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Psychedelics: an emerging treatment modality

Franklin King IV, MD

Center for Anxiety and Traumatic Stress Disorders

MGH

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Disclosures

Neither I nor my spouse has a relevant financial relationship with a commercial interest to

disclose.

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What are psychedelics?

• Psychedelic, 1956 = “mind-manifesting”

• Profound change in consciousness, relatedness, and sensory experience

• Often of spiritual importance and/or personal meaning

• Serotonergic psychedelics: mescaline, DMT (including ayahuasca), psilocybin, LSD, [MDMA]

• Other “psychedelics”: ketamine, ibogaine, THC

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“CLASSICAL” PSYCHEDELICS

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Lysergic acid diethylamide (LSD)

• Highly potent, accidentally discovered in 1943

• Minimal recognizable dose 25µg, “optimal” dose 100-200µg

• Acute effects 6-10 hours (dose dependent)E-commons

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LSD

• Primary psychedelic effect via 5HT-2A agonism

– Blocked by ketanserin

• Partial agonist at 5HT-1A (postsynaptic, inhibitory)

• Effects on numerous other 5HT, D1, D2

• Tachyphylaxis after 2-3 doses

Preller, Elife 2018

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Psilocybin

• Present in Psilocybespecies of mushrooms on 6 continents

• Used as a sacrament in Mexico for 3000 years, suppressed by Spanish conquistadors

• “Discovered” by the West in 1957

E-Commons

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Psilocybin

• Active ingredient = dephosphorylated form (psilocin)

• Usual “dose” = 15-25mg

• Acute effects 4-6 hours

• Similar pharmacology to LSD

• Most frequently studied in current phase of research

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Dimethyltryptamine (DMT)

• Ultra short acting (5-15 minutes), not orally bioavailable

• Intense visual imagery and loss of sense of self

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Ayahuasca

• Amazonian brew used as medicine and sacrament

• Contains DMT from the Psychotria shrub

• Only orally bioavailabledue to MAOI action from Banisteriopsisvine

• Acute effects 4-6 hours

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Safety & physiologic effects

• Negative effects (dose dependent): • Headache, nausea, fatigue most common (<50%)

• Sympathetic changes: • ↑BP, ↑HR (mild), ↑temperature (rare)• Mydriasis, increased reflexes

• Toxicity: no LD50 established for humans, likely ingrams or kilograms

• No cases of HPPD or prolonged psychosis in modern studies• Personal or family history of bipolar or schizophrenia

contraindicated

• Addiction and cravings not observed

Passie CNS Neuroscience and Therapeutics 2008; Mithoefer Lancet 2018

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Acute psychological effects in healthy subjects

• Altered States of Consciousness scale: 5 domains• Oceanic Boundlessness: pleasurable experiences of

depersonalization, derealization, changed sense of time, positive mood, mystical experiences

• Anxious Ego Dissolution: negatively experienced alterations in self-awareness, anxiety, fear of loss of thought control and body control

• Visual Restructuralization: enriched visual imagery, elementary hallucinations, synesthesia (usually recognized as unreal)

• Auditory Alterations (eg, AH): uncommon• Reduction of Vigilance: reduced altertness, cognitive

deficits — mild to moderateStuderus 2011

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Long term psychological effects

• Effects often long lasting: increased well being, enhanced appreciation, increased openness

• Majority of subjects in controlled settings report experience as enriching or meaningful, even if the session was marked by dysphoria

• 14-month follow-up: among 5 most personally meaningful (58%) and spiritually significant (67%) experiences in their lives

• No cases of HPPD or psychosis in any recent studyGriffiths et al J Psychopharmacol 2008Studerus et al J Psychopharmacol 2011

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USE IN DEPRESSION, ANXIETY, AND SUBSTANCE USE DISORDERS

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Psychedelic-assisted psychotherapy

• All recent studies have utilized psychological support during the treatment session

• Mostly based on models developed in 1960s (Stan Grof)

• Set and setting• Quiet room, calming décor, instrumental music,

eye shades, non-directive therapy• Therapist is available at all times, but patients

may be encouraged to “go inside” and explore their inner experience

Johnson et al J Psychopharmacol 2008

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Psychedelic-assisted psychotherapy

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Treatment resistant depression

• To date, recent studies have examined psilocybin and ayahuasca for treatment resistant depression

• Psilocybin granted “breakthrough therapy” designation by FDA, 15 clinical sites in Europe and North America for Phase 2 trial ongoing

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Effects are robust, rapid, and sustained

❖ Carhart Harris Psychopharmacology 2018: open label, N=12 subjects with treatment-resistant depression❖ Psilocybin assisted psychotherapy, 10mg <- 7 days -> 25mg

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Robust and rapid response

❖ Palhano-Fontes Psychol Med 2018: randomized, double-blind, N=29 patients with treatment-resistant depression, ayahuasca vs placebo

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• Grob et al 2011/UCLA: 30% decrease in BDI, significant decrease in trait anxiety sustained at 6 months– N=12, dx=advanced stage cancer/acute stress, GAD, adjustment disorder, or anxiety

secondary to cancer– Psilocybin 14 mg/70 kg vs niacin placebo

• Gasser et al 2014/University of Bern: trend toward decreased state anxiety sustained at 12 months– N=12, dx=life threatening medical illness/anxiety associated with medical illness– Randomized, open-label crossover; 200 µg vs 20 µg LSD

• Griffiths et al 2016/Hopkins: 80% of subjects with significant decreases in anxiety and depression at 6 months– N=51, dx=life threatening cancer/depression or anxiety– Randomized crossover design; 22 mg/70 kg psilocybin vs 1 mg (placebo)

• Ross et al 2016/NYU: 60-80% response rate for anxiety and depression at 6 months– N=29, dx=cancer (2/3 with advanced cancer)/anxiety disorder (GAD 10%, adjustment

90%)– Randomized, crossover design; psilocybin 21 mg/70 kg vs niacin placebo

Sustained effect in end of life-related depression and anxiety

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Smoking

• Smoking cessation: Johnson 2014 (Hopkins)

• N=15

• 2-3 moderate-dose psilocybin sessions + CBT

• 80% abstinent at 6 months

• 67% abstinent at 12 months, 60% at 30 months

Johnson et al J Psychopharmacol 2014

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Alcohol Use Disorder

• LSD widely used in 1960s for alcoholism

• 2012 meta-analysis of 536 subjects found beneficial effect (OR 1.96) of single LSD session

• Pilot study (N=9), substantial reductions in heavy drinking days following 1-3 psilocybin sessions + therapy

• Phase 2 clinical trial underway (NYU)

Krebs J Psychopharmacol 2012

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Opioid Use Disorder

• 1973, N=78

• Single LSD session

• Followed for 12 months

• 25% abstinent after 1 year

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Effect of therapy correlated with quality of subjective experience

• Profundity of experience consistently found to mediate both neurophysiologic findings in healthy subjects, as well as clinical recovery in patient studies

• Altered states of consciousness scale (ASC): experience of unity, spiritual experience, blissful state, insightfulness, complex imagery

• Mystical Experience Questionnaire: ineffability, mysticality, transcendence of time and space

Roseman Front Pharmacol 2018; Griffiths J Psychopharmacol 2016, Palhano-Fontes 2018

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Microdosing

• Use of very small doses (≤0.05 typical dose) with minimal acute drug effects

• Schedule varies, usually taken only a few days each week

• LSD, psilocybin most commonly used

• Observational study: increased mood, attention, well being, creativity on dosing days but no residual effects

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MDMA

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MDMA - pharmacology

• Induces 5HT and NE efflux

• Binds monoamine transporters (SERT>>NET or DAT) and prevents reuptake

• Weaker affinity to 5HT-2A than classical psychedelics

• Little effect on 5HT-1A

• May also induce oxytocin release

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MDMA acute effects

• Enhanced feelings of empathy and bonding

• Elevated or euphoric mood

• Decreased fearfulness

• Mild heightened sensory experiences

• Mild increases in HR, BP, core temp

• Bruxism, reduced appetite

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MDMA – toxicity

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MDMA-assisted psychotherapy for PTSD

• 26 veterans and first responders with treatment resistant PTSD

• Mean CAPS = 86.5

• Randomly assigned 30mg, 75mg, or 125mg MDMA

• Therapy conducted over 8 hour sessions with 2 therapists per patient

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Durability of effects

❖At 12 month followup, reduction in PTSD scores sustained

❖71% patients in treatment arms no longer met PTSD criteria

❖ Treatment arms with reduction in neuroticism and increase in openness (NEO)

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POSSIBLE MECHANISMS

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Amygdala modulation

• Amygdala: area of rich 5HT2A receptors, connect amygdala widely across multiple areas of neocortex

• Modulation of amygdala – visual cortex connection

• Amygdala involved in determining emotional meaning of visual stimuli

• Hyperconnectivity between amygdala and visual cortex involved in increased threat processing and anxiety

• Psilocybin reduced top-down amygdala -> V1 connection

Kraehenmann Neuroimage: Clinical 2016, Vollenweider Nat Rev Neurosci 2010

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Increased connectivity of visual cortex

• LSD causes increased connectivity of visual cortex to multiple other cortical regions

• Increased connectivity positive correlated with increased visual imagery during experience

Carhart Harris PNAS 2016

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Modulation of default mode network (DMN)

• DMN involved in experience of sense of self/embodiment, retrieval of autobiographical memory, daydreaming

• Balance between internally and externally directed thought

• Decreased coupling within DMN hubs (PCC, medial prefrontal cortex (mPFC)) shown with psilocybin, LSD, ayahuasca

• Magnitude of deactivation correlates with subjective effects

• Increased DMN activity in pathological rumination in depression

Carhart Harris 2011 PNAS, Palhano-Fontes 2014 PLOS ONE, Carhart Harris 2017 Sci Rep

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Opening the “thalamic filter”

• Thalamus acts as gateway for sensory information flowing to primary sensory cortex regions

• LSD shown to increase thalamic connectivity to the cortex– Dependant on 5HT2A receptors

• Common mechanisms? Similar effects observed with NMDA antagonists (eg, ketamine), as well as increased dopamine transmission

Preller PNAS 2019

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Future directions

• Numerous clinical trials ongoing

• 2 psychedelic research centers opened in 2019, more under development

• FDA closely involved in studies for psilocybin (depression) and MDMA (PTSD)

• Legal issues continue to stymie research

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Conclusion

• Compelling evidence suggests psychedelics offer potential for treatment of a variety of psychiatric conditions

• The effects are rapid, robust, and sustained

• Psychedelics are safe, and adverse events exceedingly rare in controlled settings

• Larger clinical trials are currently needed (and are underway)