Seven Controversies in Psychedelic Medicine

Alex Belser, PhD

Co-Investigator, Yale University Founding President, Nautilus Sanctuary Chief Clinical Officer, Adelia Therapeutics Chief Clinical Advisor, Cybin Disclosures

✧ Funding Sources, last 3 years ✧ Yale University ✧ NYU School of Medicine ✧ NYU Steinhardt School of Culture, Education, and Human Development ✧ MAPS Public Benefit Corporation ✧ Adelia Therapeutics ✧ Cybin ✧ Heffter Research Institute ✧ Synthesis Institute Psychedelic Effects Psilocybin Ketamine

Vollenweider, F. X., & Kometer, M. (2010). The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nature Reviews Neuroscience, 11(9), 642-651. Psychedelic Research: An overview 200 mushroom stones found in post-Mayan civilization in the Guatemala highlands

Gold Pectorals from the Sinú culture of Columbia (1200 - 1600 c.e.) Psychedelic Clinical Trials: Count 1994-2020 (excludes ketamine) Web of science: psychedelic publication count by year

Petranker, R., Anderson, T., & Farb, N. (2020). Psychedelic research and the need for transparency: Polishing Alice’s Looking Glass. Frontiers in psychology, 11, 1681.

Psilocybin + Psychotherapy Interventions for Anxiety and Depression

✧ Meta analysis: large magnitude effect sizes ✧ Large pre-post and pre-follow-up effects on anxiety and depression ✧ Hedges’ gs =1.16 to 1.47

The Experimental Effects of Psilocybin on Symptoms of Anxiety and Depression: A Meta-analysis (Simon B. Goldberg, Brian T. Pace, Christopher R. Nicholas, Charles L. Raison, Paul R. Hutson, 2020) Galvão-Coelho, N. L., Marx, W., Gonzalez, M., Sinclair, J., de Manincor, M., Perkins, D., & Sarris, J. (2021). Classic serotonergic psychedelics for mood and depressive symptoms: a meta-analysis of mood disorder patients and healthy participants. Psychopharmacology, 1-14. Seven Controversies in Psychedelic Research Seven Controversies in Psychedelic Medicine

#1: How do these drugs work? #2: Should psychedelic treatment be considered a combination therapy? #3: What theoretical approach should we use? #4: Do these drugs really work, or is it super placebo? #5: What credentials and scope of training should be required to facilitate a psychedelic medication session? #6: What specific training should be required to become a psychedelic-assisted psychotherapist? #7: Should psychedelic therapists in training undergo an experiential component? #1: How do these drugs work? Person takes Psychedelics Symptom reduction

Observer Mechanisms of Action: 3 proposed classes

1. Neurobiological mechanisms 2. Psychological mechanisms 3. Psychospiritual/mystical mediators Neurobiological Mechanisms

✧ 5HT2A receptor downregulation

✧ Enhanced cortical glutamatergic transmission in medial PFC

✧ Increased AMPA activation

✧ Reduced DMN activity

✧ Increases in cortical and subcortical BDNF levels

✧ Learning/neuroplasticity

✧ Increased functional connectivity within a limbic/paralimbic network

✧ Anti-inflammatory mechanisms (Nichols, Charles) Psychological Mechanisms

Common Factors Psychedelic-Specific Factors

✧ Therapeutic alliance ✧ Relational/attachment ✧ Empathy ✧ Emotional range ✧ Goal consensus and collaboration ✧ Embodiment ✧ Positive regard and affirmation ✧ Revised life priorities ✧ Mastery ✧ Exalted feeling of joy, bliss, or love ✧ Congruence/genuineness ✧ Ineffability ✧ Mentalization ✧ Alterations to identity during psilocybin experience ✧ Emotional experience ✧ “Bad trip” experiences of transient psychological distress Belser et al., 2017 Psychospiritual Mediators

✧ Mystical experience hypothesis → anxiety, depression, cocaine, drinking, smoking cessation

Pahnke 1963; Gasser, Kirchner, and Passie, 2014; Griffiths, et al., 2006; Griffiths, et al., 2008; MacLean, Johnson, & Griffiths, 2011; Bogenschutz, et al., 2015; Studerus, Kometer, Hasler, & Vollenweider, 2011; Ross et al, 2016; Griffiths et al., 2016; Rothberg, R. L., Azhari, N., Haug, N. A., & Dakwar, E. (2020). Mystical experience is one of many mediators

✧ Only 13% of variability in depression is ✧ 35% of the variability in anxiety is explained explained by the MEQ score by the MEQ score

✧ 87% of depression improvement is ✧ 65% of anxiety decrease is attributable to attributable to other unknown other unknown mechanisms mechanisms

Griffiths et al., 2016 #2: Should psychedelic treatment be considered a combination therapy or medication alone?

From the first meeting, psychedelic-assisted psychotherapy builds from good rapport and a strong alliance between the clinicians and the patient to optimize set and setting.

• Protocols include: 40+ hours of psychotherapy • Risk of adverse events and serious adverse events Time Intensive Combination Treatment

1. Clinician qualifications: psychotherapist and psychedelic-specific competencies 2. Extensive training to competently conduct psychedelic-assisted psychotherapy 3. Preparation psychotherapy and psychoeducation sessions 4. Psychedelic medicine administration (investigational product) psychotherapy session 5. Integration psychotherapy sessions 6. Ongoing supervision, treatment fidelity and adherence assessment What is the role of the psychotherapeutic intervention in efficacy?

This unique combination treatment combines (a) a psychotherapy intervention with (b) a pharmacological intervention. This platform may provide: 1. Independent (additive) effects 2. Interactive effects 3. Enhanced effectiveness of each intervention 4. Safety as ensured by the provision of competent psychotherapy Issue of whittling down psychotherapy

✧ It’s cheaper to skimp on the psychotherapy ✧ How much prep and how much integration is really needed? ✧ Can we substitute digital therapeutics, apps, baby monitors in clinic?

✧ Removing therapy: a dismantling study would be required ✧ Ethical risks to dropping psychotherapy entirely ✧ Avoid obfuscation re: “psychedelic support” vs. “psychedelic-assisted psychotherapy” ✧ If all the research trial providers are psychiatrists, they’re probably providing psychotherapy #3: What theoretical approach should we use in psychedelic-assisted psychotherapy?

✧ Non-directive Psychotherapy Levine, ✧ Inner-directed – MAPS ✧ Internal Family Systems – Dick Schwartz ✧ Relational/psychodynamic – Jeff Guss, Raquel Bennett ✧ Couples therapy – Anne Wagner – Canada, (MDMA) & Gita Vaid ✧ Group Work ✧ CBT – Matt Johnson smoking cessation trials ✧ Family Therapy – Annie Lalla ✧ Motivational Interviewing – META – Michael ✧ Transtheoretical Psychedelic Support – Ingmar Bogenschutz Gorman & Elizabeth Nielson ✧ Acceptance and Commitment Therapy – Hexaflex ✧ Multitheoretical Psychedelic-Assisted Psychotherapy – Model – Jordan Sloshower & Jeff Guss Alex Belser & Bill Brennan ✧ Somatic practices – Bessel Van der Kolk and Peter #4: Do these drugs really work or is it super placebo?

Current Approach Alternatives

✧ Problems of functional unblinding ✧ Standard of care comparator ✧ Dose response study ✧ Inert placebo comparator ✧ Active placebo comparator #5: What credentials and scope of training should be required to facilitate a psychedelic medication session?

1. Psychotherapists (including psychiatrists and “The psychological support is an psychiatric NPs with psychotherapy training) integral element of psilocybin therapy 2. Nurses and must be provided by trained therapists.” 3. Paraprofessionals ✧ Psychotherapy or pseudotherapy? – Bill Richards ✧ Competency in psychotherapy requires: Psychologist, Johns Hopkins, Lead ✧ 3,000 hours for master’s counselors Trainer, Compass Pathways ✧ 3,500 hours for psychologists ✧ Scope of practice conflicts #6: What specific training should be required to become a psychedelic-assisted psychotherapist?

✧ It’s not “see one, do one, teach one” ✧ Challenge: no current licensing infrastructure in 1. MAPS: 120 hours of training place 2. Compass Pathways: ~ 100+ hours ✧ Challenge: no standardized training 3. Center for Consciousness Medicine: 150 hour ✧ Iatrogenic risk 4. School of Consciousness Medicine: 250 hour ✧ Intersubjective work: requires experienced 5. Synthesis Institute: 18 months provider 6. Psychedelic apprenticeship (Timmerman, Watts & Dupuis, 2020) #7: Should psychedelic therapists in training undergo an experiential component?

✧ Experiential training is considered essential by senior facilitators ✧ Experiential training is considered essential in indigenous cultures that have used psychedelic medicine ✧ MAPS offers this experiential component to the training via a Phase 1 trial ✧ Current training paradigms don’t generally provide for legal experiential components

(Nielson & Guss, 2018; Winkler & Csemy, 2014; Winkler, Gorman & Kočárová, 2016) Seven Controversies in Psychedelic Medicine

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