the history, science and future regulation of psychedelic

The History, Science and Future Regulation of Psychedelic-Assisted Psychotherapy and Psychedelic-Supplemented Meditation

Rick Doblin, PhD - Executive Director and Founder

Multidisciplinary Association for Psychedelic Studies (MAPS, maps.org)

April 30, 2021

Meditation and Psychotherapy: Learning from Non-Ordinary States

Mr. Natural by R. Crumb

We need more psychology. We

need more understanding of

human nature. Because the only

real danger that exists is man

himself. He is the great danger and

we are pitifully unaware of it. We

know nothing of man. Far too

little. His psyche should be studied

because we are the origin of all

coming evil.

– Carl Jung

Psychedelics are

to the study of

the mind what

the microscope is

to biology and

the telescope is

to astronomy.

- Dr. Stanislav Grof

American Society for Clinical Psychopharmacology

May 30, 2019

Scottsdale, Arizona

Web of Science Psychedelic Publication Count by Year

Royalties Back to MAPS

Since its founding in 1986, MAPS has raised over $100 million

in donations for psychedelic therapy and medical marijuana

research and education.

MDMA Pharmacology

Increases release of: • serotonin (5-HT)

• norepinephrine (NE)

• dopamine (DA)

Enhances release of hormones: • oxytocin

• prolactin

• vasopressin

• cortisol

methylenedioxymethamphetamine(MDMA)

Difficulty in reducing and eliminating fear conditioning responses

Rauch SL et al. Biol Psychiatry. 2006;60(4):376-382

Prefrontal Cortex

Amygdala

Hippocampus

Model of Neurological Effects of PTSD

Increased therapeutic alliance and ability to process traumatic content

Rauch SL et al. Biol Psychiatry. 2006;60(4):376-382

Prefrontal Cortex

Amygdala

Hippocampus

Model of Neurological Effects of MDMA

Reduces fear response to painful emotions

Facilitates long-term storage of traumatic memories

Increases cognitive processing of fear response

SLC6A4 binding site and acute prosocial effects of (+/-)-3,4-methylendioxymethamphetamine (MDMA) are evolutionarily conserved in Octopus bimaculoides.

Eric Edsinger and Gul DolenCurrent Biology (2018)

1912

MDMA first synthesized and patented by the pharmaceutical company Merck as “Methylsafrylamin.”

It was an unimportant precursor in a new synthesis for clotting agents.

First pre-clinical pharmacological tests with MDMA by Merck, nothing interesting found.

1927

1953-1954

The United States Army used animal models to investigate the toxicity and behavioral effects of MDMA and seven other related compounds, but the results remained classified until 1973.

Merck conducts further animal studies, nothing interesting found.

1959

An American chemist, Alexander “Sasha” Shulgin resynthesized MDMA and experimented with the drug himself.

Mid-1970s

Alexander “Sasha” Shulgin

MDMA used in psychotherapy with good results. Estimated 500,000 doses of MDMA used in therapeutic growth settings from mid-1970s until 1984.

Recreational use of Ecstasy began in late 1970s.

Leo Zeff

Mid-1970s San Francisco: Start of MDMA-Assisted Psychotherapy

By the early 1980s, "ecstasy" (MDMA + other psychoactive substances) became a popular drug often at dance clubs and raves in the US and Europe.

1980-1984

Advocates of therapeutic use file for DEA Administrative Law Judge (ALJ) hearing within 30-day public comment period.

1984: Due to Ecstasy Use, DEA Moves to Criminalize MDMA in Schedule 1

“A monk spends his whole life cultivating the same awakened attitude it [MDMA]

gives you.”

April 15, 1985Newsweek

Brother David Steindl-Rast

“You call the Sabbath a delight. It [MDMA] is like the Sabbath at the end of a long week.”

June 1, 1985

Washington Post

Rabbi Zalman Schachter-Shalomi

The Drug Enforcement Administration (DEA) classified MDMA as a Schedule 1 controlled substance using emergency scheduling authority, later declared invalid.

1985

1986

The Multidisciplinary Association for Psychedelic Studies (MAPS) is founded April 8, 1986.1986

Reverend S.J., Good Friday Experiment study subject

“We took such an infinitesimal amount of psilocybin, and yet it connected me to infinity.”

FDA rejects five different Phase 1 or Phase 2 protocols for MDMA clinical trials.

1986-1992

FDA approves first Phase 1 dose response safety study for MDMA in humans.

Dr. Charles Grob

1992

Sponsored by MAPS, the first randomized, placebo-controlled, double-blind study investigating MDMA-assisted therapy, conducted in women with treatment-resistant PTSD, commenced in 2000 in Spain but ended due to political pressures after only 6 women were treated.

2000

Seven IRBs reject or refuse to review MAPS’ first FDA-approved MDMA/PTSD protocol.

2000-2004

Out of desperation, MAPS called Copernicus Group IRB based on their name.

Copernicus Group IRB approves the first MAPS-sponsored MDMA/PTSD protocol.

2004

Inner Directed Therapy-Therapeutic Approach

• Supporting emerging experience

• Inner healing intelligence

• Reclining, headphones with music, eyeshades

• Alternating inner focus & talking to therapists

• Allows for therapists’ individual variation

• Importance of preparation & integration

• maps.org/treatmentmanual

Photo by Nirvan Mullick, PrescriptionX – The Rick Doblin Story

MAPS completes international series of six Phase 2 pilot studies of MDMA-assisted psychotherapy for PTSD.

Nov 29, 2016 Successful End of Phase 2 Meeting with FDA.

2016

MAPS Sponsored Phase 2 Clinical Trials: MDMA-Assisted Psychotherapy for Chronic, Treatment-Resistant PTSD

Study Sample (N) Dose Comparison

Location Code Intent to Treat Active Comparator

Charleston, SC MP-1 N=23 125 mg 0 mg

Switzerland MP-2 N=14 125 mg 25 mg

Vancouver, BC MP-4 N=6 125 mg 0 mg

Charleston, SC MP-8 N=26 75 or 125 mg 30 mg

Tel Aviv, Israel MP-9 N=8 125 mg 25 mg

Boulder, CO MP-12 N=26 100 or 125 mg 40 mg

All StudiesIntent to Treat

N=105Active (75-125 mg) vs. Comparator (0-40 mg)

Range of Initial Doses Explored in Phase 2 Studies

Placebo 25 mg 30 mg 40 mg 75 mg 100 mg 125 mg 150 mg

Init

ial D

ose

of

MD

MA

(m

g)

most effectivedosage range

Neuropsychological Measures in Phase 2 Pilot Study

• Repeatable Battery for Assessment of Neuropsychological Status (RBANS)

• Immediate memory, delayed memory, language, visuospatial/constructional, attention

• Paced Auditory Serial Addition Task (PASAT)

• Rey-Osterrieth Complex Figure Test (RCFT)

Measures RBANS Baseline to 2-Month Follow-Up

Mithoefer MC, et al. J Psychopharmacol. 2011;25(4):439-452.

0

20

40

60

80

100

120

140

0 mg(N=10)

40 mg (N=6)

100 mg(N=8)

125 mg(N=30)

RB

AN

S M

ean

Sco

re (

+/-

SD)

Baseline

Primary

23%

PHASE 2: PLACEBO GROUP

No Longer Meet PTSD Diagnosis Meet PTSD Diagnosis

56%

PHASE 2: MDMA GROUP AT CONCLUSION OF TREATMENT


68%

PHASE 2: MDMA GROUP, 12-MONTH FOLLOW-UP


Lessons Learned In Phase 2 Studies

Cause of PTSD irrelevant; enroll people with PTSD from any cause

Low doses of 25-40 mg do enhance blinding but can have anti-therapeutic effect

Safety in clinical settings can be established

Medium to large effect size on the Clinician-Administered PTSD Scale (CAPS-4)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0-40 mg (N=13) 75-125 mg (N=38)

MEQ

To

tal S

core

s M

ean

(+/

-SD

)

MDMA (75-125 mg) Group had Significantly Higher MEQ Scores Across Two Blinded Sessions than the Control (0-40 mg) Group

***

Mystical Experience Scores not correlated with PTSD symptom reduction in the active dose group.

r = -.101 p = .545

FDA and MAPS reach agreement regarding the Phase 3 protocol designs through the Special Protocol Assessment process.

July 28, 2017

FDA Phase 3 Study Design:MDMA-Assisted Psychotherapy for PTSD

2-Month Follow-up

Screen & Enroll

80 or 120 mg 80 or 120 mg80 mg

Inactive Placebo

Inactive Placebo

Inactive Placebo

3 Prep Sessions 9 Integrative Psychotherapy Sessions

3 Prep Sessions 9 Integrative Psychotherapy Sessions

MAPP1100 participants to be recruited

MAPP2100 participants to be recruited

PHASE 3 STUDIES

TWO TRIALS

2017

August 15, 2017

June 12,2018 Scientific advice meeting: EMA in London

EMA agreed to accept FDA data.

Required 1 pivotal 70-person Phase 3

study.

Request we enroll some refugees and

migrants.

European locations for Phase 2 “Lead-in” studies and Phase 3 trial

● Prague, Czech Republic

● London, UK

● Cardiff, UK

● Berlin, Germany

● Hamburg, Germany

● Leiden, Netherlands

● Maastricht, Netherlands

● Moss, Norway

● Lisbon, Portugal

Cost-Effectiveness Analysis by Elliot Marseille published October 14th in PLOS One

MAT Control

$28,542,085 $20,772,136

$274,770,646 $362,865,823

755 458

12,367 7,565

Incremental cost-effectiveness ratio - Year 1

Incremental cost-effectiveness ratio - thru 30 years

$26,201

Net present costs and discounted QALYS gained, and cost-effectiveness

results for 30 years time horizon for 1,000 pts.

First-year

First-year net cost (saving) $7,769,949

Full 30 years

Total net 30 costs (savings)

Intervention and

ongoing medical

care costs

Dominant

($80,325,228)

First-year

Full 30 years

Health benefits in

QALYs

4,803

297First-year incremental QALYs gained

Incremental QALYs gained over 30 years

‘Break-even’ is ~ 3.5 years after MAT.

At that point the net discounted cost is zero while still delivering

about 1,000 QALYs.

Questions and Answers (hopefully good ones)

Phase 3: MAPP1 Results

CONFIDENTIAL- PRELIMINARYThis data is under embargo and must not be shared in any form

Information presented here is under strict embargo. If you would like to publish anything about these results,

please contact [email protected] for the paper, interviews, and embargo details.

mailto:[email protected]

Progress of Phase 3 Clinical Trials

100 participants planned131 participants enrolled

90 treatedStudy closed at 90 participants, due to COVID

100 participants planned10 of 14 sites up and running

30 participants in screening with 2

enrolled

MAPP1 Pivotal Trial

MAPP2Confirmatory Trial

More than a third of study participants had been suffering

from PTSD for over 20 years

Sources: MAPP1 data

Suicidal ideation and behavior history

Sources: MAPP1 data

P-values

0 10.5

Minimum required

for FDA approvalP < 0.05

Statistically Significant1 in 20 chance that treatment is no

more effective than placebo

p = 0.50Not Significant

1 in 2 chance that the treatment is no more effective than placebo

P < 0.001 Robust / Very Persuasive

1 in 1000 chance that treatment is no more effective than placebo

MAPP1: p < 0.0001 1 in 10,000 chance that treatment is

no more effective than placebo

Preliminary

These data are under strict embargo. If you would like to publish anything about these results, please contact [email protected] for the paper, interviews, and embargo details.


Efficacy of MDMA Therapy

These data are under strict embargo. If you would like to publish anything about these results, please contact [email protected] for the paper, interviews, and embargo details.


Therapeutic Effect Sizes of SSRIs

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8

Trivial

0.9 1

Small Medium Large

Paxil Study #627:

0.09 (failed)

Zoloft Study #640: 0.31

Zoloft Study #671: 0.37

Paxil Study #648:

0.45

Paxil Study #651:

0.56

... 2

1MDMA Therapy effect sizes likely understates the superiority of MDMA Therapy. Effect size is calculated based on the difference between the MDMA + Therapy group and the Placebo + Therapy group. Zoloft and Paxil are compared to an inactive placebo (think sugar pill). MDMA Therapy uses an active control: psychotherapy with a sugar pill. Therefore, the real-world effect size for MDMA Therapy will likely be even higher.

MDMA Therapy

Phase 3

0.911

Subtracting

therapy-only

control group

2.1Full Treatment

of MDMA plus

Therapy

Very Large

Preliminary

Phase 3 Results - ⅔ of the MDMA + Therapy study participants no longer qualified for a PTSD diagnosis after three MDMA sessions

Sources: MAPP1 Results

Note: “Control + Therapy Group” value was 23% and “MDMA + Therapy Group” at the 2-Month Follow Up was 56%

No longer meet requirements for a PTSD diagnosisMeet PTSD diagnosis requirements

30% 23%67%

Control + Therapy Group MDMA + Therapy Group

2-Month Follow Up

(Available

next year)

12-Month Follow Up

Preliminary

Phase 2 result: 23% Phase 2 result: 56% Phase 2 result: 68%

Patients with Dissociative Subtype - a more challenging variant of PTSD - responded to MDMA Therapy even better than those without!

Preliminary

P < 0.0001 P = 0.0027Source: MAPP1 data

Note: One Phase 2 trial (N=26) already showed large effect size and statistically robust outcomes for a more homogenous PTSD sample, mostly

male (73%), veterans (85%), and first responders. Mithoefer et al.

It’s not just the most experienced therapists that are driving results

Quality of our Therapy Training Program

Incredible therapeutic potential of MDMA

No site effects were observed

Results were evenly distributed across different clinical sites

Safety of MDMA Therapy Demonstrated: Participants with Adverse Events of Special Interest

● Serious Adverse Events of Suicidal ideation and/or Attempt. ○ 0 participants in MDMA group○ 2 participants in placebo group

1 attempted suicide twice during the study, 1 self-hospitalized with severe suicidal ideation to prevent self-harm, without actual attempt

• No other SAEs on study

Safety of MDMA Therapy Demonstrated: Participants with Adverse Events of Special Interest

● Suicidality (Suicidal ideation)○ 3 participants in MDMA group ○ 5 participants in placebo group

● Cardiovascular (Irregular heartbeats, palpitations)○ 0 participants in MDMA group○ 1 participants in placebo group

● Abuse potential (Dependence, substance use disorder)○ 0 participants in MDMA group○ 0 participants in placebo group

Preliminary

Most frequent non-serious

adverse events for the MDMA

group:

● Muscle tightness

● Decreased appetite

AE MDMA Placebo

Muscle Tightness 30 (65.2%) 6 (13.6%)

Decreased Appetite 24 (52.2%) 5 (11.4%)

Hyperhidrosis (sweating) 10 (21.7%) 1 (2.3%)

Feeling Cold 9 (19.6%) 3 (6.8%)

Restlessness 7 (15.2%) 0

Mydriasis (dilated pupils) 7 (15.2%) 0

Bruxism (teeth grinding) 6 (13%) 1 (2.3%)

Nystagmus (eye wiggling) 6 (13%) 0

Dizziness Postural 6 (13%) 2 (4.5%)

Blood Pressure Increased 6 (13%) 0

Feeling Jittery 6 (13%) 0

Non-Cardiac Chest Pain 5 (10.9%) 1 (2.3%)

Dry Mouth 5 (10.9%) 2 (4.5%)

Safety: Non-Serious Treatment Emergent Adverse Events

Sources: Preliminary MAPP1 data

Summary of Results of MAPP1

✅ Very Small p-value (0.0001)

✅ Large and Very Large effect sizes (0.91 placebo/therapy subtracted, 2.1 MDMA/therapy within subjects)

✅ Replicated results from Phase 2 trials

✅ No site-to-site variability

✅ Good Safety Profile and no increase in suicidality in MDMA group

▪ Only prescribed by certified therapists, trained by the sponsor

▪ Only administered in certified clinics

▪ Defined safety screening for specified patient population

▪ Centralized pharmacy

Post Approval Risk Evaluation and Mitigation Strategies (REMS)

▪ Total lifetime limit of doses of 10-12

▪ Patient Registry

MAPSCertified MDMA

CompassCertified

Psilocybin

UsonaCertified

Psilocybin

KetamineAssisted

Psychotherapy

Licensed Legalization

LICENSE TO BUY DRUGS

ID: 012 345 6789

RICHARD DOBLIN

ISSUED: 04/20/2020

Licensed Legalization

Sara Gael M.A.

Psychedelics in Lifelong Zen Meditators

Vanja Palmers

Reference: https://pubmed.ncbi.nlm.nih.gov/30965131/

the history, science and future regulation of psychedelic

Documents