FDA as Honest BrokerFDA as Honest Broker

• FDA’s institutional mission is to develop medicines to reduce suffering.

• FDA is not in favor of psychedelics or marijuana, just in favor of research.

• FDA responded fairly rapidly to submissions and did not cause most delays.

FDA Organizational ChangesFDA Organizational Changes

• The Division at FDA that blocked most psychedelic research throughout the 1970s and 1980s had the review of Schedule 1 Drugs taken away in 1989.

• New policies, ratified by an FDA Drug Abuse Advisory Committee in 1992 and reaffirmed by FDA management in 1999, permit well-designed human research with psychedelics and marijuana.

FDA’s Track RecordFDA’s Track RecordFDA’s Track RecordFDA’s Track Record

• Since 1990, FDA has approved human studies with:

• DMT• MDMA• Ibogaine• Psilocybin• Mescaline• Marijuana

Missing In ActionMissing In Action

Psychedelic Research Around the World- Therapy Studies

Psychedelic Research Around the World- Therapy Studies

• Ketamine in the treatment of heroin addiction, Dr. Evgeny Krupitsky, St. Petersburg, Russia.

• Single v. Multiple (3) Doses of Ketamine-Assisted Psychotherapy (KPT), Double-blind

• Five year study, now in the second year.

• Co-funded MAPS and Heffter ($10K each/yr)

Dr. Krupitsky’s Previous Ketamine Research

Dr. Krupitsky’s Previous Ketamine Research

• This study follows a 3-year study comparing one high-dose KPT session (2 mg/kg i.m.) to one low-dose, placebo control session (0.2 mg/kg i.m.).

• The rate of abstinence in the high dose group was significantly higher than that of the low dose group, starting from the first month and then within all twenty-four months of follow-up.

• Paper in review by J. of Substance Abuse Treatment

Patient Account: Mr. P.F.Patient Account: Mr. P.F.

• Dose is 2.0 mg/kg i.m.

• “I am one of the stars. Then the whole dome collapsed and turns into one dot. A gold splash appears against the blue background. It turns into a flower. The flower opens and there, in the flower, I see my son, and somebody’s voice is saying: “That is most important.”

Dr. Krupitsky’s Ketamine Therapy-1st Stage

Dr. Krupitsky’s Ketamine Therapy-1st Stage

• Preliminary non-drug psychotherapy in order to build Therapeutic Alliance. Review the subject’s personal motives for treatment, goals for new life without drugs, theory about the causes of addiction and its’consequences and so on.

• Discuss the effects of Ketamine.

Dr. Krupitsky’s Ketamine Therapy - 2nd Stage

Dr. Krupitsky’s Ketamine Therapy - 2nd Stage

• Session is directed toward the resolution of personality problems and formation of a stable orientation to a future without drugs.

• Carefully direct the subject’s experiences by verbal influences and guiding the musical background toward the symbolic resolution of personality conflicts as well as a final cathartic peak experience.

Dr. Krupitsky’s Ketamine Therapy -3rd Stage

Dr. Krupitsky’s Ketamine Therapy -3rd Stage

• Non-drug integrative therapy sessions.

• Discuss and interpret the personal significance of the symbolic content of their experience with the psychotherapist.

• Generate new insights that enable subjects to integrate new, often unexpected, meanings, values and attitudes.

Dr. Krupitsky’s Ketamine Research

Dr. Krupitsky’s Ketamine Research

• 60 Subjects receive 3 KPT sessions

• 60 subjects receive 1 KPT session ( the first session for everyone is a KPT session) and 2 Placebo sessions.

• Sessions take place after completion of in-patient detox, Sessions 4 weeks apart. When subjects return for second session, randomized to either 3 or 1 KPT sessions.

Dr. Krupitsky’s Ketamine Research

Dr. Krupitsky’s Ketamine Research

• 52 patients randomized so far into either single or multiple KPT sessions group.

• 5 additional patients dropped out after the first ketamine session, and didn’t show up for the second session one month later.

Dr. Krupitsky’s Ketamine Research

Dr. Krupitsky’s Ketamine Research

• Measures• Abstinence, followed for two years through Urine

Tests, Reports of Significant Others

• Complete Battery of Psychological Measures such as MMPI, Zung Depression Scale,

• Hallucinogen Rating Scale

• Locus of Control Scale

• Questionnaire of Terminal Life Values, Purposes-in-Life Test, and Spirituality Scale

Jose Carlos Bouso MDMA/PTSD Protocol

Jose Carlos Bouso MDMA/PTSD Protocol

• MDMA in the treatment of women survivors of sexual assault suffering from chronic posttraumatic stress disorder (PTSD).

• Double-blind, Placebo-controlled, Dose-Response Pilot Study. Funded by MAPS.

• The only study in the world currently investigating the therapeutic use of MDMA.

Personal Account: MarcelaPersonal Account: Marcela

• 1984: “Adam [MDMA] has helped me look at all this suffering, see my life, as a whole and understand it better. It has given me the courage to face the fears instead of ignoring them, to know that the most important thing is to struggle to trust myself.”

• Fall 2000: Licensed therapist, MA degree, therapist on MDMA/PTSD study in Madrid.

Jose Carlos Bouso MDMA/PTSD Protocol

Jose Carlos Bouso MDMA/PTSD Protocol

• PURPOSES OF THE STUDY To determine the most effective therapeutic dose of MDMA as an adjunct to psychotherapy with women suffering from PTSD as a result of having survived sexual assault.

• To gather preliminary evidence about the therapeutic effectiveness of MDMA as an adjunct to psychotherapy in women suffering from PTSD as a result of having survived sexual assault.

Jose Carlos Bouso MDMA/PTSD Protocol-Rationale

Jose Carlos Bouso MDMA/PTSD Protocol-Rationale

• Within a psychotherapeutic context, MDMA Within a psychotherapeutic context, MDMA can help to create an environment where the can help to create an environment where the subject can re-experience her trauma subject can re-experience her trauma without the terror she has associated with it. without the terror she has associated with it.

• This successful reliving of the traumatic This successful reliving of the traumatic event is thought to give the patient a greater event is thought to give the patient a greater sense of subjective control over the memory sense of subjective control over the memory – thereby reducing the symptoms of PTSD.– thereby reducing the symptoms of PTSD.

Jose Carlos Bouso MDMA/PTSD Protocol-Rationale

Jose Carlos Bouso MDMA/PTSD Protocol-Rationale

• This ease of accessing and expressing deep This ease of accessing and expressing deep feelings breaks the affective hold of the feelings breaks the affective hold of the disorder, permitting an acceleration of the disorder, permitting an acceleration of the process of establishing a therapeutic process of establishing a therapeutic alliance, the variable most predictive of alliance, the variable most predictive of therapeutic changestherapeutic changes..

Jose Carlos Bouso MDMA/PTSD Protocol

Jose Carlos Bouso MDMA/PTSD Protocol

• 29 Subjects, 5 have been treated to date.

• 4 Subjects in 50 mgs group (3 MDMA, 1 placebo)• 7 Subjects in 75 mgs group (5 MDMA, 2 placebo)• 7 Subjects in 100 mgs group (5 MDMA, 2 placebo)• 7 Subjects in 125 mgs group (5 MDMA, 2 placebo)• 4 Subjects in 150 mgs group (3 MDMA, 1 placebo)

MDMA Research in Spain: Basic Safety Studies

MDMA Research in Spain: Basic Safety Studies

• Dr. Magi Farre, Dr.Jordi Cami and Team Institut Municipal d'Investigacio Medica (IMIM), Barcelona, Spain. Spanish Government funded.

• Phase 1 Studies, Pharmacokinetics,

• Effects of MDMA and Alcohol and immune system functioning.

US Psilocybin/OCD StudyUS Psilocybin/OCD Study

• Dr. Francisco Moreno, U. of Arizona

• Pilot study of psilocybin in patients with Obssesive/Compulsive Disorder.

• First FDA-approved investigation of psilocybin in patients in 30 years!

• Heffter and MAPS funded.

Research ObjectivesResearch Objectives

• Evaluate the safety and therapeutic potential of serotonin (5-HT)-2A/2C receptor agonist treatment of OCD.

• Note: Primarily pharmacologic, not psychotherapeutic mechanism of action is proposed. However, MAPS has brought experts to U. of A. to train the researchers in how to work with psychedelic experiences.

Basic Design ElementsBasic Design Elements

• Double-blind pilot study, 10 patients.

• Outpatients, will not be hospitalized prior to or after the psilocybin experience.

• Dose-escalation study, 4 dose levels, 0.025, 0.1, 0.2 and 0.3 mgs/kg,

• Up to 4 Sessions, each 2 weeks apart.

Local ConnectionLocal Connection

• Psilocybin manufactured for MAPS by Organix, Inc. in Woburn, MA.

• $12,250 for one gram, the world’s most expensive psilocybin!

Dr. Mash’s Ibogaine ResearchDr. Mash’s Ibogaine Research

• Deborah Mash, Ph.D. University of Miami, treating patients with ibogaine to reduce withdrawal from opiates and cocaine, and to promote abstinence. About 150 treated.

• NIDA rejected grant application so Dr. Mash established a clinic in St. Kitts. Treatments funded by patients, mostly a safety study with limited follow-up.

www.healingvisions.comwww.healingvisions.com

Personal Account- RobertoPersonal Account- Roberto

• Roberto: “All of a sudden, out of the water, this big angel came out. It was like Mother Earth, like my creator, something higher than me letting me know everything was going to be all right."

Personal Account- RobertoPersonal Account- Roberto

• "I can’t say more... I don’t know how to explain it. I got in touch with the kid who got lost between the drug world and the insanity of my life. And now I’m more at peace. I still have to fight my addiction, but now I feel like I got a foundation."

Dr. Mabit’s Ayahuasca ResearchDr. Mabit’s Ayahuasca Research

• Dr. Jacques Mabit, Takiwasi, Peru

• Uses ayahuasca and other plants to treat drug addicts within a shamanistic context.

The Spirit of Ayahuasca by Pablo Amaringo

The Spirit of Ayahuasca by Pablo Amaringo

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•

Dr. Vollenweider’s Research TeamUniversity of Zurich

Dr. Vollenweider’s Research TeamUniversity of Zurich

• Franz Vollenweider, U. of Zurich, 14 people

• Psilocybin dose-response studies

• MDMA Neurotoxicity, Blocking studies

• Heffter and Swiss Government funded

•

University of Zurich- MDMAUniversity of Zurich- MDMA

• Prospective MDMA Neurotoxicity Study

• MDMA-naive subjects and controls. Doses of 1.5 -1.7 mgs/kg. Pilot study completed.

• PET scan, same ligand as used by George Ricaurte to measure serotonin uptake sites.

• PET Scan before and two weeks after MDMA. No significant serotonin changes.

• Paper being written, report sent to FDA.

University of Zurich- PsilocybinUniversity of Zurich- Psilocybin

• Preparing for a psilocybin therapy study.

• Patient population still being discussed but probably people with eating disorders.

Future Directions Future Directions

• “ We have moved beyond the model psychosis framework. We have left that behind.” Dr. Franz Vollenweider August 9, 2001

Dr. Tancer’s MDMA ResearchDr. Tancer’s MDMA Research

• Dr. Manny Tancer, Dr. Bob Schuster, Wayne State, Michigan.

• They are conducting a series of MDMA mechanism of action and safety studies looking at temperature, receptor sites, co-administration with SSRIs

• NIDA Funded for 5 years.

Dr. Roy Mathew’s Mescaline Research Dr. Roy Mathew’s

Mescaline Research

• Dr. Roy Mathew, Duke University Medical School, Durham, North Carolina.

• Using PET to study time perception under the influence of mescaline (has used THC)

• First FDA-approved study in the US with mescaline in over 35 years.

Dr. Mithoefer’s MDMA/PTSD Protocol

Dr. Mithoefer’s MDMA/PTSD Protocol

• Double-Blind, Placebo-controlled, Pilot study.

• 20 subjects receive 13-14 hours of non-drug psychotherapy for preparation and integration.

• All 20 receive two 6-8 hour therapy sessions, 3-5 weeks apart. 12 receive a dose of 125 mgs. of MDMA each time, 8 inactive placebo.

Dr. Mithoefer/MAPS MDMA/PTSDDr. Mithoefer/MAPS MDMA/PTSD

• FDA approves protocol on November 2, 2001. We’re still working on IRB approval.

• This is the first FDA-approved MDMA therapy protocol since 1985, when MDMA was criminalized.

MAPS and MDMA ResearchMAPS and MDMA Research

• As part of FDA application, MAPS funded a comprehensive review of virtually the entire published literature on MDMA, at a cost of $80,000 over two years. This is posted on the MAPS website.

• Congress recently passed an Anti-Ecstasy bill that gives NIDA $1.5 million for an MDMA literature review.

Dr. Mithoefer’s MDMA/PTSD Protocol

Dr. Mithoefer’s MDMA/PTSD Protocol

• Measures• Standard PTSD outcome instruments• Neurocognitive evaluations• Physiological, blood

• Subjects must have failed on one course of SSRIs (since Zoloft and Paxil are the only FDA- approved medicines for PTSD).

MAPS and MDMA ResearchMAPS and MDMA Research

• MAPS has elaborated a 5-year, $5 million Clinical Plan designed to develop MDMA into an FDA-approved prescription medicine.

• In press, J. of Psychoactive Drugs

Next ProtocolNext Protocol

• After MDMA/PTSD protocol is underway, MAPS will submit to FDA a protocol to administer MDMA to hospice patients to treat anxiety and depression associated with terminal illness.

• History of LSD research in cancer patients was quite promising. This Timeless Moment by Laura Huxley.

NIDA Imagery:Ideology, not Science

NIDA Imagery:Ideology, not Science

Basis of NIDA ImageBasis of NIDA Image

• PET study 14 MDMA users, 15 Controls

• Average exposure to MDMA - 228 times

• Average dose each time - 386 mgs.

• Serotonin uptake sites are reduced in MDMA users v. controls

• McCann U, Szabo Z, Scheffel U, Dannals R, Ricaurte G. Positron emission tomographic evidence of toxic effect of MDMA ("Ecstasy") on brain serotonin neurons in human beings. Lancet. 1998 Oct 31;352(9138):1433-7.

Scatter Plot of MDMA and Control Subjects

Is NIDA’s Image True to the Data?Is NIDA’s Image True to the Data?

• A fair comparison : PET scans of the MDMA and control subjects closest to mean values.

• Is NIDA’s slide of subjects at or near the extremes, or at the mean?

• If not the means, the comparison captures individual variability unrelated to MDMA

Leshner Testimony to Senate Subcommittee on Government Affairs 7/30/01

Dr. Chang’s SPECT StudyPart 1/ Retrospective

Dr. Chang’s SPECT StudyPart 1/ Retrospective

• 21 MDMA users compared to 21 controls

• Mean use of MDMA 211 times, median 75

• Estimated mean total dosage 13.1 grams

• Chang, L. et al., Psychiatry Research: Neuroimaging, Section 98, pp. 15-28, 2000.

Dr. Chang’s Data MDMA Users v. Controls

• No significant difference in global or regional rCBF between 21 MDMA users and 21 controls at baseline.

• “Low dose recreational MDMA uses does not cause detectable persistent rCBF changes in humans.”

• Low dose = median 211 exposures, average lifetime consumption of 13.1 grams!

Dr. Chang’s StudyPart 2 ProspectiveDr. Chang’s StudyPart 2 Prospective

• 10 of the 21 MDMA users with baseline scans in Part 1 were given MDMA 2X in Dr. Charlie Grob’s Phase 1 study, then given another SPECT scan.

• 8 scanned 2-3 weeks after dosing

• 2 scanned 2-3 months after dosing

Dr. Chang’s DataProspective MDMA Study

Dr. Chang’s DataProspective MDMA Study

• 8 subjects, 2-3 weeks after 2 doses of MDMA, lower rCBF in several regions.

• 2 subjects, 2-3 months after 2 doses of MDMA, elevated rCBF in several regions.

• Short term drop, return to baseline, no long-term change in CBF seen in SPECT scans.

MDMA SPECT Scan Shown on MTV and Oprah

MDMA SPECT Scan Shown on MTV and Oprah

Holes in the BrainHoles in the Brain

Graphically Manipulated ImageGraphically Manipulated Image

Future PotentialFuture Potential

• "Psychedelics, used responsibly and with proper caution, would be for psychiatry what the microscope is for biology and medicine or the telescope is for astronomy."

• Dr. Stan Grof