How do serotonergic and dopaminergic drugs differ in their effects?

Serotonergic drugs, like psilocybin and LSD, primarily target the serotonin system, generally leading to a state of contentment within immediate experience. Dopaminergic drugs, conversely, tend to place individuals into an external view, focusing on what's possible in the world and the need to act. MDMA affects both simultaneously, creating a unique experience often used for trauma.

What is the process of a psychedelic session in a clinical trial?

Participants undergo extensive psychiatric and cardiovascular screening. Preparation involves 4-8 hours of getting to know guides and discussing potential experiences. During the session, typically 20-30mg of pure psilocybin is ingested in pill form, with eye shades and music in a safe setting. The focus is on allowing emotional responses and letting go of control, often with cardiovascular monitoring.

How do psychedelics facilitate changes in self-representation and neuroplasticity?

Psychedelics are thought to profoundly alter existing 'models' of reality, including the sense of self, which can lead to a transformed understanding of one's identity. This 'letting go' of control, facilitated by the drug and therapeutic environment, allows for a deep emotional and perceptual experience that can reshape neural circuitry, leading to lasting changes in how individuals view themselves and their problems.

What happens after a psychedelic session, during the 'integration' phase?

As participants transition out of the psychedelic state, they have an initial discussion with their guides. That night, they write about their experience (homework). The next day, a 1-2 hour integration session allows for discussion of the experience's meaning, linking it to therapeutic goals. Patients are advised to sit on major life decisions for a few weeks post-session.

Are 'flashbacks' a real danger of psychedelic use?

The concept of 'flashbacks' is complex. Hallucinogen-Persisting Perceptual Disorder (HPPD) is a real, rare phenomenon involving persistent perceptual distortions, never seen in clinical trials but occurring in illicit use, suggesting rare neurological susceptibility. More common are state-dependent learning effects or temporary perceptual anomalies (a 'free trip') in the day or two following an experience, which are not distressing.

What are the common therapeutic uses and mechanisms of MDMA?

MDMA, an entactogen, primarily causes serotonin release and robust increases in dopamine. It is mainly used clinically for trauma, especially PTSD. The combination of serotonin and dopamine effects may reduce amygdala reactivity, facilitating the reprocessing and reconsolidation of traumatic memories in a less threatening way.

What are the primary dangers of psychedelic use?

The two main dangers are destabilization in individuals with severe psychiatric illnesses (schizophrenia, bipolar disorder/mania) and 'bad trips.' While screening can mitigate the former, anyone can have a bad trip under high doses or non-ideal environments, potentially leading to anxiety, fear, disorientation, and in rare, illicit cases, injury or death due to impaired judgment.

What is microdosing and is there scientific evidence for its benefits?

Microdosing involves taking about a tenth of an entry-level psychedelic dose. Claims include improved focus (like Adderall) and mood (like Prozac). However, peer-reviewed double-blind studies have not shown significant benefits for creativity, cognition, or sustained mood improvement, sometimes even showing impairment. Most observed effects are likely placebo, although some speculate about genuine antidepressant effects.

Are there long-term health risks associated with microdosing?

One concern is the risk of heart valve problems (valvulopathy) from chronic agonism of the serotonin 2B receptor, an effect seen with drugs like Fen-Phen. While not a concern for occasional therapeutic macrodoses, taking psychedelics twice a week for years, as some microdosers might, theoretically poses a greater risk that requires further research.

What is the legal status and future of psychedelics in the US?

Federally, psychedelics are Schedule I compounds and illegal to possess/sell/use. State and local decriminalization efforts vary, but do not override federal law. MDMA is expected to receive FDA approval for PTSD treatment within three years, and psilocybin for depression a few years later. This approval is for prescription use within controlled clinical settings, not general recreational availability.

How is psychedelic research funded, beyond government grants?

While some NIDA funding exists for studying abuse potential, the majority and most interesting psychedelic research is funded by private philanthropy. Organizations like the Heffter Research Institute, Beckley Foundation, and the Council on Spiritual Practices, along with significant gifts from entities like the Steven and Alexandra Cohen Foundation and the Tim Ferriss collaborative, have been crucial in enabling this pioneering work.

What is the potential for psychedelics in treating neurological injuries like TBI?

This is an exploratory area, based on anecdotes of cognitive improvement and rodent research showing increased neural plasticity (dendrite growth, new connections) post-psychedelic administration. Dr. Johnson's lab hopes to study this in retired athletes with repetitive head impacts, assessing cognitive function and MRI changes to see if direct brain repair is possible, alongside depression treatment.

How can one participate in a legitimate psychedelic clinical trial?

Dr. Johnson's lab (Johns Hopkins) posts information on its website: HopkinsPsychedelic.org. For broader searches across the US and Europe, Clinicaltrials.gov lists studies on psilocybin, MDMA, and other psychedelics. Participation is strictly within the context of specific, FDA-approved experimental protocols for designated disorders.

Key Moments

Psychedelics for Treating Mental Disorders | Dr. Matthew Johnson

Andrew Huberman

Science & Technology6 min read173 min video

Sep 20, 2021|610,694 views|12,575|1,326

andrew huberman huberman lab podcast huberman podcast dr. andrew huberman neuroscience huberman lab dr. matthew johnson matt johnson Psychedelics johns hopkins lsd mushrooms

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Key Moments

TL;DR

Psychedelics show promise for treating mental disorders, especially at high doses with integrated therapy.

Key Insights

Psychedelics encompass various pharmacological classes, all profoundly altering one's sense of reality, with classic psychedelics primarily targeting the serotonin 2A receptor for unique effects.

Therapeutic use involves a rigorous process: extensive screening, preparation, a high-dose session in a supportive environment, and follow-up integration to process experiences and facilitate lasting change.

Psychedelics likely promote neuroplasticity by temporarily 'dissolving' or challenging ingrained models of reality and self-perception, enabling individuals to re-evaluate deeply held beliefs and traumatic memories.

MDMA, an entactogen, differentiates itself by primarily inducing serotonin and dopamine release, fostering emotional connection and empathy, making it particularly effective for trauma, potentially with less risk of a 'bad trip' compared to classic psychedelics.

Microdosing lacks robust scientific evidence for its purported benefits like enhanced cognition or mood, and long-term use, especially of serotonin 2B agonists, raises concerns about potential heart valve issues.

Current legal landscapes for psychedelics are complex: federally illegal but with local decriminalization, and a growing movement towards FDA approval for therapeutic use under strict medical supervision, not over-the-counter sales.

DEFINING PSYCHEDELICS AND THEIR NEUROCHEMICAL ACTIONS

Psychedelics are a diverse group of compounds known for profoundly altering one's sense of reality and self. Pharmacologically, they span several classes, with 'classic psychedelics' like LSD and psilocybin acting primarily as agonists or partial agonists at the serotonin 2A receptor. Other classes include NMDA antagonists such as ketamine, kappa-opioid agonists like Salvinorin A, and releasers of monoamines such as MDMA. This diverse chemical landscape impacts different neuromodulator systems, leading to a wide spectrum of subjective experiences, but all share the capacity to challenge and reshape ingrained models of perception and self.

THE THERAPEUTIC MODEL AND PATIENT JOURNEY

The clinical application of psychedelics involves a structured, multi-stage process. Initial stages include comprehensive psychiatric and cardiovascular screening to exclude individuals with conditions like psychotic disorders or severe heart disease. This is followed by extensive preparation, where patients build rapport with their guides and are educated about the range of potential experiences. The high-dose psychedelic session (e.g., 20-30mg psilocybin) occurs in a comfortable, supportive environment with trained facilitators. Unlike recreational use, the therapeutic setting emphasizes 'letting go' of control, allowing individuals to fully explore their internal experiences without judgment or expectation.

THE 'LET GO' PHENOMENON AND SELF-REPRESENTATION

A core aspect of psychedelic therapy is the encouragement for individuals to surrender to the experience. This 'letting go' facilitates a profound alteration in self-representation, a fundamental shift in how one perceives their identity and place in the world. Instead of habitual coping mechanisms or ingrained negative self-narratives, individuals can experience a 'dis-habituation'—a fresh, unfiltered perception of phenomena. This allows for a deeper connection with internal sensations and emotions, leading to insights about trauma, addiction, or self-worth. The safety and trust established with guides are crucial for enabling this deep dive into altered states of consciousness.

FROM EXPERIENCE TO LASTING CHANGE: THE ROLE OF INTEGRATION

The psychedelic experience itself is just one part of the therapeutic process; critical to long-term benefits is the integration phase. As patients transition out of the acute effects of the drug, they are encouraged to reflect, write, and discuss their insights. This process continues with follow-up 'integration sessions' with therapists, where experiences are unpacked and connected to life goals and challenges. This supportive environment helps individuals incorporate the profound learnings into their daily lives, transforming transient insights into sustained behavioral and psychological changes. This structured integration maximizes the therapeutic potential, promoting neuroplasticity that reshapes neural circuits over time.

MDMA: A UNIQUE ENTACTOGEN FOR TRAUMA THERAPY

MDMA stands distinct from classic psychedelics, primarily functioning as an entactogen by releasing serotonin and dopamine. Clinically, MDMA is being explored with significant success for PTSD due to its ability to foster emotional connection, empathy, and a reduced fear response (e.g., in the amygdala). This unique neurochemical profile allows individuals to reprocess traumatic memories with less emotional intensity, facilitating reconsolidation of these memories in a different, less distressing way. The risk of profoundly challenging experiences ('bad trips') is generally lower with MDMA, making it a potentially gentler entry point for trauma work than classic psychedelics.

MICRODOSING: CLAIMS VERSUS SCIENTIFIC EVIDENCE

Microdosing involves taking sub-perceptual doses of psychedelics, often with claims of enhancing mood, focus, and creativity, or acting as an alternative to ADHD medications or antidepressants. However, current peer-reviewed research for microdosing is limited and has thus far yielded no significant evidence for sustained benefits, sometimes even showing mild cognitive impairment. The observed positive effects are largely attributed to strong placebo or expectancy effects. Furthermore, long-term microdosing of compounds with serotonin 2B agonist activity, common in many psychedelics, raises theoretical concerns about potential cardiovascular risks, specifically heart valve damage, similar to issues seen with withdrawn diet drugs like fen-phen.

RISKS AND CAUTIONS: DE-STABILIZATION AND SUSCEPTIBILITY

Despite their therapeutic potential, psychedelics carry significant risks, particularly for individuals with specific predispositions. The most critical risk is the destabilization of individuals with severe psychiatric illnesses, such as schizophrenia or bipolar disorder (manic phase). While studies rigorously screen for these conditions, illicit use carries the danger of exacerbating latent or active psychoses. 'Bad trips'—experiences of intense anxiety, fear, or profound disorientation—can occur even in controlled settings, highlighting the need for a supportive and therapeutic environment to navigate these challenging states. Misinformation and anecdotal reporting often overstate or misattribute risks, emphasizing the importance of controlled research.

LEGAL LANDSCAPE AND THE PATH TO MEDICAL APPROVAL

The legal status of psychedelics is complex. Federally, they remain Schedule I compounds, making possession and sale illegal. However, some states and municipalities have moved towards decriminalization or state-level legalization for therapeutic use (e.g., Oregon's psilocybin therapy initiative). The FDA has designated MDMA for PTSD and psilocybin for depression as 'breakthrough therapies,' accelerating their development for clinical approval. This means these compounds are on a path to being prescribed by physicians within structured clinical models, not for general public access. This medicalization contrasts with broader decriminalization movements, as clinical research is essential regardless of public legal status to establish safety, efficacy, and optimal therapeutic protocols.

FUTURE DIRECTIONS: NEUROLOGICAL INJURY AND PHILANTHROPY'S ROLE

Beyond psychiatric disorders, there is growing exploratory interest in psychedelics for neurological injury, such as traumatic brain injury (TBI) and stroke. Anecdotal reports from individuals with repetitive head impacts suggest improved cognitive function and mood. This aligns with rodent research demonstrating various forms of neural plasticity, like the growth of dendrites and new synaptic connections, following psychedelic administration. While early days, this work, often funded by private philanthropy (e.g., Heffter Research Institute, Beckley Institute, Tim Ferriss Collaborative, Steven and Alexandra Cohen Foundation), seeks to investigate whether these compounds can directly repair brain damage and improve neurological function. This funding has been critical for advancing research that historically received limited federal support.

Mentioned in This Episode

●Supplements

●Products

●Companies

●Organizations

●Books

●Drugs & Medications

●Concepts

●People Referenced

Common Questions

Psychedelics are substances that profoundly alter one's sense of reality, including the sense of self. They span different pharmacological classes, including classic psychedelics like LSD, psilocybin, DMT, and mescaline (all serotonin 2A receptor agonists), and NMDA antagonists like ketamine and PCP. MDMA stands in its own class as an entactogen.

Topics

Neuroscience & the Brain Mental Health & Psychology Psychedelic Therapy Addiction Treatment Depression Treatment Medicine & Clinical Mental Disorders

Mentioned in this video

Books

Psychiatric and Statistical Manual of Mental Disorders

The psychiatric 'Bible' used for diagnosing mental disorders, referenced during the screening process for psychedelic clinical trials to identify disqualifying conditions like psychotic disorders or bipolar disorder.

How to Change Your Mind

A book by Michael Pollan that prominently features Dr. Johnson and his work on psychedelic therapies.

The Doors of Perception

A book by Aldous Huxley describing his mescaline experiences, where he focused on the profound qualities of ordinary objects like chairs and drapes.

Psychedelics and Philosophy

A forthcoming book by philosopher Chris Letheby, which explores the naturalistic explanation of psychedelic experiences and their therapeutic effects.

Organizations

New York Times

A prominent newspaper that has featured Dr. Johnson and his work on psychedelics.

Johns Hopkins School of Medicine

An academic medical institution where Dr. Johnson is a professor of psychiatry and directs the Center for Psychedelic and Consciousness Research.

Gunn High School

An infamous high school in Palo Alto, California, known for its high suicide rate, which Dr. Huberman mentions in the context of adolescent depression.

Heffter Research Institute

A philanthropic organization that has funded much of Dr. Johnson's early psychedelic research, and whose founding member is Dennis McKenna.

National Institutes of Health

A primary source of federal funding for scientific research, which historically has an institute (NIDA) devoted to exploring negative effects of drugs, but now also includes NCCIH for complementary health.

Steven and Alexandra Cohen Foundation

A philanthropic foundation that provided half of the $17 million gift that established the Center for Psychedelic and Consciousness Research at Johns Hopkins.

Center for Psychedelic and Consciousness Research

A research center at Johns Hopkins School of Medicine directed by Dr. Matthew Johnson, focused on understanding how psychedelic compounds work and their therapeutic potential.

MAPS

An organization focused on MDMA research for PTSD, which has 'held the candle' for psychedelic research during difficult times and is developing MDMA towards FDA approval.

NCCIH

An NIH institute that evolved from NCCAM, now supporting research into complementary health approaches, including areas like breathwork and hypnosis, suggesting a broader scope of research interest within NIH.

Beckley Foundation

An organization based in England, headed by Amanda Feilding, that provided early funding for Dr. Johnson's psilocybin smoking cessation research.

DEA

The federal law enforcement agency responsible for drug enforcement, which handles a tiny fraction of total drug arrests compared to local and state authorities.

NIDA

An NIH institute that has funded some of Dr. Johnson's psychedelic work, specifically geared towards understanding compounds as drugs of abuse, although beneficial effects can also be observed in such studies.

Council on Spiritual Practices

An organization that funded original work at Johns Hopkins, led by Bob Jesse, focusing on the nature of mystical experience from psychedelics outside of disease treatment.

People

Michael Pollan

Author of 'How to Change Your Mind,' who has written extensively about psychedelics and featured Dr. Johnson's work.

Aldous Huxley

Author of 'The Doors of Perception,' known for his classic descriptions of mescaline experiences, including the 'chairiness of the chair.'

Tim Ferriss

An investor and collaborator who, along with Steven and Alexandra Cohen, contributed significantly to the $17 million gift for the Center for Psychedelic and Consciousness Research at Johns Hopkins.

Amanda Feilding

Head of the Beckley Foundation, an organization that funded some of Dr. Johnson's early research.

Bob Jesse

A key figure who funded original work at Johns Hopkins through the Council on Spiritual Practices, focusing on the mystical experiences induced by psychedelics.

Tim Leary

A prominent figure in the 1960s psychedelic movement, referred to as an advocate who 'goaded people into doing' psychedelics.

Matthew Johnson

Professor of psychiatry at Johns Hopkins School of Medicine and director of the Center for Psychedelic and Consciousness Research. He is a leading expert on how psychedelic compounds impact the brain and human behavior.

Chris Letheby

A philosopher in Australia with a forthcoming book on 'Psychedelics and Philosophy,' whose work explores if psychedelic experiences and their therapeutic effects can be explained from a naturalist point of view, focusing on changes in self-representation.

Terence McKenna

A 'classic bard' of DMT effects, known for prolific lectures on psychedelic experiences in the '80s and '90s, who described the sense of self remaining intact while the sensorium changed on DMT.

Richard Schultes

A pioneer in ethnobotany at Harvard who discovered various tribes using ayahuasca and DMT-containing snuffs in South America, later inspiring Terence McKenna.

Syd Barrett

The first singer of Pink Floyd, who 'went crazy early on' and developed schizophrenia, a case illustrating the potential for psychedelics to destabilize individuals with psychiatric predispositions.

Dennis McKenna

Brother of Terence McKenna and an ethnobotanist, a founding and active board member of the Heffter Research organization, which funds psychedelic research.

Huston Smith

A scholar of religion who wrote about mystical experiences from psychedelics and how society often dismisses the attribution of these profound experiences to drug effects.

Pink Floyd

A famous band whose first singer, Syd Barrett, developed schizophrenia, in a case Dr. Johnson uses to illustrate susceptibility to psychedelics.

Drugs & Medications

mescaline

A phenethylamine-based classic psychedelic found in peyote and San Pedro cacti, that also acts on serotonin 2A receptors.

Salvinorin A

A kappa-opioid agonist and active compound in Salvia divinorum, capable of producing strong reality-altering experiences similar to smoked DMT.

PCP

An NMDA antagonist psychedelic, grouped with ketamine and dextromethorphan in this class of compounds.

dimethyltryptamine

A classic psychedelic found in many plants, known for producing strong, reality-altering experiences, often compared to smoked Salvia divinorum.

dextromethorphan

An NMDA antagonist psychedelic, often found in cough syrup and known for recreational 'Robo-tripping', with similar subjective effects to classic psychedelics.

LSD

Lysergic acid diethylamide, a classic psychedelic compound that also acts as an agonist at the serotonin 2A receptor, known for profoundly altering sense of reality.

Spravato

An intra-nasal form of esketamine marketed by Janssen, FDA-approved for treatment-resistant depression, but not typically used with integrated psychedelic therapy.

MDMA

A compound called an 'entactogen,' primarily acting through serotonin release, and structurally related to amphetamine. It is being developed for PTSD treatment due to its ability to facilitate emotional connection.

psilocybin

A classic psychedelic compound found in 'magic mushrooms', which acts as an agonist at the serotonin 2A receptor and is being studied for treating depression and other mental disorders.

Ketamine

An NMDA antagonist psychedelic known to induce dissociative and insightful experiences, used therapeutically and recreationally, with different effects based on dosage.

Adderall

An amphetamine-based drug mentioned as being in the phenethylamine class, similar to mescaline and MDMA in base chemical structure but with different receptor interactions.

Bath Salts

Cathinone derivatives that gained notoriety due to a highly publicized incident in Florida, where media misattributed extreme violent behavior to their use. Dr. Johnson uses this as an example of xenophobia in drug attribution.

Ayahuasca

A plant-based brew containing DMT and MAO inhibitors, allowing oral activity of DMT. Known for its profound psychedelic effects.

Prozac

A well-known SSRI antidepressant, which microdosing psilocybin is sometimes claimed to be a 'better version' of.

SSRIs

A class of traditional antidepressants like Prozac, which microdosing psilocybin is sometimes claimed to be a 'better version' of. They augment extracellular serotonin to reduce depressive symptoms.

Companies

Janssen

Pharmaceutical company that markets Spravato (esketamine) for treatment-resistant depression.

Belcampo

A regenerative farm in Northern California that raises organic, grass-fed, and humanely-certified meats using regenerative agriculture practices.

Athletic Greens

An all-in-one vitamin, mineral, and probiotic drink mentioned as a podcast sponsor, which Dr. Huberman takes daily for foundational nutritional needs.

InsideTracker

A personalized nutrition platform that analyzes blood and DNA data to provide insights and suggestions for health goals, mentioned as a podcast sponsor.

Thorne

A supplement company partnered with the podcast for its high quality standards in ingredients and precision in amounts.

Supplements

Vitamin D3

A vitamin mentioned as important for metabolic and cardiac health, provided as a year's supply with Athletic Greens.

Vitamin K2

A vitamin mentioned as important for metabolic and cardiac health, provided as a year's supply with Athletic Greens.

Legislation & Policy

Controlled Substances Act

Federal legislation under which psychedelics are classified as Schedule I compounds, making them illegal at the federal level.

Prop 215

A California proposition from 1996 that legalized medical cannabis, setting a precedent for state-level drug laws differing from federal ones.

Media

60 Minutes

A television news program that featured Dr. Johnson's work on psychedelic therapies for mental disorders.

Concepts

serotonin 2A receptor

A specific subtype of serotonin receptor that all classic psychedelics (LSD, psilocybin, DMT, mescaline) primarily target as agonists or partial agonists, mediating their psychoactive effects.

Locations

Oregon

A US state that has an initiative for state-level legalization of psilocybin therapy, and known for being experimental with euthanasia and plant compounds.

Amsterdam

A city known for its long-standing legal availability of psilocybin truffles, used as a comparison for potential future US psychedelic legality.

Abbot Kinney Boulevard

A location in Venice, California where one can purchase cannabis with a marijuana card, used as an example of local cannabis legality.

condition

Hallucinogen-Persisting Perceptual Disorder

A recognized disorder in the DSM where a small number of people experience persisting perceptual disorders (like halos or tracers) after psychedelic use, distinct from state-dependent learning or temporary post-session anomalies. Often linked to illicit use and rare neurological susceptibility.

Products

Fen-Phen

A diet drug combination that was pulled from the market due to serotonin 2B agonist effects leading to heart valve problems (valvulopathy).