factors in MDMA’s effects

Safety and Neurotoxicity of MDMA

• Discussion focuses on pure MDMA in laboratory or clinical settings
• 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
• Combining caffeine with amphetamines or MDMA can increase neurotoxicity
• Animal studies: some evidence of loss of serotonergic tone in brains of animals given MDMA 
  • Depletion of neuromodulators in the short term is not the same as long-​​term depletion or loss of neurons
• Non-​​human primate studies: data suggests MDMA might not be as neurotoxic as thought based on rodent studies
  MDMA and Neurotoxicity
• MDMA, also known as ecstasy, has been controversial due to claims of neurotoxicity 
• 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
• Some studies on moderate and heavy MDMA users with minimal exposure to other drugs show little evidence of decreased cognitive performance 
  • However, there is an increase in impulsivity, but it is unclear whether MDMA causes this or if more impulsive people are more likely to take 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 and Neurotoxicity
• Environmental and behavioral conditions are important when considering MDMA’s potential neurotoxicity 
  • Pure MDMA vs. mixed with other substances (e.g., methamphetamine)
  • MDMA taken with caffeine or in high-​​temperature environments can increase neurotoxicity
• Polypharmacology: the ingestion of other compounds before, during, or after MDMA session can impact its effects

MDMA Crash and Myths

• Crash: 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
  • Taking amino acid precursors to serotonin (L‑tryptophan) or dopamine (L‑tyrosine) is not supported by evidence and may be detrimental
• Prolactin: hormone that increases after MDMA ingestion, potentially causing the crash 
  • Prolactin is involved in various functions, including lethargy and decreased dopamine
  • P5P (a metabolite of vitamin B6) may suppress prolactin and help with the crash, but more research is needed

PTSD and Trauma

• PTSD: post-​​traumatic stress disorder, caused by emotional trauma from single or multiple events 
  • Can be first-​​person or third-​​person experiences
• Treatment for PTSD 
  • Quality talk therapy with rapport, support, and insight
  • Dr. Paul Conti’s book “Trauma” recommended for understanding trauma and its treatment
• MDMA is being explored in clinical trials for augmenting treatment for PTSD
  MDMA-​​Assisted Therapy for PTSD
• Talk therapy alone often doesn’t provide long-​​lasting relief for PTSD sufferers 
• Prescription drug therapies, such as SSRIs, can provide some relief but may have side effects
• Combining talk therapy with drug treatment can improve outcomes
• MDMA-​​assisted therapy is being explored as a potential treatment for PTSD
• PTSD affects brain circuitry and neural communication between the brain and body
• MDMA can reduce the levels of activity in the hippocampal-​​amygdala-​​insula circuitry, potentially providing relief for PTSD sufferers

Clinical Trials

• Maps group has conducted clinical trials to study the effects of MDMA-​​assisted therapy on PTSD
• Trials involve giving patients talk therapy and MDMA or talk therapy and placebo
• Patients have already done talk therapy without MDMA, then do talk therapy under the influence of MDMA, and finally do sessions of talk therapy not under the influence of MDMA
• Placebo group does the same number of therapy sessions but without MDMA

Results

• Overall rate for clinically effective response to MDMA-​​assisted therapy is 88% vs. 60% for the placebo and therapy alone
• MDMA-​​assisted therapy has the potential to provide significant relief for PTSD sufferers and may lead to legalization for clinical use in the future
  MDMA-​​Assisted Therapy for PTSD
• 390-​​minute therapy sessions with two therapists 
  • Discuss PTSD symptoms and traumatic events
  • No drugs involved in these sessions
• Participants divided into two groups 
  • One group receives MDMA during three therapy sessions 
    • First session: 80mg MDMA + 40mg booster
    • Second session: 120mg MDMA + optional 60mg booster
    • Third session: 120mg MDMA + optional 60mg booster
  • Other group receives placebo during three therapy sessions
• Results
  • 88% success rate for MDMA-​​assisted therapy vs. 60% for therapy and placebo
  • 67% of people in the MDMA group no longer met criteria for PTSD by the end of treatment
  • No other known treatment for a psychiatric disorder with such a high success rate

Additional Findings

• MDMA-​​assisted therapy also helped resolve alcohol use disorder and other substance use disorders in many cases
• Dissociative form of PTSD, which is usually hard to treat, showed improvement with MDMA-​​assisted therapy 
  • Allows patients to get closer to traumatic experiences and reframe them in a more empathetic context
• 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
• Potential for cost-​​effective mental health care and relief from various mental health issues
  MDMA Therapy for PTSD
• Clinical studies show positive results for MDMA therapy in treating PTSD 
• No increase in suicide attempts or suicidality observed in MDMA therapy group
• MDMA combined with talk therapy significantly reduces PTSD symptoms
• MAPS group working to keep MDMA therapy within legal and legislative boundaries

MDMA Effects

• Synthesized by humans, not plants or animals
• Increases dopamine and serotonin, creating highly motivated, prosocial, empathic states
• Potential for neurotoxicity, but data suggests reasonable doses may not be neurotoxic

Neuroplasticity and Mental Health

• MDMA therapy aims to access neuroplasticity, the nervous system’s ability to modify itself in response to experience
• Goal is to improve the functioning of the nervous system
• MDMA is part of a larger trend in exploring compounds like psilocybin, LSD, ayahuasca, and ketamine for mental health treatment

Supporting MDMA Research

• MAPS conducting clinical trials on MDMA therapy
• Public interest in these trials is expected to grow