psilocybin and safety in clinical trials. anderson... · psilocybin and safety in clinical trials...

Psilocybin and Safety in Clinical Trials

Brian T. Anderson, MD, MSc

Staff PsychiatristUCSF/ZSFG

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

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)

Preparation VisitsEstablish trust

Psychoeducation

Forming intentions while setting aside expectations

Set, setting and support system


Medication VisitsMinimal interaction

Supportive, non-directive

Encouraged to direct attention inward

“Trust, let go, be open”

Music sets emotional tone


Integration VisitsDebriefing on the experience

Exploration and interpretation

Behavior change in the “afterglow”

Grounding in the day-to-day


• Exclusion criteria

Common exclusion criteriaPsychotic disorder (+family history)Bipolar disorder (+family history)

Acute suicidalityCardiac disease

Uncontrolled hypertensionPregnancy / breastfeeding

Seizure disorderCNS disease

Regular use of psychiatric medications

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)


Study

N

Profile



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)


10

AUD

0.4mg/kg


36

Age(mean): 46

Naive

0.43mg/kg

(30mg/70kg)


12

TRD

Age(med):39

25mg


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


0.6mg/kg

59mg


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

Studerus 2011 J Psychopharm

Studerus 2011 J Psychopharm

Psilocybin-related adverse events





Leary et al, 1963


9 TR-OCD

Age(mean):41

≥1 prior use

0.3mg/kg

Leary et al, 1965


12 Cancer, Anxiety

Age:36-58

0.2mg/kg

Pahnke et al, 1963

20 Seminarians


15 TUD 0.43mg/kg

Pahnke et al, 1965

40 Seminarians

Age: 21-55

Naive

40mg po (30mg im)


10 AUD 0.4mg/kg


36 Age(mean): 46

Naive

0.43mg/kg (30mg/70kg)


12 TRD

Age(med):39

25mg




29 Cancer, Anxiety

Age(mean):56.3

0.3mg/kg

Brown et al, 2017

12 Age(mean): 43




Age(mean):56.3

0.314mg/kg (22mg/70kg)


Age ≥50 years

0.36mg/kg 32mg


Healthy volunteers


Study

N

Profile



Study

N

Profile



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)


10

AUD

0.4mg/kg


36

Age(mean): 46

Naive

0.43mg/kg

(30mg/70kg)


12

TRD

Age(med):39

25mg


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


0.6mg/kg

59mg


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


Grob, et al. 2011. Arch Gen Psych

Anxiety & CancerDBRCT

Cross-overN=12

Psilocybin therapy efficacy?

Grob, et al. 2011. Arch Gen Psych





Leary et al, 1963


9 TR-OCD

Age(mean):41

≥1 prior use

0.3mg/kg

Leary et al, 1965


12 Cancer, Anxiety

Age:36-58

0.2mg/kg

Pahnke et al, 1963

20 Seminarians


15 TUD 0.43mg/kg

Pahnke et al, 1965

40 Seminarians

Age: 21-55

Naive

40mg po (30mg im)


10 AUD 0.4mg/kg


36 Age(mean): 46

Naive

0.43mg/kg (30mg/70kg)


12 TRD

Age(med):39

25mg




29 Cancer, Anxiety

Age(mean):56.3

0.3mg/kg

Brown et al, 2017

12 Age(mean): 43




Age(mean):56.3

0.314mg/kg (22mg/70kg)


Age ≥50 years

0.36mg/kg 32mg


Healthy volunteers


Study

N

Profile



Study

N

Profile



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)


10

AUD

0.4mg/kg


36

Age(mean): 46

Naive

0.43mg/kg

(30mg/70kg)


12

TRD

Age(med):39

25mg


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


0.6mg/kg

59mg


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


Treatment-Resistant DepressionOpen-label

N=12


Carhart-Harris, et al. 2016 Lancet Psychiatry

Carhart-Harris, et al.2016.Lancet Psychiatry


Carhart-Harris, et al. 2016 Lancet Psychiatry





Leary et al, 1963


9 TR-OCD

Age(mean):41

≥1 prior use

0.3mg/kg

Leary et al, 1965


12 Cancer, Anxiety

Age:36-58

0.2mg/kg

Pahnke et al, 1963

20 Seminarians


15 TUD 0.43mg/kg

Pahnke et al, 1965

40 Seminarians

Age: 21-55

Naive

40mg po (30mg im)


10 AUD 0.4mg/kg


36 Age(mean): 46

Naive

0.43mg/kg (30mg/70kg)


12 TRD

Age(med):39

25mg




29 Cancer, Anxiety

Age(mean):56.3

0.3mg/kg

Brown et al, 2017

12 Age(mean): 43




Age(mean):56.3

0.314mg/kg (22mg/70kg)


Age ≥50 years

0.36mg/kg 32mg


Healthy volunteers


Study

N

Profile



Study

N

Profile



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)


10

AUD

0.4mg/kg


36

Age(mean): 46

Naive

0.43mg/kg

(30mg/70kg)


12

TRD

Age(med):39

25mg


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


0.6mg/kg

59mg


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


Griffiths, et al. 2016. J Psychopharm

Anxietyor Depression & Cancer

DBRCTCross-over

N=51Cohen’s d=0.8 (5-weeks)


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

Psilocybin-assisted Group Therapy for Demoralization in Long-term AIDS Survivors

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.

0.30mg/kg

0.36mg/kg

Psilocybin therapy - Risk mitigation

StandardDose

Informed consent

Psychoeducation

Exclusion criteria

Risk assessments (C-SSRS)

PsychotherapyContact hoursApproach

Music


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


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?

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

[email protected]

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]

psilocybin and safety in clinical trials. anderson... · psilocybin and safety in clinical trials...

Documents