Therapeutic potential of psychedelics in substance use disorders
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WISAM 2018 Conference Sept. 27‐28, 2018
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
1WISAM 2018 Conference Sept. 27‐28, 2018
Acknowledgements
Funding Support Collaborators
Outline
Psilocybin and MDMA
• Background
• Safety and Abuse potential
• Dosing and Administration
Protocol
• Relevant studies
• Possible Mechanisms
• Considerations
2WISAM 2018 Conference Sept. 27‐28, 2018
Psilocybin
Background
• Psychedelic: “Mind‐manifesting capability, revealing” or
having “useful or beneficial properties of the mind”
(Osmond, 1957)
• Classics:
Psychedelic: “mind‐manifesting capability,
Psilocybin, Mescaline, DMT,revealing”
LSD or having
“useful or beneficial
• Psilocybin properties
(psilocin) of the
is a 5‐HT2a, mind” (Osmond,
1a receptor 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
3WISAM 2018 Conference Sept. 27‐28, 2018
Some Past and Current Modern
Psilocybin Studies
• Zurich (2000‐): Neuroimaging
• Hopkins (2006‐2011): 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)
4WISAM 2018 Conference Sept. 27‐28, 2018
Population Data
• Lower mental illness rates1
• Reduced odds of past‐month psychologic
distress, past year suicidal thinking, past‐year
suicidal planning, or past‐year suicide attempt2
• Decreased rate of supervision failure in inmates3
1Krebs et al. (2013). PLoS One; NSDUH; 2Hendricks et al. (2015). JoPsychopharm; NSDUH;
3Hendricks et al. (2014). J Ppsychopharm
Dosing
• Typical: 0.28‐0.43 mg/kg
• UW Study: 0.3‐0.6 mg/kg
(18.8‐59.2 mg)
• Oral onset: ~30‐60 min
• Peak effects: ~2 hours
• 1‐5 doses /4‐6 weeks
• Total duration: 4‐8 hours
5WISAM 2018 Conference Sept. 27‐28, 2018
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 Setting: environment & context
• Pre‐dose preparation • Interpersonal support
• Careful screening • Safe & secure room
• Expectations/concerns • Room with comfortable &
• Integration positive décor
• Personal objects if possible
6WISAM 2018 Conference Sept. 27‐28, 2018
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 Experience1
• Mystical (Unity, Noetic, Sacred)
• Transcendence of time and space Challenging Experiences3
• Deeply felt positive mood • Fear
• Ineffability • Grief
• Isolation
• Experience of dying
• Insanity
Ego Dissolution2 • Physio distress
• Dissolution of my self or ego • Paranoia
• 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
1Maclean et al (2012). J for the Scientific Study of Religion; 2Nour (2016). Frontiers in Human Neuroscience;
3Barrett (2017). Human Psychopharm Clin & Exp.
7WISAM 2018 Conference Sept. 27‐28, 2018
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
• Greater communication
between various major brain
hub networks
• Decreased communication
within hubs.
•Psilocin similar in structure to serotonin
•5‐HT2a receptors*
•‐Pretreatment with ketanserin
• Default mode network which
together represents self‐related
functioning
• Self‐referential processing, self‐
awareness, metacognition
• Decreased activity correlates
with degree of ego dissolution
Carhart‐Harris et al. (2014). Frontiers in Human Neuroscience
8WISAM 2018 Conference Sept. 27‐28, 2018
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 0.3 – 0.4 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).
9WISAM 2018 Conference Sept. 27‐28, 2018
Psilocybin for Tobacco Cessation
Johnson et al. (2014) J Psychopharmacol, 983‐92.
Johnson et al. (2017) J Am J Drug Alcohol Abuse, 55‐65
• 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, 55‐65
Linear regression of Mystical Experience
and long‐term change in cotinine
10WISAM 2018 Conference Sept. 27‐28, 2018
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
Secondary Changes in Mystical experience, ego‐dissolution, insight,
Direct effects
effects e.g. CBF, BOLD, experience of awe, unconstrained thought,
on 5‐HT
glutamate Connectivity, autobiographical content, exposure to challenging
receptors
receptors MEG representations, positive affect
Integration through counseling + meditation, social support, art, music, nature, etc.
Persisting Effects
Positive mood, Changes in beliefs &
Long‐term neuroplastic decreased anxiety, Changes in personality values
openness, prosocial gratitude, mindfulness,
and functional changes fear, rumination, motivation spirituality, relationships,
craving, distress nature
Adapted from Bogenshutz & Pommy. (2012). Drug Testing & Analysis
11WISAM 2018 Conference Sept. 27‐28, 2018
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
12WISAM 2018 Conference Sept. 27‐28, 2018
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 trial1
• No misuse/dependence in PTSD trial patients1
• Limited evidence of structural or functional brain alterations in
moderate MDMA users2
• Post MDMA may lead to short‐term neurochemical depletion,
feelings of anhedonia, lethargy, anger, insomnia, decreased
appetite, and depression in recreational users3
1Mithoefer et al. (2013). J of Psychopharm; 2Mueller et al. (2013). Neurosci & BioBehav Rev.; 3Parrot (2014). J of Psychoactive Drugs
13WISAM 2018 Conference Sept. 27‐28, 2018
Neurobiology
MDMA Effects Effects relate to PTSD Neurobiological Correlate
symptoms
Decrease Positive mood and less avoidance Release of pre‐synaptic 5‐HT1A/1B
Anxiety/Depression of therapy and emotions receptors
Alter perception of
See old problems in a new light Increased activity at 5‐HT2A receptors
meaning
Increase levels of Increase motivation to engage;
Release of dopamine and noradrenaline
arousal cognitive process; recount trauma
Increased alpha 2‐adrenoreceptor
Increase relaxation Reduces hypervigilance
activity
Improve fear Reflect on traumatic memory
Release noradrenaline and cortisol
extinction learning without being overwhelmed
Increase emotional
Therapeutic alliance and openness
attachment, trust, Multiple factors including oxytocin
to reflect on painful memories
empathy
Reduce subjective
Reflect on painful memories with Decreased cerebral blood flow in
fear response on
optimal arousal amygdala & hippocampus
recall
Sessa (2017). Neuroscience Letters
MDMA Protocol
• Dose: 80‐120 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
14WISAM 2018 Conference Sept. 27‐28, 2018
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 (100‐125 mg)
15WISAM 2018 Conference Sept. 27‐28, 2018
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 = 2.8
• 125 mg: –44∙3 [28.7] d = 1.1
• 30 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
16WISAM 2018 Conference Sept. 27‐28, 2018
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 • New York, NY | private
• San Francisco, CA | academic • Charleston, SC | private
• San Francisco, CA | private • Madison, WI | academic
• Boulder, CO | private • Boston, MA | private practice
• Fort Collins, CO | private • Montreal, Canada | private
• Farmington, CT | academic • Vancouver, Canada | academic
• New Orleans, LA | private • Israel | private
• New York, NY | academic
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
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