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Psilocybin and Safety in Clinical Trials
Brian T. Anderson, MD, MSc
Staff PsychiatristUCSF/ZSFG
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DISCLOSURES
I declare no financial conflicts of interest
Psilocybin is a Schedule I drug with no FDA-approved medical indication
The use of generic, oral crystalline psilocybin in the treatment of mood, anxiety, and trauma-related disorders has been in the public
domain for decades
In the past 4 years my research has been supported by: Carey Turnbull; Heffter Research Institute; NIMH R25 MH060482; River Styx Foundation; SaiseiFoundation; Sarlo Foundation; SFVA Advanced Neuroscience Fellowship; Stupski Foundation;
UCSF AIDS Research Institute; Usona Institute
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Psilocybin Therapy (a.k.a. Psychedelic-assisted Psychotherapy)
(No Rx) Preparation visits (~6-8hr total)
(Rx) Medication visit (~8-12hr)
(No Rx) Integration visits (~4-8hr total)
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Preparation VisitsEstablish trust
Psychoeducation
Forming intentions while setting aside expectations
Set, setting and support system
Psilocybin Therapy (a.k.a. Psychedelic-assisted Psychotherapy)
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Medication VisitsMinimal interaction
Supportive, non-directive
Encouraged to direct attention inward
“Trust, let go, be open”
Music sets emotional tone
Psilocybin Therapy (a.k.a. Psychedelic-assisted Psychotherapy)
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Integration VisitsDebriefing on the experience
Exploration and interpretation
Behavior change in the “afterglow”
Grounding in the day-to-day
Psilocybin Therapy (a.k.a. Psychedelic-assisted Psychotherapy)
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• Exclusion criteria
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Common exclusion criteriaPsychotic disorder (+family history)Bipolar disorder (+family history)
Acute suicidalityCardiac disease
Uncontrolled hypertensionPregnancy / breastfeeding
Seizure disorderCNS disease
Regular use of psychiatric medications
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Healthy volunteers Clinical populations Study N Profile Max. dose
(wt-based) Max. dose (absolute)
Study N Profile Max. dose (wt-based)
Max. dose (absolute)
Leary et al, 1963
175 Age(med): 29.5 100mg/24hr Moreno et al, 2006
9 TR-OCD
Age(mean):41
≥1 prior use
0.3mg/kg
Leary et al, 1965
32 Prisoners 70mg Grob et al, 2011
12 Cancer, Anxiety
Age:36-58
0.2mg/kg
Pahnke et al, 1963
20 Seminarians
30mg Johnson et al, 2014
15 TUD 0.43mg/kg
Pahnke et al, 1965
40 Seminarians
Age: 21-55
Naive
40mg po (30mg im)
Bogenschutz et al, 2015
10 AUD 0.4mg/kg
Griffiths et al, 2006
36 Age(mean): 46
Naive
0.43mg/kg (30mg/70kg)
Carhart-Harris et al, 2016
12 TRD
Age(med):39
25mg
Studerus et al, 2011
110 0.315mg/kg (n=41 at this dose)
28mg Ross et al, 2016
29 Cancer, Anxiety
Age(mean):56.3
0.3mg/kg
Brown et al, 2017
12 Age(mean): 43
≥1 “substantial” experience
0.6mg/kg 59mg Griffiths et al, 2016
51 Cancer, Anxiety, Depression
Age(mean):56.3
0.314mg/kg (22mg/70kg)
[UCSF] 18 LTAS, Demoralization
Age ≥50 years
0.36mg/kg 32mg
[NYU] 100 AUD 0.57mg/kg AUD=Alcohol use disorder; LTAS=Long-term AIDS Survivor; TRD=Treatment-resistant depression; TR-OCD=Treatment-resistant Obsessive Compulsive Disorder; TUD=Tobacco use disorder
Healthy volunteers
Clinical populations
Study
N
Profile
Max. dose (wt-based)
Max. dose (absolute)
Study
N
Profile
Max. dose (wt-based)
Max. dose (absolute)
Leary et al, 1963
175
Age(med): 29.5
100mg/24hr
Moreno et al, 2006
9
TR-OCD
Age(mean):41
≥1 prior use
0.3mg/kg
Leary et al, 1965
32
Prisoners
70mg
Grob et al, 2011
12
Cancer, Anxiety
Age:36-58
0.2mg/kg
Pahnke et al, 1963
20
Seminarians
30mg
Johnson et al, 2014
15
TUD
0.43mg/kg
Pahnke et al, 1965
40
Seminarians
Age: 21-55
Naive
40mg po
(30mg im)
Bogenschutz et al, 2015
10
AUD
0.4mg/kg
Griffiths et al, 2006
36
Age(mean): 46
Naive
0.43mg/kg
(30mg/70kg)
Carhart-Harris et al, 2016
12
TRD
Age(med):39
25mg
Studerus et al, 2011
110
0.315mg/kg
(n=41 at this dose)
28mg
Ross et al, 2016
29
Cancer,
Anxiety
Age(mean):56.3
0.3mg/kg
Brown et al, 2017
12
Age(mean): 43
≥1 “substantial” experience
0.6mg/kg
59mg
Griffiths et al, 2016
51
Cancer, Anxiety,
Depression
Age(mean):56.3
0.314mg/kg
(22mg/70kg)
[UCSF]
18
LTAS,
Demoralization
Age ≥50 years
0.36mg/kg
32mg
[NYU]
100
AUD
0.57mg/kg
AUD=Alcohol use disorder; LTAS=Long-term AIDS Survivor; TRD=Treatment-resistant depression; TR-OCD=Treatment-resistant Obsessive Compulsive Disorder; TUD=Tobacco use disorder
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Studerus 2011 J Psychopharm
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Studerus 2011 J Psychopharm
Psilocybin-related adverse events
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Healthy volunteers Clinical populations Study N Profile Max. dose
(wt-based) Max. dose (absolute)
Study N Profile Max. dose (wt-based)
Max. dose (absolute)
Leary et al, 1963
175 Age(med): 29.5 100mg/24hr Moreno et al, 2006
9 TR-OCD
Age(mean):41
≥1 prior use
0.3mg/kg
Leary et al, 1965
32 Prisoners 70mg Grob et al, 2011
12 Cancer, Anxiety
Age:36-58
0.2mg/kg
Pahnke et al, 1963
20 Seminarians
30mg Johnson et al, 2014
15 TUD 0.43mg/kg
Pahnke et al, 1965
40 Seminarians
Age: 21-55
Naive
40mg po (30mg im)
Bogenschutz et al, 2015
10 AUD 0.4mg/kg
Griffiths et al, 2006
36 Age(mean): 46
Naive
0.43mg/kg (30mg/70kg)
Carhart-Harris et al, 2016
12 TRD
Age(med):39
25mg
Studerus et al, 2011
110 0.315mg/kg (n=41 at this dose)
28mg Ross et al, 2016
29 Cancer, Anxiety
Age(mean):56.3
0.3mg/kg
Brown et al, 2017
12 Age(mean): 43
≥1 “substantial” experience
0.6mg/kg 59mg Griffiths et al, 2016
51 Cancer, Anxiety, Depression
Age(mean):56.3
0.314mg/kg (22mg/70kg)
[UCSF] 18 LTAS, Demoralization
Age ≥50 years
0.36mg/kg 32mg
[NYU] 100 AUD 0.57mg/kg AUD=Alcohol use disorder; LTAS=Long-term AIDS Survivor; TRD=Treatment-resistant depression; TR-OCD=Treatment-resistant Obsessive Compulsive Disorder; TUD=Tobacco use disorder
Healthy volunteers
Clinical populations
Study
N
Profile
Max. dose (wt-based)
Max. dose (absolute)
Study
N
Profile
Max. dose (wt-based)
Max. dose (absolute)
Leary et al, 1963
175
Age(med): 29.5
100mg/24hr
Moreno et al, 2006
9
TR-OCD
Age(mean):41
≥1 prior use
0.3mg/kg
Leary et al, 1965
32
Prisoners
70mg
Grob et al, 2011
12
Cancer, Anxiety
Age:36-58
0.2mg/kg
Pahnke et al, 1963
20
Seminarians
30mg
Johnson et al, 2014
15
TUD
0.43mg/kg
Pahnke et al, 1965
40
Seminarians
Age: 21-55
Naive
40mg po
(30mg im)
Bogenschutz et al, 2015
10
AUD
0.4mg/kg
Griffiths et al, 2006
36
Age(mean): 46
Naive
0.43mg/kg
(30mg/70kg)
Carhart-Harris et al, 2016
12
TRD
Age(med):39
25mg
Studerus et al, 2011
110
0.315mg/kg
(n=41 at this dose)
28mg
Ross et al, 2016
29
Cancer,
Anxiety
Age(mean):56.3
0.3mg/kg
Brown et al, 2017
12
Age(mean): 43
≥1 “substantial” experience
0.6mg/kg
59mg
Griffiths et al, 2016
51
Cancer, Anxiety,
Depression
Age(mean):56.3
0.314mg/kg
(22mg/70kg)
[UCSF]
18
LTAS,
Demoralization
Age ≥50 years
0.36mg/kg
32mg
[NYU]
100
AUD
0.57mg/kg
AUD=Alcohol use disorder; LTAS=Long-term AIDS Survivor; TRD=Treatment-resistant depression; TR-OCD=Treatment-resistant Obsessive Compulsive Disorder; TUD=Tobacco use disorder
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Grob, et al. 2011. Arch Gen Psych
Anxiety & CancerDBRCT
Cross-overN=12
Psilocybin therapy efficacy?
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Grob, et al. 2011. Arch Gen Psych
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Healthy volunteers Clinical populations Study N Profile Max. dose
(wt-based) Max. dose (absolute)
Study N Profile Max. dose (wt-based)
Max. dose (absolute)
Leary et al, 1963
175 Age(med): 29.5 100mg/24hr Moreno et al, 2006
9 TR-OCD
Age(mean):41
≥1 prior use
0.3mg/kg
Leary et al, 1965
32 Prisoners 70mg Grob et al, 2011
12 Cancer, Anxiety
Age:36-58
0.2mg/kg
Pahnke et al, 1963
20 Seminarians
30mg Johnson et al, 2014
15 TUD 0.43mg/kg
Pahnke et al, 1965
40 Seminarians
Age: 21-55
Naive
40mg po (30mg im)
Bogenschutz et al, 2015
10 AUD 0.4mg/kg
Griffiths et al, 2006
36 Age(mean): 46
Naive
0.43mg/kg (30mg/70kg)
Carhart-Harris et al, 2016
12 TRD
Age(med):39
25mg
Studerus et al, 2011
110 0.315mg/kg (n=41 at this dose)
28mg Ross et al, 2016
29 Cancer, Anxiety
Age(mean):56.3
0.3mg/kg
Brown et al, 2017
12 Age(mean): 43
≥1 “substantial” experience
0.6mg/kg 59mg Griffiths et al, 2016
51 Cancer, Anxiety, Depression
Age(mean):56.3
0.314mg/kg (22mg/70kg)
[UCSF] 18 LTAS, Demoralization
Age ≥50 years
0.36mg/kg 32mg
[NYU] 100 AUD 0.57mg/kg AUD=Alcohol use disorder; LTAS=Long-term AIDS Survivor; TRD=Treatment-resistant depression; TR-OCD=Treatment-resistant Obsessive Compulsive Disorder; TUD=Tobacco use disorder
Healthy volunteers
Clinical populations
Study
N
Profile
Max. dose (wt-based)
Max. dose (absolute)
Study
N
Profile
Max. dose (wt-based)
Max. dose (absolute)
Leary et al, 1963
175
Age(med): 29.5
100mg/24hr
Moreno et al, 2006
9
TR-OCD
Age(mean):41
≥1 prior use
0.3mg/kg
Leary et al, 1965
32
Prisoners
70mg
Grob et al, 2011
12
Cancer, Anxiety
Age:36-58
0.2mg/kg
Pahnke et al, 1963
20
Seminarians
30mg
Johnson et al, 2014
15
TUD
0.43mg/kg
Pahnke et al, 1965
40
Seminarians
Age: 21-55
Naive
40mg po
(30mg im)
Bogenschutz et al, 2015
10
AUD
0.4mg/kg
Griffiths et al, 2006
36
Age(mean): 46
Naive
0.43mg/kg
(30mg/70kg)
Carhart-Harris et al, 2016
12
TRD
Age(med):39
25mg
Studerus et al, 2011
110
0.315mg/kg
(n=41 at this dose)
28mg
Ross et al, 2016
29
Cancer,
Anxiety
Age(mean):56.3
0.3mg/kg
Brown et al, 2017
12
Age(mean): 43
≥1 “substantial” experience
0.6mg/kg
59mg
Griffiths et al, 2016
51
Cancer, Anxiety,
Depression
Age(mean):56.3
0.314mg/kg
(22mg/70kg)
[UCSF]
18
LTAS,
Demoralization
Age ≥50 years
0.36mg/kg
32mg
[NYU]
100
AUD
0.57mg/kg
AUD=Alcohol use disorder; LTAS=Long-term AIDS Survivor; TRD=Treatment-resistant depression; TR-OCD=Treatment-resistant Obsessive Compulsive Disorder; TUD=Tobacco use disorder
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Treatment-Resistant DepressionOpen-label
N=12
Psilocybin therapy efficacy?
Carhart-Harris, et al. 2016 Lancet Psychiatry
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Carhart-Harris, et al.2016.Lancet Psychiatry
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Psilocybin therapy efficacy?
Carhart-Harris, et al. 2016 Lancet Psychiatry
-
Healthy volunteers Clinical populations Study N Profile Max. dose
(wt-based) Max. dose (absolute)
Study N Profile Max. dose (wt-based)
Max. dose (absolute)
Leary et al, 1963
175 Age(med): 29.5 100mg/24hr Moreno et al, 2006
9 TR-OCD
Age(mean):41
≥1 prior use
0.3mg/kg
Leary et al, 1965
32 Prisoners 70mg Grob et al, 2011
12 Cancer, Anxiety
Age:36-58
0.2mg/kg
Pahnke et al, 1963
20 Seminarians
30mg Johnson et al, 2014
15 TUD 0.43mg/kg
Pahnke et al, 1965
40 Seminarians
Age: 21-55
Naive
40mg po (30mg im)
Bogenschutz et al, 2015
10 AUD 0.4mg/kg
Griffiths et al, 2006
36 Age(mean): 46
Naive
0.43mg/kg (30mg/70kg)
Carhart-Harris et al, 2016
12 TRD
Age(med):39
25mg
Studerus et al, 2011
110 0.315mg/kg (n=41 at this dose)
28mg Ross et al, 2016
29 Cancer, Anxiety
Age(mean):56.3
0.3mg/kg
Brown et al, 2017
12 Age(mean): 43
≥1 “substantial” experience
0.6mg/kg 59mg Griffiths et al, 2016
51 Cancer, Anxiety, Depression
Age(mean):56.3
0.314mg/kg (22mg/70kg)
[UCSF] 18 LTAS, Demoralization
Age ≥50 years
0.36mg/kg 32mg
[NYU] 100 AUD 0.57mg/kg AUD=Alcohol use disorder; LTAS=Long-term AIDS Survivor; TRD=Treatment-resistant depression; TR-OCD=Treatment-resistant Obsessive Compulsive Disorder; TUD=Tobacco use disorder
Healthy volunteers
Clinical populations
Study
N
Profile
Max. dose (wt-based)
Max. dose (absolute)
Study
N
Profile
Max. dose (wt-based)
Max. dose (absolute)
Leary et al, 1963
175
Age(med): 29.5
100mg/24hr
Moreno et al, 2006
9
TR-OCD
Age(mean):41
≥1 prior use
0.3mg/kg
Leary et al, 1965
32
Prisoners
70mg
Grob et al, 2011
12
Cancer, Anxiety
Age:36-58
0.2mg/kg
Pahnke et al, 1963
20
Seminarians
30mg
Johnson et al, 2014
15
TUD
0.43mg/kg
Pahnke et al, 1965
40
Seminarians
Age: 21-55
Naive
40mg po
(30mg im)
Bogenschutz et al, 2015
10
AUD
0.4mg/kg
Griffiths et al, 2006
36
Age(mean): 46
Naive
0.43mg/kg
(30mg/70kg)
Carhart-Harris et al, 2016
12
TRD
Age(med):39
25mg
Studerus et al, 2011
110
0.315mg/kg
(n=41 at this dose)
28mg
Ross et al, 2016
29
Cancer,
Anxiety
Age(mean):56.3
0.3mg/kg
Brown et al, 2017
12
Age(mean): 43
≥1 “substantial” experience
0.6mg/kg
59mg
Griffiths et al, 2016
51
Cancer, Anxiety,
Depression
Age(mean):56.3
0.314mg/kg
(22mg/70kg)
[UCSF]
18
LTAS,
Demoralization
Age ≥50 years
0.36mg/kg
32mg
[NYU]
100
AUD
0.57mg/kg
AUD=Alcohol use disorder; LTAS=Long-term AIDS Survivor; TRD=Treatment-resistant depression; TR-OCD=Treatment-resistant Obsessive Compulsive Disorder; TUD=Tobacco use disorder
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Griffiths, et al. 2016. J Psychopharm
Anxietyor Depression & Cancer
DBRCTCross-over
N=51Cohen’s d=0.8 (5-weeks)
Psilocybin therapy efficacy?
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Adverse Event During Psilocybin Session Low Dose (N = 52) High Dose (N = 53)
Elevated Systolic Blood Pressure (> 160) 9 (17%) 18 (34%)
Elevated Diastolic Blood Pressure (> 100) 1 (2%) 7 (13%)
Psychological Discomfort 6 (12%) 17 (32%)
Anxiety 8 (15%) 14 (20%)
Physical Discomfort 4 (8%) 11(21%)
Nausea/Vomiting 0 8 (15%)
Elevated Heart Rate (> 110) 1 (2%) 3 (6%)
Mild Headache 0 1 (2%)
Paranoia 0 1 (2%)
Griffiths et al. 2016 J.Psychopharm
Psilocybin-related adverse events
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Psilocybin-assisted Group Therapy for Demoralization in Long-term AIDS Survivors
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DemoralizationA syndrome characterized by poor
coping and a sense of hopelessness, helplessness, and a loss of meaning and
purpose in life.
Older Long-term AIDS Survivors
Diagnosis of HIV prior to ARVs
Model of chronic existential distress
“Older” ≥50 y.o.
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0.30mg/kg
0.36mg/kg
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Psilocybin therapy - Risk mitigation
StandardDose
Informed consent
Psychoeducation
Exclusion criteria
Risk assessments (C-SSRS)
PsychotherapyContact hoursApproach
Music
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Psilocybin therapy - Risk mitigation
UCSFPeer support
Group therapyShared member phone numbersLetter to another participant
Touchstone object for medication visit
Clinical experience with the population
Phone number of study MD
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Psilocybin therapy - Risk mitigation
Future Suggestions
Registry / data-sharing
Embed trials in existing clinical infrastructures
Escalating, two-dose treatment protocols[Psychedelic-naïve; Complex trauma; Frail ego structure]
Apprenticeship / supervision
Personal experience?
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Conclusions
Drug, set and setting
Functional unblinding and large effect sizes
Zero psilocybin-related serious adverse events (so far)
Many expected adverse reactions
Many means of preventing harms
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Medical
DSM: Erick Hung
Josh Biddle
Sanjay Reddy
Leah Rorvig
Sylver Quevedo
Kelan Thomas
MentorJosh Woolley
MentorJenny Mitchell
Co-IChris Stauffer
Co-IJim Dilley
Alicia Danforth Rob Daroff
Clinical
Alex Trope
Bob Grant
Celina De Leon
Debbie McDivitt
Emily Williams
Eve Ekman
Gabby Agin-Liebes
Jae Sevelius
Joe Zamaria
Julie Feuer
Pegi Walker
Staff & Volunteers
Andrew Hooker
Catriona Miller
Christine Milentis
Eric Miller
Hannah Tierney
Laura Radocchia
Lisa Lin
Paul Abramson
Phillip Perl
Ryan McPhee
Psilocybin and Safety in Clinical TrialsSlide Number 2Psilocybin Therapy (a.k.a. Psychedelic-assisted Psychotherapy)Slide Number 4Psilocybin Therapy (a.k.a. Psychedelic-assisted Psychotherapy)Psilocybin Therapy (a.k.a. Psychedelic-assisted Psychotherapy)Slide Number 7Slide Number 8Slide Number 9Slide Number 10Slide Number 11Slide Number 12Slide Number 13Slide Number 14Slide Number 15Slide Number 16Slide Number 17Slide Number 18Slide Number 19Slide Number 20Slide Number 21Slide Number 22Slide Number 23Slide Number 24Slide Number 25Slide Number 26Psilocybin therapy - Risk mitigationPsilocybin therapy - Risk mitigationPsilocybin therapy - Risk mitigationConclusionsSlide Number [email protected]