Therapeutic potential of psychedelics in substance use disorders

Transcription

1 Therapeutic potential of psychedelics in substance use disorders Randy T Brown MD, PhD, FASAM Associate Professor randy.brown@fammed.wisc.edu Conflicts of Interest Statement No conflicts of interest to report concerning this presentation 1

2 Funding Support Acknowledgements Collaborators Outline Psilocybin and MDMA Background Safety and Abuse potential Dosing and Administration Protocol Relevant studies Possible Mechanisms Considerations 2

3 Psilocybin Background Psychedelic: Mind manifesting capability, revealing or having useful or beneficial properties of the mind (Osmond, 1957) Psychedelic: Classics: mind manifesting Psilocybin, Mescaline, capability, DMT, revealing LSD or having useful Psilocybin or beneficial (psilocin) properties is a 5 HT2a, of the 1a receptor mind (Osmond, agonist 1957) Schedule I since 1970 Controlled Substance Act in US Classic psychedelics: psilocybin, mescaline, DMT, LSD No currently accepted medical use A high potential for abuse 3

4 Some Past and Current Modern Psilocybin Studies Zurich (2000 ): Neuroimaging Hopkins ( ): Mystical Experience, Dosing, Personality UCLA (2010): Cancer patients New Mexico (2015): Alcohol dependence Hopkins (2016): Tobacco cessation UCL/Kings College (2016 ): Depression (Open label) UCL (2013 ): Neuroimaging NYU/Hopkins (2016): Depression/anxiety in terminal cancer UW Madison (2016; 2019): High dose PK; Opioid; Depression UA Birmingham (2016 ): Cocaine use disorder Safety No evidence of neurotoxic effects Transient BP/HR Possible headache within 24 hours after dosing Impairs judgement thus context, support, and preparation are important No withdrawal Low risk of hallucinogen persisting perceptual disorder (HPPD) Negative interaction with serious psychiatric diagnoses (e.g. psychosis, bipolar) 4

5 Population Data Lower mental illness rates 1 Reduced odds of past month psychologic distress, past year suicidal thinking, past year suicidal planning, or past year suicide attempt 2 Decreased rate of supervision failure in inmates 3 1 Krebs et al. (2013). PLoS One; NSDUH; 2 Hendricks et al. (2015). JoPsychopharm; NSDUH; 3 Hendricks et al. (2014). J Ppsychopharm Dosing Typical: mg/kg UW Study: mg/kg ( mg) Oral onset: ~30 60 min Peak effects: ~2 hours 1 5 doses /4 6 weeks Total duration: 4 8 hours 5

6 Psilocybin Protocol Comprehensive psychiatric/psychological and medical screening Two monitors/guides/therapists/facilitators Study physician(s) & research coordinator(s) In a safe, secure, and supportive setting 6 8 hours of pre dosing counseling before initial dose Eye shades, headphones for pre set music playlist May stay overnight or discharge under care of their support person Integration session the next morning Phone check ins and additional integration sessions prior to next dose The UW SETTing Set: person s psychological state Pre dose preparation Careful screening Expectations/concerns Integration Setting: environment & context Interpersonal support Safe & secure room Room with comfortable & positive décor Personal objects if possible 6

7 Psilocybin Session Psychedelic vs psycholytic therapy Non directive approach, guiding when necessary Centering or personal ritual Lay down and relax into their experience Emotional support and reassurance Agreement that they would let us know if they need help Help participant be curious about their experience ( Trust, Let Go, Be Open ) Challenging Experience ( In and through ) Johns Hopkins Treatment room courtesy of MAPS Mystical Experience, Ego Dissolution & Challenging Experiences Mystical Experience 1 Mystical (Unity, Noetic, Sacred) Transcendence of time and space Deeply felt positive mood Ineffability Ego Dissolution 2 Dissolution of my self or ego One with the universe Sense of union with others Decrease sense of importance Disintegration of self or ego Less absorbed by my own issues and concerns Challenging Experiences 3 Fear Grief Isolation Experience of dying Insanity Physio distress Paranoia 1 Maclean et al (2012). J for the Scientific Study of Religion; 2 Nour (2016). Frontiers in Human Neuroscience; 3 Barrett (2017). Human Psychopharm Clin & Exp. 7

8 Mystical Experience Meaningfulness, Well Being, Spirituality, Positive Behavior Personality Dimension of Openness Griffiths et al. (2008). J of Psychopharmacology Maclean et al.(2011). J of Psychopharmacology Greater whole brain communication Psilocin similar in structure to serotonin 5 HT2a receptors* Pretreatment with ketanserin Greater communication between various major brain hub networks Decreased communication within hubs. Default mode network which together represents self related functioning Self referential processing, selfawareness, metacognition Decreased activity correlates with degree of ego dissolution Carhart Harris et al. (2014). Frontiers in Human Neuroscience 8

9 Psilocybin for Alcohol Use Disorder Bogenschutz et al. (2015) J Psychopharmacol, 1 11 N = 10 adults with DSM IV AUD pilot study 12 Psychosocial sessions 7 Motivational Enhancement Therapy 3 Psilocybin session preparation sessions 2 Post psilocybin integration sessions 2 doses of oral psilocybin one month apart 0.3mg/kg, and mg/kg (7 received dose 2) Figure 3. Drinking outcomes and effect sizes.means shown are for all available data (n = 10 at baseline, n = 9 at all other time points). p-values are from paired t-tests (df = 8). 9

10 Psilocybin for Tobacco Cessation Johnson et al. (2014) J Psychopharmacol, Johnson et al. (2017) J Am J Drug Alcohol Abuse, N = 15 adults Average of 6 failed attempts to stop smoking Cognitive Behavioral Therapy (CBT) Quit date concurrent with first of 3 psilocybin doses 2 3 oral doses of 20 30mg/70kg one month apart 12 of 15 (80%) were cotinine free (urine) at 6 months after quit date 10 of 15 (67%) were abstinent at 12 months Psilocybin for Tobacco Cessation Johnson et al. (2017) J Am J Drug Alcohol Abuse, Linear regression of Mystical Experience and long term change in cotinine 10

11 Possible therapeutic time course and stages of psilocybin Majic et al.(2015). J of Psychopharmacology Psilocybin/Classic Psychedelics Drug Participant Setting Acute Brain Effects Acute Psychological Effects Direct effects on 5 HT receptors Secondary effects e.g. glutamate receptors Changes in CBF, BOLD, Connectivity, MEG Mystical experience, ego dissolution, insight, experience of awe, unconstrained thought, autobiographical content, exposure to challenging representations, positive affect Integration through counseling + meditation, social support, art, music, nature, etc. Long term neuroplastic and functional changes Positive mood, decreased anxiety, fear, rumination, craving, distress Persisting Effects Changes in personality openness, prosocial motivation Changes in beliefs & values gratitude, mindfulness, spirituality, relationships, nature Adapted from Bogenshutz & Pommy. (2012). Drug Testing & Analysis 11

12 UW Opioid Use Disorder Study Without concurrent MAT, opioid overdose is a major risk There may be a buprenorphine psilocybin interaction based on mouse data 12 adults stable on buprenorphine MAT for 6 months to receive doses of psilocybin at a monthly interval Initial step toward efficacy study of psilocybin + MAT for Opioid Use Disorder (improve retention/use rates?) 23 MDMA 3,4 Methylenedioxymethamphetamine 12

13 Background 1912 Invented by Merck 1978 Used as an adjunct to psychotherapy Emergency Scheduling Act in 1985/86 MDMA binds 5 HT transporter Release/reuptake inhibition of NE and DA Increases affiliative neurohormones oxytocin and vasopressin Safety Transient BP/HR/temp Jaw tension, nausea, blurred vision, appe te Lack of evidence of neurocognitive decline associated with MDMA in PTSD trial 1 No misuse/dependence in PTSD trial patients 1 Limited evidence of structural or functional brain alterations in moderate MDMA users 2 Post MDMA may lead to short term neurochemical depletion, feelings of anhedonia, lethargy, anger, insomnia, decreased appetite, and depression in recreational users 3 1 Mithoefer et al. (2013). J of Psychopharm; 2 Mueller et al. (2013). Neurosci & BioBehav Rev.; 3 Parrot (2014). J of Psychoactive Drugs 13

14 Neurobiology MDMA Effects Decrease Anxiety/Depression Alter perception of meaning Increase levels of arousal Increase relaxation Improve fear extinction learning Increase emotional attachment, trust, empathy Reduce subjective fear response on recall Effects relate to PTSD symptoms Positive mood and less avoidance of therapy and emotions See old problems in a new light Increase motivation to engage; cognitive process; recount trauma Reduces hypervigilance Reflect on traumatic memory without being overwhelmed Therapeutic alliance and openness to reflect on painful memories Reflect on painful memories with optimal arousal Neurobiological Correlate Release of pre synaptic 5 HT1A/1B receptors Increased activity at 5 HT2A receptors Release of dopamine and noradrenaline Increased alpha 2 adrenoreceptor activity Release noradrenaline and cortisol Multiple factors including oxytocin Decreased cerebral blood flow in amygdala & hippocampus Sessa (2017). Neuroscience Letters MDMA Protocol Dose: mg Onset: ~30 60 min Peak effects: ~1 2 hours Half dose: ~1.5 2 hours Annie and Michael Mithoefer Follow and facilitate rather than direct the experience Help explore and validate new perspectives Alternate between talking and periods of inner focus As effects subside, encourage patient to reflect on and accept the validity of the experience Interaction between the effects of the MDMA, the therapeutic setting and the mindsets of the patients and the therapists 14

15 Psychotherapeutic Elements Establishing a Safe and Supportive Therapeutic Setting and a Mindset Conducive to Healing Anxiety Management Training/Stress Inoculation Training Exposure Therapy and Optimal Arousal Cognitive Restructuring Transference and Countertransference Working with the Multiplicity of the Psyche Somatic Manifestations of Trauma Mithoefer. MAPS Bulletin Phase 2 Trial Randomized Double blind Dose response Trial Mithoefer et al. (2018). Lancet Psychiatry Military Veteran, Firefighters, Police Officers CAPS IV > 50 Failed previous pharmacotherapy or psychotherapy Groups: 30 mg (n =7); 75 mg (n = 7); 125 mg (n = 12) Outpatient psychiatric clinic Two blinded session, 3 5 weeks apart with two trained therapists Three prep sessions & post dose daily phone contact for a week and three weekly integration sessions 30 & 75 mg groups crossed over to have 3 open label sessions with flexible dosing ( mg) 15

16 Phase 2 Trial Randomized Double blind Dose response Trial Mithoefer et al. (2018). Lancet Psychiatry Results: CAPS IV change at 1 month follow up (p=0.001): 30 mg: 11.4 [12.7] vs. 75 mg: 58.3 [9.8]; d = mg: 44 3 [28.7] d = mg crossover showed similar improvement CAPS IV change at 12 month follow up (p=.0001): Baseline: 87.1 [16.1] Combined at 12 Month: 38.8 [28.1] 67% no longer met CAPS IV Diagnostic Criteria for PTSD vs 21% in placebo arm Phase 2 Trial Double blind Trial Mithoefer et al. (2018). Lancet Psychiatry 16

17 A Randomized, Double Blind, Placebo Controlled, Multi Site Phase 3 Study of the Efficacy and Safety of Manualized MDMA Assisted Psychotherapy for the Treatment of Severe PTSD Los Angeles, CA private San Francisco, CA academic San Francisco, CA private Boulder, CO private Fort Collins, CO private Farmington, CT academic New Orleans, LA private New York, NY academic New York, NY private Charleston, SC private Madison, WI academic Boston, MA private practice Montreal, Canada private Vancouver, Canada academic Israel private Considerations Safety/abuse Distinguishing from recreational use Blinding/expectancy/naiveté Limited well controlled RCTs Replication Highly selected samples Lack of diverse samples Subjective vs pharmacological properties Funding Implementation & scale Randy.Brown@fammed.wisc.edu 17