MDMA: Science, Therapy, Benefits & Risks | Huberman Lab Podcast 

PIHKAL: A Chemical Love Story by Alexander Shulgin and Ann Shulgin Provides insights into the discovery and synthesis of MDMA and the interactions between illegal drug exploration and clinical psychiatric treatments

Trauma: The Invisible Epidemic by Paul Conti M.D. Delves into the profound impact of trauma on individuals and society, providing insights into its causes, effects, and potential paths toward healing

The Body Keeps the Score by Bessel van der Kolk M.D. A seminal work that sheds light on the effects of trauma on the mind and body, emphasizing the importance of integrating body-oriented therapies

Huberman delves into MDMA, or “ecstasy,” discussing its effects on emotional processing and its potential for treating PTSD and substance addictions. The episode explores MDMA’s impact on mood, empathy, motivation, and threat detection, and how it can enhance talk therapy Can’t get enough of Andrew Huberman? Check out our member-only collection packed with Huberman’s greatest tips

Host- Andrew Huberman (@hubermanlab)

MDMA, also known as ecstasy or molly, is a compound that affects dopamine and serotonin release It falls into the category of empathogens, promoting social connectedness and empathy

Its history dates back to its synthesis by the drug company Merck in the early 1900s, but it remained unexplored until rediscovered by Alexander Shulgin Shulgin and a small group of friends, including therapists and physicians, conducted underground explorations and shared their findings

Unlike natural compounds such as mescaline or psilocybin, MDMA is a synthetic compound

MDMA is being explored for its therapeutic potential in treating PTSD, showing promising results in clinical trials Despite its potential benefits, MDMA remains classified as a Schedule 1 drug and is illegal in the United States

The potential neurotoxicity of MDMA, specifically its impact on serotonin and dopamine neurons, is a significant concern The scientific community is divided into groups studying the toxicity and utility of MDMA, influencing its legal status and its potential for PTSD treatment

MDMA’s chemical structure consists of three, or four methylene dioxide methamphetamine MDMA acts as a methamphetamine, blocking dopamine reuptake and increasing dopamine levels MDMA prevents the reuptake of dopamine, leading to more dopamine in the synapse

The methamphetamine component of MDMA interferes with dopamine repackaging into vesicles As a result, MDMA causes significant increases in dopamine release and dopaminergic tone

MDMA also increases serotonin levels by blocking serotonin reuptake and interfering with its repackaging The increase in serotonin release caused by MDMA is three to eight times greater than dopamine release

MDMA’s combination of increased dopamine and serotonin leads to unique effects Dopaminergic effects include mood elevation, stimulation, alertness, and positive motivation

The increases in serotonin activate neural networks associated with social connection and empathy MDMA’s serotonin effects create a pro-social effect and enhance empathy for oneself and others

The combination of dopaminergic and serotonergic effects classifies MDMA as an empathogen MDMA’s empathogenic properties make it potentially beneficial for PTSD treatment

It is important to separate MDMA from other psychedelics and ketamine in terms of its effects and therapeutic potential Psilocybin and LSD are considered classic psychedelics that mainly increase serotonin activation

Psilocybin and LSD closely resemble serotonin and activate the 5HT2A receptor, producing mystical experiences Psilocybin and LSD are being extensively studied for the treatment of major depression

Ketamine is a dissociative anesthetic and NMDA receptor blocker used for depression treatment Ketamine creates a sense of dissociation from emotions and is currently legal for medical use

MDMA is distinct from classic psychedelics and ketamine MDMA is considered an empathogen or an entactogen It creates a sense of affiliation and empathy, rather than producing mystical experiences Also, it’s more of a mood-impacting drug than a mystical one

The effects of MDMA differ from classic psychedelics in terms of hallucinations and overall experience

MDMA produces unique effects distinct from other drugs like psilocybin, LSD, ketamine, and methamphetamine

The combination of increased dopamine and even larger increases in serotonin contribute to the energetic and pleasurable effects of MDMA MDMA creates a sense of energy without irritability and promotes emotional warmth and empathy towards others and oneself MDMA also increases trust, which is essential in the therapeutic context

However, MDMA alone does not cure PTSD; it enhances the effectiveness of talk therapy for PTSD MDMA engages specific neural circuits to augment therapy MDMA increases serotonin, but it seems to act on different receptors than psilocybin and LSD

MDMA largely activates the serotonin 1B receptor, which impacts brain circuits related to trust and social engagement The dopamine increase caused by MDMA enhances motivation and desire to engage in activities

Quality MDMA therapy involves building rapport and trust with the therapist as well as engaging in conversations with oneself

Trauma is defined as an event that fundamentally changes the brain in maladaptive ways Under the influence of MDMA, individuals are more willing to trust the therapist and explore challenging thoughts and emotions related to trauma

MDMA facilitates the rewiring of the relationship to trauma and the exploration of new possibilities Understanding the neural circuitry and potential neuroplastic changes caused by MDMA is crucial before delving into its clinical applications and potential toxicity

Understanding the effects of MDMA on the human brain: One approach is to use functional magnetic resonance imaging (fMRI) to study resting functional connectivity, which examines the interconnectedness and activity of brain areas when a person is at rest The resting state functional connectivity provides a baseline for understanding the subsequent effects of MDMA and allows researchers to investigate the default mode network (DMN) The DMN is active when the brain is not focused on external stimuli or specific tasks, and it is associated with self-referential thinking, imagination, and daydreaming By analyzing fMRI data, researchers can identify which brain areas are more or less active during resting state and observe changes in brain networks after administering MDMA Studies can also compare individuals who have never taken MDMA to those who have taken it multiple times, examining differences in brain activation and connectivity Additionally, experiments can involve administering different dosages of MDMA and exposing participants to specific stimuli, such as happy or sad faces, self-images, or traumatic memories, to investigate how the brain responds

Research on MDMA’s effects has been conducted in humans and animal models Animal studies, including those involving laboratory mice and even cephalopods like octopuses, have explored the social behavior changes induced by MDMA Studies in humans, such as those conducted by Harriet DeWitt at the University of Chicago, have focused on MDMA’s impact on sociability and neural responses to social threats and reward

MDMA has been found to reduce the perceived threat of facial expressions, specifically through a decrease in amygdala activity The amygdala is involved in the brain’s threat-detection systems

Participants under the influence of MDMA tend to rate happy faces as more positive and threatening faces as less threatening compared to when they are not on MDMA

Dosages of MDMA used in studies typically range from 0.75 to 1.5 milligrams per kilogram of body weight, with some studies also including a booster dose The specific dosage of MDMA is important when considering its toxicity, as toxicity can scale with the dosage administered Understanding the effects of MDMA on subjective experiences and brain networks involves considering the dosages used in studies, which typically fall within the range mentioned above

Post-Traumatic Stress Disorder (PTSD) is characterized by a heightened connectivity between the amygdala and a brain region called the insula The insula plays a crucial role in interoception, which is the perception of our feelings, including pure sensations, emotional states, and overall well-being from our skin inward

Interoception can be consciously directed, allowing us to focus on sensations such as the fullness of our gut or our emotional states It is distinct from exteroception, which is our ability to focus on external stimuli like visual or auditory attention

The insula contains a detailed map of interoception, covering the complete body surface, including internal organs Through functional imaging techniques, it has been observed that stimulating different parts of the insula results in individuals reporting sensations in corresponding body regions

The amygdala, often associated with fear and threat detection, is part of a broader network that includes the hippocampus, involved in memory formation and storage

Individuals with PTSD exhibit stronger connections between the amygdala and the insula compared to those without PTSD This heightened connectivity suggests increased input from the brain’s threat detection centers to the insula, responsible for interoception

People with PTSD often experience memories, discomfort, agitation, or bodily sensations associated with traumatic events due to this intensified connectivity Functional imaging studies have shown that individuals with PTSD exhibit altered connectivity between the amygdala and insula, both during trauma recall and at rest

Administering 1.5 milligrams per kilogram of MDMA to individuals with PTSD, in conjunction with therapy, weakens the connections between the amygdala and insula

The degree of reduction in connectivity correlates directly with the relief of PTSD symptoms experienced by the individuals

The observed changes in connectivity provide compelling evidence for the relationship between the amygdala-insula circuit and symptom reduction in PTSD Comparing different individuals’ responses to MDMA treatment strengthens the understanding of how changes in the brain are associated with symptom relief

Remarkably, single sessions of MDMA-assisted therapy have led to full remission of PTSD symptoms in some individuals The greater the reduction in amygdala-insula connectivity, the more significant the reduction in clinically relevant PTSD symptoms, supporting a causal relationship

These findings contribute to a mechanistic and logical framework for comprehending the effects of MDMA and understanding the underlying brain changes that alleviate PTSD symptoms

Classic psychedelics like psilocybin and LSD increase lateral connectivity between different areas of the neocortex, leading to long-lasting changes associated with relief from major depression and enhanced creativity Unlike classic psychedelics, MDMA does not produce long-lasting increases in lateral connectivity between brain networks, likely due to its impact on different serotonin receptors However, MDMA does induce changes in resting state functional connectivity within limbic structures such as the amygdala and related regions involved in threat detection

A study conducted by Dr. Robin Carhart-Harris and colleagues demonstrated that individuals who took MDMA at the discussed dosages reported significant increases in positive mood and decreased blood flow to the amygdala and hippocampus These changes in mood and brain activity were observed both during MDMA’s influence and afterward during the brain’s resting state

MDMA appears to induce neuroplasticity that alters the overall activation level of threat detection networks and their connections to memory systems

During an MDMA session, individuals experience reduced feelings of threat, increased pro-social behavior, and enhanced empathy toward themselves and others After the session, individuals exhibit a diminished threat response to previously troubling memories

The effects of MDMA on the brain are both short-term and long-term, consistently pointing towards decreased threat detection, increased positivity, heightened pro-social tendencies, and reduced activity in threat detection centers of the brain

MDMA increases dopamine and serotonin levels in the brain, with a stronger impact on serotonin through the serotonin 1B receptor

A study conducted on mice by Dr. Robert Malenka’s laboratory: The study explored the effects of MDMA on different brain networks and neurotransmitters involved in the motivational and pro-social aspects of MDMA The study found that dopamine release by MDMA establishes the rewarding effects of an experience, similar to other stimulant drugs Serotonin release within the nucleus accumbens, a part of the reward pathway, is responsible for the pro-social effects of MDMA The activation of the serotonin 1B receptor in the nucleus accumbens by MDMA reinforces social interaction

The effects of dopamine and serotonin vary depending on the specific brain networks and receptors involved

MDMA’s release of both dopamine and serotonin sets in motion parallel circuits: Rewarding experiences (dopamine component) Increasing empathy and sociability (serotonin component)

MDMA’s polypharmacology, involving serotonin and dopamine release together, leads to distinct effects compared to drugs that increase only dopamine or serotonin

Selective serotonin reuptake inhibitors (SSRIs) increase serotonin levels but do not produce the same effects as MDMA, suggesting the importance of specific receptor activation

The complexity of polypharmacology highlights the role of serotonin activation at specific receptors and in particular brain areas, such as the nucleus accumbens The nucleus accumbens, part of the mesolimbic reward pathway, plays a crucial role in establishing a reward response to the current experience

MDMA acts as an empathogen, reinforcing empathy and social connection during its influence and leading to long-lasting effects on neural networks associated with empathy and social behavior even after the drug wears off

MDMA increases levels of oxytocin release in the brain Oxytocin acts as a neurohormone, modulating the activity of other circuits Oxytocin acts as a hormone by affecting many sites within the brain and body

Oxytocin is involved in pair bonding, both between parent and child and bonding between friends and lovers Oxytocin is also involved in the painful process of breaking bonds Humans can have strong oxytocin responses to their pets, particularly dogs

MDMA increases oxytocin release, leading to a significant increase in circulating oxytocin levels MDMA at a dose of 1.5 milligrams per kilogram of body weight produces the most significant changes in oxytocin MDMA-induced increases in oxytocin do not appear to be directly related to the prosocial effects of MDMA

Animal studies with MDMA and oxytocin receptor blockers suggest that oxytocin is necessary for the sociability effects of MDMA Taking oxytocin by nasal spray increases oxytocin levels but does not increase sociability

The data suggest that MDMA’s effects on motivation, sociability, and empathy are primarily mediated by dopamine and serotonin, rather than oxytocin Overall, the role of oxytocin in the effects of MDMA appears to be relatively minor compared to dopamine and serotonin

MDMA is commonly used recreationally but is illegal to possess or sell Recreational drugs, including MDMA, are often contaminated with fentanyl, a highly deadly substance Sourcing MDMA is crucial due to the risk of contamination and associated harm

MDMA and methamphetamine increase dopamine and serotonin levels in the brain, which can promote electrical activity in other neurons

Methamphetamine and MDMA can be neurotoxic when a large amount of dopamine is released Methamphetamine is neurotoxic even with a single dose, affecting dopamine and serotonergic neurons

Combining caffeine with amphetamines can increase their neurotoxicity, as can combining caffeine with MDMA Animal studies using high doses of MDMA have shown some loss of serotonergic tone in the brains of animals

Depletion of neuromodulators in the short term is not the same as long-term depletion or loss of neurons

There are no known studies in non-human primates or humans showing toxicity of pure MDMA at clinically relevant doses However, there is a wide variation in individual susceptibility to neurotoxicity, and it is difficult to predict who may be more susceptible to harm from MDMA

Pure MDMA should not be assumed to be safe or non-neurotoxic, and caution should be exercised due to individual differences and potential interactions with other substances

Studies have explored the neurotoxicity, neurocognitive, and behavioral effects of taking MDMA in different quantities

A landmark study titled “Residual neurocognitive features of long-term ecstasy users with minimal exposure to other drugs” focused on individuals who have taken MDMA multiple times and had minimal exposure to other drugs The study included a population of people who self-identify as members of the Church of Latter-day Saints (LDS) and have taken MDMA ranging from one to 200 doses The study aimed to confirm that the participants took pure MDMA and no other drugs, as interactions between drugs can create neurotoxicity The findings of the study indicated that moderate and heavy users of MDMA (22 to 450 doses) showed little evidence of decreased cognitive performance in standard cognitive tests However, there were some indications of poor strategic self-regulation, possibly reflecting increased impulsivity The direction of the effect (whether MDMA use leads to impulsivity or impulsive individuals are more likely to use MDMA) is unknown The study did not examine brain structures or levels of serotonin and dopamine in these individuals The overall conclusion from these studies is that if pure MDMA is taken without other neurotoxic drugs, and in a controlled clinical setting, the risk for toxicity appears to be lower than what is often portrayed in the popular press However, there is still a risk of neurotoxicity with high doses, frequent use, and co-administration with other drugs The environmental conditions and behaviors under which MDMA is taken are crucial Increases in body temperature can lead to neurotoxicity, as serotonin and dopamine also affect temperature regulation The LDS community generally discourages drug use, including caffeine, cocaine, and alcohol The study focused on a subgroup within the LDS community that self-identifies as using MDMA, but the specifics of permission or authorization for MDMA use within this community are unclear

Further research is needed to understand the potential effects of MDMA on brain structures, serotonin and dopamine levels, and the long-term implications of MDMA use

The post-MDMA crash is a common phenomenon characterized by a drop in mood, increased lethargy, and lack of motivation There are myths and misinformation surrounding the post-MDMA crash and ways to prevent it or reduce its effects

Some suggestions found on the internet include taking serotonin or dopamine precursors such as 5-HTP or L-tryptophan and L-tyrosine However, there is no evidence supporting their effectiveness, and they may even further deplete serotonin and dopamine

MDMA causes significant increases in dopamine, serotonin, and oxytocin levels, and dopamine increases are followed by an increase in prolactin release Prolactin is a hormone involved in various functions in the body, including milk letdown, sexual arousal, and fat storage, and it is associated with lethargy and decreased dopamine The increase in prolactin during and after MDMA ingestion may contribute to the crash experienced by individuals

Some people have started exploring the use of P5P (a metabolite of vitamin B6) to suppress prolactin as a potential way to mitigate the crash effects Currently, no standardized clinical trials are investigating the use of P5P or other prolactin-suppressing substances to reduce the post-MDMA crash

Clinicians using MDMA for PTSD treatment are beginning to pay attention to the role of prolactin and exploring interventions to address its effects

Further research is needed to determine the efficacy and safety of using P5P or other methods to suppress prolactin after MDMA ingestion Huberman promises to provide updates on any findings regarding the use of post-MDMA session P5P or other strategies to suppress prolactin

PTSD (post-traumatic stress disorder) is a condition caused by emotional trauma, either from personal experiences or witnessing traumatic events

Trauma can result in long-term modifications in brain function and lead to PTSD Traumatic events can be single events (e.g., car accidents, sexual assault) or ongoing experiences (e.g., relationships, childhood, wartime)

Quality talk therapy for trauma involves a good rapport between patient and therapist, providing support and creating a safe space for exploration Effective talk therapy for trauma includes the components of rapport, support, and insight However, about half of the people undergoing talk therapy for PTSD do not achieve long-lasting relief, and few achieve complete remission

SSRIs (selective serotonin reuptake inhibitors) are commonly prescribed drugs for PTSD treatment SSRIs can provide symptom relief for about 40-60% of people with PTSD, but they may also have side effects like libido changes, appetite changes, sleep disruptions, and decreased motivation Combining quality talk therapy with prescription drug treatment improves outcomes, but the reverse is not always true Even with quality talk therapy and SSRIs, a significant number of people with PTSD do not achieve significant or long-lasting relief

MDMA (3,4-methylenedioxymethamphetamine) is being explored as a potential treatment for PTSD The idea of using MDMA for PTSD treatment emerged due to the limited effectiveness of talk therapy and SSRIs alone

PTSD symptoms include anxiety, panic attacks, dissociative symptoms, brain fog, distraction, sleep issues, and a higher risk of substance abuse and other mental health comorbidities

People with PTSD may have difficulties in relationships, work, and experience physical health problems PTSD affects approximately 8% of people in the United States, with comorbidities ranging from 17-65% Suicidality rates are higher among individuals with PTSD PTSD affects brain circuitry and neural communication between the brain and body

Trauma memories are not stored in the body, but rather in neural circuits involving the insula, a brain structure that maps the body’s surface PTSD is caused by altered brain network activations, such as heightened amygdala-to-insula pathway activation and hippocampus-to-amygdala-to-insula circuitry activation

MDMA has shown potential as a therapeutic treatment for PTSD MDMA can reduce activity in the hippocampal to the amygdala to insular circuitry, leading to persistent long-lasting reductions in brain network activation

The MAPS group, based in Santa Cruz, California, has conducted large-scale clinical trials exploring the use of MDMA-assisted therapy for PTSD treatment The trials involve administering MDMA to patients with PTSD while also providing talk therapy. Two notable studies include: “MDMA-assisted therapy for severe PTSD: a randomized double-blind placebo-controlled phase 3 study” “The effects of MDMA-assisted therapy on alcohol and substance use in a phase 3 trial for the treatment of severe PTSD.” In the trials, patients undergo three 90-minute therapy sessions without MDMA to discuss their PTSD symptoms and traumatic experiences The patients are then divided into two groups: one receiving MDMA during therapy sessions and the other receiving a placebo The MDMA group takes MDMA three times during therapy sessions, with increasing doses: 80mg + 40mg booster, 120mg + 60mg booster, and 120mg + 60mg booster Both groups receive three 90-minute therapy sessions one week apart after the final MDMA or placebo session The overall rate for clinically effective response to MDMA-assisted therapy is 88% compared to 60% for therapy with placebo alone 67% of individuals in the MDMA plus therapy group no longer meet the criteria for PTSD after treatment The success rate of 88% with MDMA-assisted therapy is significantly higher than other psychiatric disorder treatments. There is growing discussion about the potential legalization of MDMA for therapeutic use in clinical settings, potentially as early as 2024

MDMA plus talk therapy treatment has shown success in resolving addiction to alcohol and other substances in people with PTSD Successful PTSD treatments often involve patients discussing their traumatic experiences in detail

MDMA therapy provides a pro-social and empathic environment, allowing patients to engage with their trauma and reframe their experiences The emotional burden of traumatic experiences is diminished, allowing patients to lead productive lives

MDMA therapy has the potential in treating PTSD, depression, alcohol use disorder, and eating disorders

MDMA activates specific brain networks, facilitating cognitive and somatic reframing of traumatic events This reframing leads to positive outcomes and improved functioning

The addition of MDMA to talk therapy for PTSD does not seem to increase adverse effects compared to placebo and therapy alone No increases in suicide attempts, suicidality, or obsession with suicide were observed in the MDMA group

The MAPS group has made significant efforts to ensure the responsible and legal use of MDMA in clinical settings MDMA is no longer solely associated with recreational use, and its therapeutic potential is being recognized in the mental health community

Clinical trials have shown that when MDMA is combined with quality talk therapy, it can significantly reduce or eliminate PTSD symptoms The long-term effects and potential problems associated with MDMA use in this context are still being studied

MDMA’s ability to increase dopamine and serotonin levels contributes to its pro-social and empathic effects Neurotoxicity concerns exist, but data suggest that at reasonable doses and when not combined with other drugs, MDMA may not be excessively neurotoxic

Caution should be exercised with sympathomimetic drugs, and the purity of MDMA is important to avoid potentially lethal fentanyl contamination The ongoing clinical trials conducted by MAPS are expected to generate significant interest

We are at an important time for the treatment of psychiatric disorders and neuroscience Various compounds are being explored for their potential to access neuroplasticity and promote adaptive changes in the nervous system

The ultimate goal of talk therapy and drug therapies, including MDMA-assisted therapy, is to facilitate neuroplasticity and improve overall functioning