Dr. Robin Carhart-​​Harris: The Science of Psychedelics for Mental Health

Dr. Robin Carhart-​​Harris on Psychedelics

• Leading researcher in the field of psychedelics and their effects on neural circuitry
• Studies how psychedelics like psilocybin (magic mushrooms) change neural circuitry for learning and new ideas
• Conducts clinical trials showing psilocybin can alleviate major depression in over 67% of participants
• Explores the use of psychedelics for mental health, creativity, intelligence, and more

History and Definition of Psychedelics

• Term “psychedelic” coined by Humphrey Osmond in the 1950s 
  • Dissatisfied with the term “psychotomimetics” (drugs that mimic psychosis)
  • Wanted a term that better represented the psychological effects of compounds like mescaline and LSD
• Etymology: “Psyche” (Ancient Greek for human mind or soul) + “delic” (to make clear, visible, manifest, or reveal) 
  • Psychedelics reveal aspects of the human mind/​​soul that are not ordinarily visible
• Classic psychedelics work on the serotonin 2A receptor in the brain 
  • Pharmacology is important, but subjective experience (phenomenology) cannot be neglected
    Psychedelics and the Mind
• Psychedelics can reveal something about the mind that can’t be revealed otherwise 
  • Subconscious processing, like blind sight, is an example of non-​​conscious processing
  • Depth psychology, psychoanalysis, and psychodynamic psychology discuss the unconscious mind 
    • Personal unconscious: repressed memories, traumatic experiences, difficult relationships
    • Collective unconscious: transpersonal aspects of the human mind
• Classic psychedelics like LSD and psilocybin can bring up repressed material in psychotherapy 
  • Emotional release and insights can catalyze the therapeutic process

Microdosing vs. Macrodosing

• Microdosing: taking a sub-​​perceptible dose of a psychedelic, typically LSD or psilocybin 
  • May improve well-​​being and aspects of cognition, but evidence is still thin
• Macrodosing: taking a perceptible dose of a psychedelic, inducing altered states of consciousness
• Conversion between magic mushrooms and psilocybin: 
  • 1 gram of magic mushrooms contains an average of 6–12 milligrams of psilocybin

Clinical Trials with Psilocybin

• Study comparing 25 mg of psilocybin to 10 mg of psilocybin and a drug called escitalopram (Lexapro)
  • 25 mg of psilocybin is a perceptible dose, inducing hallucinations and altered states of consciousness
• Other trials have investigated psilocybin for the treatment of depression
• Results from these studies are still being analyzed and debated, but they show promise for the therapeutic potential of psychedelics
  Psilocybin in Clinical Trials
• 25 milligrams of psilocybin roughly equivalent to 2 grams of magic mushrooms 
  • Exact conversion not well-​​established, caution advised in dosing
• Clinical trials show promising results in treating depression with psilocybin 
  • Two sessions with doses ranging from 10 to 25 milligrams
• The experience during sessions may be crucial for transformation from depressed to non-​​depressed state 
  • Data suggests that the magnitude of certain experiences predicts therapeutic outcomes

Psychedelic Therapy Sessions

• Patients typically wear an eye mask, with eyes closed
• Music is a staple component in all published studies 
  • Starts spacious, builds and becomes atmospheric, then coaxes emotion
  • Music may play a significant role in the therapy’s success
• Psychedelic therapy is a combination treatment, with a synergy between the drug and the therapy

Letting Go in Psychedelic Therapy

• Letting go is a key principle in psychedelic therapy 
  • Encourages patients to trust, let go, and be open
• Trust is essential for therapeutic rapport 
  • Measured on the morning of dosing, predicts quality of experience and therapeutic outcomes
• Readiness to surrender and not resist is important for the therapy’s success
  Psychedelic Experience Phases
• Early phase dominated by negative emotions and anxiety 
  • Struggle against the general drug effects
  • Fear of losing one’s mind or dying
• Latter phase often more positive 
  • Possibly due to breakthroughs or calmer states

Brain Communication Under Psychedelics

• Increased global functional connectivity or communication in the brain 
  • Communication transcends modules and becomes more intermodular
  • Effect correlates with the magnitude of the subjective effect
• Activation of serotonin 2A receptor thought to be responsible for increased communication 
  • Computational modeling work supports this idea

Non-​​Hallucinogenic Psychedelic Therapeutics

• Movement to develop drugs that alleviate symptoms of depression or trauma without hallucinations 
  • Based on understanding of how psychedelics like psilocybin and MDMA work
  • Controversial as it removes the subjective experience aspect of traditional psychedelics
• Pharmaceutical companies and startups interested in developing these drugs 
  • More appealing to patients and the medical system
  • Avoids the mental imagery associated with traditional psychedelic experiences
    Skepticism and Microdosing
• Skepticism about microdosing due to lack of compelling logic and potential wishful thinking 
• Microdosing aims to provide therapeutic action without psychedelic effects 
  • Subperceptible dosages over a longer period of time
  • May have some pharmacological effects, but not necessarily psychedelic
• No clear examples of drugs that selectively agonize serotonin 2A receptor without being psychedelic 
  • Lyseride used in Parkinson’s treatment, but more of a dopamine agonist

Neuroplasticity and Connectivity

• Increased connectivity between brain areas observed during and after psychedelic experiences 
  • Correlates with the strength of the therapeutic outcome for depression
  • Suggests a more flexible mode of brain functioning
• Extreme modularity of brain function may be depressive 
  • Increased crosstalk between different modules of the brain correlated with positive therapeutic outcomes
• Therapeutic value in being able to move along the continuum from linear to nonlinear thinking 
  • Severe mental illness like depression may involve getting stuck at one location on this continuum

Depression and Cognitive Bias

• Depressive states and extreme anxiety states can alter the perception of time 
  • Negative state feels like it will go on forever or return at random
• Decrease in modularity or opening up of the brain system may relate to an opening up of the mind after psychedelic dosing 
  • Improvement in well-​​being observed in healthy individuals after taking psilocybin
    First-​​Time Psychedelic Use Trial
• Completed, but not yet published or submitted 
• Conducted during COVID-​​19 pandemic
• Participants: healthy volunteers, middle-​​aged (average age 40), equal proportion of male and female
• All staff were female
• Significant improvements in well-​​being observed at the end of the trial

Trial Design

• Participants had never used a classic psychedelic before
• Aim: to understand the effects of first-​​time psychedelic use on well-​​being and other psychological variables
• Participants received a single dose of psilocybin
• Followed by integration sessions to help process the experience
• Results showed significant improvements in well-​​being, even in healthy individuals without depression or other mental health issues

Implications and Future Directions

• Suggests that psychedelics may have potential benefits for a wider population, not just those with mental health disorders
• Raises questions about the potential role of psychedelic therapy in promoting mental health and well-​​being in the general population
• Further research needed to explore the long-​​term effects of psychedelic use and the optimal frequency and dosage for promoting well-​​being
  Psilocybin Study on Healthy Volunteers
• Repeated measures design 
  • Baseline data, placebo, and brain scans
  • Healthy, middle-​​aged participants with no prior psychedelic experience
• 1 mg placebo dose of psilocybin 
  • EEG headsets to record brain activity
  • MRI scans before and after to examine brain connectivity and anatomy
• 25 mg dose of psilocybin 
  • Significant improvements in psychological well-being
  • Increased informational complexity of ongoing brain activity (entropic brain effect)
  • Correlation between the magnitude of the subjective effect and the entropic brain effect
• MRI results
  • Anatomical brain changes observed
  • Diffusion tensor imaging used to examine white matter tracts
  • Changes in major tracts between the prefrontal cortex, thalamus, and striatum
  • Decrease in axial diffusivity, indicating increased tract integrity
  • Similar to changes seen in a developing brain

Psilocybin Study on Fibromyalgia

• Fibromyalgia: generalized chronic pain, often controversial and misunderstood
• Psilocybin therapy for fibromyalgia patients 
  • 25 mg dose of psilocybin
  • EEG cap during sessions
  • Eye mask used during the experience
• No specific focus on pain during the session
• Differences between classic psychedelic therapy and MDMA therapy 
  • MDMA therapy involves more dialogue and empathic connection
  • MDMA trials may not use eye masks, allowing for more visual interaction between participants and therapists
    Combination of Psilocybin and MDMA
• Some people self-​​administer combination psilocybin and MDMA 
  • Referred to as a “hippie flip”
  • Psilocybin can lead to deep introspection and darker thoughts
  • MDMA has a serotonergic and dopaminergic effect, providing balance
• Potential for therapeutic use 
  • No current studies or trials on this combination
  • Could potentially enhance therapeutic outcomes
  • Requires further research and investigation
    Combining Compounds in Psychedelic Therapy
• Underground therapists using combinations of compounds (e.g., MDMA and psilocybin) in therapy 
  • Trial and error approach, learning from experience
  • Precision medicine and personalized medicine: certain combinations may work better for specific patients
• Psilocybin can take patients to deep places, but can be aggressive 
  • May not be suitable for PTSD patients who may resist the experience
• MDMA offers a more positive and reliable experience 
  • Can make it easier for patients to confront trauma without being overwhelmed
  • Limitation: may not take patients as deep as classic psychedelics

DMT and 5‑MeO-​​DMT

• DMT: a classic psychedelic, direct agonist of the serotonin 2A receptor 
  • Less potent than psilocybin, but can produce wild effects at standard doses
  • Often smoked or vaped, both recreationally and therapeutically
• 5‑MeO-​​DMT: similar to DMT in kinetics, but different pharmacologically and subjectively 
  • More reliable ego dissolution experience, less visual
  • Also smoked or vaped

Ego Dissolution

• Ego dissolution: temporary elimination of the idea that things stop and start between us and everything else 
  • Can lead to a sense of belonging, meaning, and understanding that we are not as important as we think
• Serotonin 2A activation can cause ego dissolution 
  • Boundaries between self and others blur, leading to a sense of connection and unity
    Ego Dissolution and Psychedelics
• Ego dissolution: sense of self going away, feeling interconnected with others and the worl 
• Psychedelics can help people access empathy for themselves and others
• Classic psychedelics target serotonin 2A receptors, heavily expressed in the human cortex
• Entropic brain action: psychedelics scramble up activity in the cortex, spreading out the system and causing ego dissolution

Psychedelic Therapy Limitations

• Ego dissolution effects don’t last; ego can come back with a vengeance
• People may relapse if they haven’t done integration work
• In trials, relapse is more common than lasting wellness

Current State of Psychedelic Legality

• Labs using government money and philanthropy to study clinical applications of psychedelics
• Therapists administering psychedelics illegally based on published studies
• Recreational, open market, black market: caution for fentanyl-​​laced substances
• Pharma and FDA: psychedelics currently illegal unless used in clinical trials
• Decriminalization vs. legalization: e.g., psilocybin decriminalized in Oakland, CA, but not legal

Future of Psychedelic Legality

• Unclear timeline for when psychedelics may become legal for prescription or purchase without risk
• Ongoing clinical trials and research may influence legislation and public perception
  Psilocybin and MDMA in Clinical Trials
• Psilocybin mushrooms decriminalized in Oakland 
  • Sold in some headshops and churches
  • No licenses yet for selling
• FDA licensing of psychedelics as medicines 
  • Major inflection point for legal prescription across the US and beyond
• MDMA therapy for post-​​traumatic stress disorder (PTSD)
  • Phase 3 trials led by Maps
  • 67% remission rates, long-​​term effects
  • Possible rollout as early as next year
  • Maps may become the provider, possibly as a pharma company
• Psilocybin therapy for treatment-​​resistant depression 
  • Phase 3 trials led by Compass
  • Earliest estimate for approval around 2026
• Groundswell of activity in psychedelic research 
  • Investigating various psychiatric disorders (except schizophrenia)
  • Positive results in difficult-​​to-​​treat disorders
• Comparison to meditation research 
  • Psychedelics catching up to meditation in terms of acceptance and research
  • Increased interest from donors and universities
• Importance of proper safeguards and standards in psychedelic therapy 
  • Avoiding scandals and setbacks like gene therapy
    Mental Health Crisis and Psychedelic Therapy
• Mental health treatments haven’t progressed much since the 1950s 
• Psychedelic therapy offers a different approach, not a daily drug
• Not everyone will want to use psychedelics, but they should be an option
• Psychedelic therapy is a major paradigm challenge

Gratitude for Psychedelic Research

• Small group of individuals driving the paradigm shift
• Potential for improvements in mental health and physical health outcomes
• Dr. Robin Carhart-​Harris’s research focuses on the history, uses, and mechanisms of psychedelics

Supporting Psychedelic Research

• Links to studies and Dr. Carhart-​Harris’s laboratory provided in the show notes
• Follow Dr. Carhart-​​Harris on Twitter for updates on psychedelic science