This review (2014) outlines the historic development of the non-profit association MAPS in its mission to develop medical, legal, and cultural contexts for people to benefit from the careful uses of psychedelics and marijuana. These efforts include the development of psychedelics into prescription medicines, training therapists, establishing treatment centers, supporting scientific research into spirituality, creativity, and neuroscience, and educating the public about the risks and benefits of psychedelic substances. They introduced the first double-blind, placebo-controlled trial of MDMA-assisted psychotherapy for posttraumatic stress disorder (PTSD) in 1994 and had planned for FDA prescription approval in 2021. Their ongoing efforts include plans for introducing (LSD)-assisted psychotherapies, parallel to harm-reduction strategies, such as the Zendo Project.
This article describes the teenage vision of the founder of the Multidisciplinary Association for Psychedelic Studies (MAPS) that humanity’s future would be aided by the therapeutic and spiritual potential of psychedelic substances. The article traces the trajectory of MAPS from inception in 1986 to its present, noting future goals with respect to research, outreach, and harm reduction. MAPS was created as a non-profit psychedelic pharmaceutical company in response to the 1985 scheduling of 3,4-methylenedioxymethamphetamine (MDMA). Overcoming many hurdles, MAPS developed the first double-blind, placebo-controlled trial of MDMA-assisted psychotherapy for posttraumatic stress disorder (PTSD) and plans for FDA prescription approval in 2021. MAPS’ program of research expanded to include a trial of lysergic acid diethylamide (LSD)-assisted psychotherapy for anxiety when facing life-threatening illness, observational studies of ibogaine in the treatment of addiction, and studies of MDMA for social anxiety in people with autism spectrum disorders. MAPS meets the challenges of drug development through a clinical research team led by a former Novartis drug development professional experienced in the conduct, monitoring, and analysis of clinical trials. MAPS’ harm-reduction efforts are intended to avoid backlash and build a post-prohibition world by assisting non-medical users to transform difficult psychedelic experiences into opportunities for growth.
Emerson and colleagues frame the paper as a historical account of the Multidisciplinary Association for Psychedelic Studies (MAPS), describing its origins in the mid-1980s and the organisational response to the criminalisation of MDMA. The introduction emphasises the founder Rick Doblin's personal motivations—shaped by encounters with LSD and by political and moral concerns about dehumanising social processes—and situates MAPS' mission within a wider ‘‘psychedelic renaissance’’ of renewed clinical research into psychedelics and entheogens. The paper sets out to trace MAPS' trajectory from its precursor organisations through regulatory struggles, early clinical and safety research, and the development of an infrastructure intended to advance psychedelics as prescription medicines. It highlights both scientific milestones (pilot and Phase II clinical trials with MDMA and other psychedelics) and parallel activities in therapist training and harm reduction, with an explicit aim of explaining how MAPS intends to move toward potential regulatory approval and broader clinical implementation.
Papers cited by this study that are also in Blossom
Bouso, J. C., Doblin, R., Farré, M. et al. · Journal of Psychoactive Drugs (2008)
Dumont, G., Sweep, F., van der Steen, R. et al. · Social Neuroscience (2009)
Mithoefer, M. C., Wagner, M. T., Mithoefer, A. T. et al. · Journal of Psychopharmacology (2012)
Papers in Blossom that reference this study
The extracted text does not present a formal Methods section describing systematic review procedures or primary data collection for the paper itself. Rather, the article reads as an organisational history and programme description that chronicles MAPS' activities, regulatory submissions, funded studies, and programme development over time. Operationally, the narrative draws on MAPS' regulatory interactions (IND and protocol submissions to the U.S. Food and Drug Administration and related agencies), sponsored clinical trials and observational studies, and the progressive build-out of a clinical research infrastructure. Where trial designs are described, the authors report standard clinical-research elements such as randomisation, double-blinding, placebo control, staged open-label follow-up (‘‘Stage 2’’), dose-escalation, and use of co-therapist teams. When specific trials are summarised, details provided include target populations, sample sizes where reported, dosing practices and protocol amendments (for example, the introduction of a supplemental half‑dose and later clinical titration options).
The paper narrates a chronological sequence of regulatory challenges, safety studies, and clinical trials that constituted MAPS' MDMA development programme and related research. Early organisational and regulatory events included the 1984 reconstitution of a precursor non-profit to litigate DEA scheduling decisions, a series of failed FDA applications in the late 1980s, and subsequent investment in preclinical toxicity and human safety work. MAPS opened a Drug Master File and secured sources of pure MDMA for research. The first FDA‑sanctioned U.S. Phase I study was conducted in 1994; it identified transient increases in body temperature, heart rate and blood pressure in some healthy volunteers but no clinically significant safety signals in controlled settings. Clinical efficacy work began with pilot and Phase II programmes. A MAPS‑sponsored pilot in Spain (starting 2000) enrolled six women with treatment‑resistant PTSD before political pressure halted the study in 2002; no adverse events were reported and mild improvement signals were noted. The first U.S. randomized, double‑blind, placebo‑controlled Phase II study (MP‑1), led by Michael Mithoefer in Charleston, enrolled mostly women survivors of sexual assault or childhood sexual abuse (average PTSD duration >19 years). At the two‑month follow‑up, over 80% of subjects who received MDMA‑assisted psychotherapy no longer met diagnostic criteria for PTSD, compared with 25% in the placebo group. A later publication of results from an early U.S. pilot (20 subjects) reported clinically and statistically significant reductions in PTSD severity, and long‑term follow‑up (mean 41 months) suggested sustained benefits; three participants experienced relapse after stressful life events and were eligible for an open‑label ‘‘relapse’’ intervention, which again reduced CAPS scores. A Swiss Phase II pilot (MP‑2) with 12 subjects produced clinically meaningful improvements with a trend toward statistical significance and suggested increasing benefits at 12‑month follow‑up. Across these studies, no serious adverse events attributable to the protocol were reported. Protocol modifications made during the Phase II programme included increasing the number of MDMA‑assisted sessions from two to three, permitting a supplemental half‑dose about two hours after the initial dose to prolong therapeutic effects, and offering placebo subjects the option of open‑label Stage 2 treatment to improve blinding and retention. By 2013 MAPS had trial provisions to clinically titrate Stage 2 doses to 100 mg or 125 mg based on subject response. Beyond MDMA for PTSD, MAPS expanded its research portfolio: a Swiss LSD‑assisted psychotherapy study for end‑of‑life anxiety (first subject enrolled 2008; 12 subjects treated through 2011, long‑term follow‑up completed 2012); observational ibogaine treatment studies for opioid dependence (30 subjects in Mexico with one‑year follow‑up data; an investigator‑sponsored study in New Zealand); and a planned exploratory, randomized, double‑blind, placebo‑controlled Phase II pilot of MDMA‑assisted therapy for social anxiety in adults on the autism spectrum (12 MDMA‑naïve adults). The organisation also reports over 4,500 Medline‑indexed papers using the keywords MDMA or ecstasy and estimates that basic MDMA research cost over $300 million, helping to reduce the need for some preclinical work. Institutional capacity and forward planning are reported in detail: by 2013 MAPS had established a clinical research department with SOPs, electronic data capture (eCRF), monitoring capacity and a staff of about 17 (including part‑time medical monitors and CRAs), four active MDMA/PTSD sites conducting five studies, and 11 FDA‑approved protocols across three clinical programmes. Projected plans included completing primary Phase II endpoints in late 2015, holding an End of Phase II meeting with the FDA in 2016, and conducting two Phase III studies of approximately 200 subjects each (staggered between 2016 and 2021), with an anticipated regulatory decision about MDMA as a prescription medication in 2021. To support Phase III and expanded access, MAPS estimated the need to train about 300 therapists between 2015 and 2019 and to secure a GMP manufacturer of MDMA. The authors also report that NIDA refused to provide DEA‑licensed marijuana, blocking the organisation's marijuana research. On the harm‑reduction front, MAPS describes field programmes beginning in 2001 that provide on‑site support for difficult psychedelic experiences. Initiatives include KosmiCare at Portugal's Boom Festival (with pill‑testing and collaboration with local health services) and the Zendo Project initiated in 2012 (services at Burning Man and international events). The authors report that these harm‑reduction services have helped reduce arrests and hospitalisations at festivals and serve as training opportunities for therapists.
Emerson and colleagues interpret the history as evidence that a non‑profit, mission‑driven ‘‘psychedelic pharmaceutical’’ model can navigate regulatory, scientific and political barriers to reintroduce psychedelic‑assisted therapies into clinical care. They argue that MAPS' strategy—controlling research direction, following standard drug‑development processes, building clinical infrastructure, and training therapists—has produced proof‑of‑principle data and a foundation for larger efficacy trials. The paper positions the findings relative to prior controversy and regulatory resistance, noting that initial FDA and DEA opposition gradually softened as MAPS completed preclinical and Phase I safety work and as controlled clinical protocols demonstrated tolerability and preliminary efficacy. The authors emphasise that toxicity concerns diminished when MDMA use was framed as a few supervised therapeutic sessions rather than chronic daily dosing. They also highlight the complementary role of harm reduction in reducing public fear and legal backlash, and in providing practical training opportunities for aspiring therapists. Key limitations and uncertainties are acknowledged: early trials were small and sometimes interrupted by political pressure (for example the Spain pilot), and regulatory and logistical delays slowed progress in some jurisdictions (notably Health Canada and the NIDA‑related blockade on marijuana research). The authors also note ongoing needs for larger, multicentre Phase III trials, a GMP drug supplier, broad therapist training, and demonstration of consistent protocol adherence across sites. Finally, they recognise that accelerated regulatory pathways might be available but are not guaranteed, and that timelines (including the projection of a 2021 regulatory decision) depend on successful completion of planned studies and FDA interactions. Implications discussed by the authors focus on the potential for MDMA‑assisted psychotherapy to address chronic, treatment‑resistant PTSD and to open a pathway for other psychedelics in psychiatric treatment, contingent on rigorous Phase III evidence and appropriate clinical infrastructure. They advocate continued clinical research, therapist training, and community harm‑reduction efforts as parallel priorities to support safe and effective implementation should regulatory approval be achieved.
to devote himself to renewing psychedelic research, which had been halted all over the world, and to eventually become a legal psychedelic psychotherapist. Three historical events profoundly influenced Rick and motivated his choice of life mission: the legacy of the Holocaust, the potentially catastrophic nuclear arms race, and the Vietnam War. In all of these conflicts, psychological factors such as projection, denial, scapegoating, and dehumanization played a central role. After trying LSD several times at age 18 at New College of Florida, and having illuminating but difficult experiences, Rick went to the guidance counselor seeking assistance. The guidance counselor handed him a manuscript copy of LSD researcher Dr. Stanislav Grof's Realms of the Human Unconscious, which acted like a Rosetta Stone for Rick's future. Dr. Grof wove together science, spirituality, and psychotherapy. His book enabled Rick to better understand LSD's potential to promote psychological health and reduce projection and denial, and to catalyze profound spiritual/mystical unitive states of consciousness that mitigated against scapegoating and dehumanization. As the UNESCO charter says, "Since wars begin in the minds of men, it is in the minds of men that the defenses of peace must be constructed." As Albert Einstein wrote, "The splitting of the atom has changed everything but our mode of thinking and hence we drift toward unparalleled catastrophe. What shall be required if mankind is to survive is a new mode of thinking." Influenced by these statements pointing to the crucial nature of psychological factors in human survival, Rick decided to work towards reviving psychedelic research and mainstreaming psychedelic psychotherapy and spirituality. This seemed to Rick the most potent strategy to building a healthier, sustainable world. Now, 42 years later, due to research sponsored by MAPS, Heffter Research Institute, Beckley Foundation, and the Council on Spiritual Practices and others, there is a renaissance in psychedelic research with more studies underway around the world than at any time in the last 40-plus years. We've progressed to the point where the prescription use of psychedelic psychotherapy is within reach by 2021.
In early 1984, Rick Doblin, Debby Harlow, and Alise Agar revived the non-profit organization, the Earth Metabolic Design Lab (EMDL), as a vehicle to coordinate the response of the psychedelic psychotherapy community to the move by the Drug Enforcement Administration (DEA) to criminalize MDMA. At that time, in the midst of the escalation of the Drug War by the Reagan Administration, MDMA was sold in public settings for recreational use under the name Ecstasy. MDMA's recreational use had emerged from the therapeutic and personal growth use of MDMA, which began in the mid-1970s under the code name Adam, of which the DEA had no knowledge. The DEA crackdown was just a matter of time. Fortunately, while MDMA was legal, it was possible to introduce key people in psychiatry and religion and public policy to MDMA, in the hopes that some would be willing to testify in the lawsuit EMDL planned to file once the DEA decided to act to criminalize MDMA. EMDL also proceeded to gather together the psychedelic community on its Board of Advisors. On July 27, 1984, DEA filed in the Federal Register its intentions to criminalize all uses of MDMA, with public comment permitted for 30 days. In early August, Rick went to DEA headquarters in Washington, DC, and filed papers seeking a DEA Administrative Law Judge (ALJ) hearing. The hearing was granted and, after extensive testimony, the DEA ALJ decided to recommend to the DEA Administrator that MDMA be placed in Schedule 3, leaving its therapeutic use legal while criminalizing its recreational use. Unfortunately, the DEA Administrator rejected the DEA ALJ recommendation and placed MDMA in Schedule 1, criminalizing all uses. EMDL then sued DEA in the Appeals Court over its rationale for rejecting the ALJ recommendation. EMDL won, causing the DEA to develop another rationale. Eventually, the DEA persuaded the Appeals Court that it had a valid rationale and MDMA was criminalized. Rick then realized that the only way to legalize the therapeutic use of MDMA was to work through the FDA drug development process by conducting research demonstrating that MDMA was safe and efficacious for a specific clinical indication. However, MDMA was off-patent, was controversial, was only meant to be used a few times in the context of psychotherapy and not daily like other psychiatric medications, and was meant to be administered in the context of psychotherapy and not as a stand-alone pharmacotherapy. As a result, MDMA's therapeutic potential was not going to be developed by the pharmaceutical industry. Due to the increasing Drug War mentality of the federal government, National Institutes of Health (NIH) funding into the beneficial uses of MDMA was not going to happen (and still hasn't taken place 28 years later). Furthermore, due to the controversy, funding for MDMA research from major foundations was also not likely (and has not yet occurred). In April 1986, to facilitate research into the therapeutic uses of MDMA-assisted psychotherapy, Rick started MAPS as a non-profit pharmaceutical company.
MDMA was synthesized in 1912 and patented in Germany by Merck in 1914, but was not the subject of human research at that time. In the 1950s, it was briefly researched by the U.S. government but was forgotten until the middle 1970s, when it was rediscovered by the psychedelic therapy community. Early observers noted increased acceptance of self and others, increased tolerance of emotionally upsetting material, and the ability to address these issues without extreme disorientation or ego loss). In the U.S., MDMA was used as an adjunct to psychotherapy by a number of psychiatrists and therapists in the treatment of neuroses, relationship problems, and PTSD. To pursue the vision of developing psychedelics as prescription drugs through FDA-approved studies, Rick knew that he needed to: (1) have control over the direction of the research; (2) follow standard drug development processes; (3) become a fund-raiser; and (4) remain independent of investors and political limitations that come with for-profit corporations and academic-based research. MAPS was formed with the mission to develop medical, legal, and cultural contexts for people to benefit from the careful uses of psychedelics and marijuana. This mission includes: (1) developing psychedelics and marijuana into prescription medicines; (2) training therapists and working to establish a network of treatment centers; (3) supporting scientific research into spirituality, creativity, and neuroscience; (4) educating the public about the risks and benefits of psychedelics and marijuana. MDMA was selected as the initial drug target because it seemed to offer patients a unique, gentle, yet profound experience of self-acceptance and an enhanced ability to feel and integrate complex, challenging emotions. Compared to other psychedelics like LSD or psilocybin, MDMA has minimal effects on perception or one's sense of self-control. This made MDMA a suitable drug to administer to psychedelic-naïve patients as well as to therapists in training to administer MDMA-assisted psychotherapy. Another reason for working initially with MDMA was that the nations of the world were beginning to fund basic research into the risks of MDMA/ecstasy, with all of that research in the public domain. As of 2014, there are over 4,500 scientific papers referenced in Medline using the keywords MDMA or ecstasy, produced at an estimated cost of over $300 million. As a result of the enormousness of the existing body of research, the funding necessary to begin MAPS' MDMA drug development program was drastically reduced, as all basic safety studies were complete. Upon formation of the non-profit and with the standard preclinical animal toxicity studies required by the FDA funded by EMDL and transferred to MAPS, Rick immediately opened a Drug Master File (DMF). Pure MDMA was needed to move forward. Fortunately, Rick had connected with Purdue chemist Dave Nichols, Ph.D. Dave consulted on the requirements with an FDA chemist and produced a kilogram of pure MDMA (which has been used for all MAPS U.S. studies to this point), funded by Rick at a cost of $4000, or $4 a gram. Upon opening the DMF, five different applications for permission to conduct human research with MDMA were submitted to the FDA between 1986 and 1988, to the Neuropharmacologic Drug Products Division directed by Dr. Paul Leber. All five applications were rejected. Three protocols for double-blind controlled trials were from researchers at, respectively, Harvard Medical School, UC San Francisco Medical School, and U. of New Mexico Medical School, and were all rejected. Two applications submitted by individual physicians were for single case studies, one by Dr. George Greer for a terminal cancer patient who had been successfully treated for pain with MDMA-assisted psychotherapy prior to the criminalization of MDMA, and the other by Dr. Francisco Di Leo for a unipolar depression patient (Rick's grandmother) for whom all available treatments had been attempted without success. Both of these single-patient investigational new drugs (INDs) were also rejected. The FDA based its rationale for rejecting these applications on the hypothetical risk of functional consequences of potential neurotoxicity from MDMA. MDMA researchers claimed that the rejection of all efforts to conduct FDAapproved MDMA research was based not on rational risk/benefit assessments but on an underlying cultural prejudice against medical research with drugs that were criminalized, and on one or more FDA officials' personal opposition to human research with psychedelics. Since FDA Review Divisions are sometimes described as operating like fiefdoms under the control of their directors, proponents felt profoundly stymied. Proponents claimed that concerns about MDMA neurotoxicity, which numerous studies had failed to link with functional or behavioral consequence, and which, in any case, had not been clearly demonstrated to occur at all at therapeutic dose levels, were reminiscent of scientific research in the 1960s that inaccurately claimed to prove that LSD damaged chromosomes and would cause birth defects. In order to better understand the risks of MDMA, MAPS began funding animal toxicity studies at Stanford) and helping to provide MDMA-using volunteers for human safety studies involving spinal taps at, conducted by Dr. George Ricaurte. In 1992, the MAPS IND for MDMA was filed and the FDA reviewed a MAPS-supported protocol submitted by Dr. Charles Grob, then at UC Irvine, for a study of the use of MDMA in the treatment of pain, anxiety, and depression in cancer patients. The FDA's Drug Abuse Advisory Committee recommended that the cancer patient study be postponed and that a Phase 1 dose-response safety study be conducted first. The FDA accepted the Advisory Committee's recommendation that human clinical research with psychedelics be resumed and be reviewed with the same rigorous standards the FDA used to evaluate research with all other potential prescription drugs. The protocol was redesigned and the first doubleblind, placebo-controlled U.S. Phase 1 study sanctioned by the FDA was conducted in 1994. Findings suggested that MDMA caused a significant increase in body temperature and heart rate in some healthy volunteers. However, these increases were found to be transient and generally tolerable in a controlled clinical setting. Subsequent trials confirmed that MDMA produced significant increases in heart rate and blood pressure that were likely to be well-tolerated by healthy individuals. The noted elevation in body temperature was not clinically significant. After the first study revealed no unusual risks and indicated that MDMA could be safely administered within a clinical research context, Dr. Grob submitted a protocol for the study of cancer patients in 1997. Negotiations with the FDA moved slowly. However, FDA opposition lessened as MAPS and Dr. Grob persisted in their efforts to obtain permission for research into the use of MDMA-assisted psychotherapy in cancer patients. A July 24, 1999, teleconference with the FDA concerning MDMA psychotherapy research to treat anxiety, depression, and pain in cancer patients went very well, with the FDA indicating a willingness to approve a "proof of principle" study. Unfortunately, Dr. Grob's other work-related responsibilities made it difficult for him to work on the approval process for this research project. He subsequently decided to focus on the use of psilocybin, instead of MDMA, in cancer patients, on the theory that psilocybin research would be less controversial than MDMA research. On March 18, 2000, Rick Doblin and Michael Mithoefer met at an ayahuasca conference in San Francisco, and begin talking about conducting MDMA psychotherapy research in the U.S. This marked the beginning of their effort to study subjects with chronic, treatment-resistant PTSD. However, they were still a few years away from starting in the U.S. Investigation of the therapeutic effects of MDMA finally started in 2000 in a MAPS-sponsored dose response pilot study in Spain in women survivors of sexual assault with treatment-resistant PTSD). On November 9, 2000, the first subject was treated in Jose Carlos Bouso's study in Madrid. Unfortunately, the study was halted on May 13, 2002, due to political pressure from the Madrid Anti-Drug Authority. Prior to its suspension, six women were enrolled and treated without any adverse events (AEs) or signs of deteriorating mental health, and with some mild signs of improvement, with single doses ranging from 50 to 75 mg. In 2001, the first MAPS protocol for MDMA-assisted psychotherapy was approved by the FDA for subjects with chronic, treatment-resistant PTSD. However, it took over two years for it to be approved by the DEA and an Independent Review Board (IRB). In 2002, Rick published a paper in the Journal of Psychoactive Drugs discussing, in detail, MAPS' selection of MDMA as the drug it focused on and PTSD as the clinical indication. In, for a study of 12 subjects using MDMA-assisted psychotherapy for the treatment of anxiety secondary to advanced stage cancer in people who were receiving only palliative treatments. One subject completed the experimental treatment and was a treatment success. A second subject participated in the first of two experimental sessions before dropping out due to a decision to resume chemotherapy. No additional subjects were enrolled and the study was closed due to enrollment challenges. MAPS plans to resume this line of research in the future. In 2004, the relationship with Michael Mithoefer resulted in him being the principal investigator of the first FDA-approved U.S. Phase 2, randomized, doubleblind, placebo-controlled study of MDMA-assisted psychotherapy for the treatment of chronic, treatment-resistant PTSD. The study, designated as MP-1, was conducted in Charleston, South Carolina, by husband and wife cotherapist team Michael Mithoefer, M.D., board-certified in psychiatry and emergency medicine, and Annie Mithoefer, B.S.N, psychiatric and cardiac nurse. The study enrolled mostly women survivors of sexual assault or childhood sexual abuse, along with two male veterans of the Iraq War. The subjects' average duration of PTSD was over 19 years. At the two-month follow-up, over 80% of the subjects who went through the MDMA-assisted psychotherapy no longer had sufficient symptoms to be diagnosed with PTSD, as compared to 25% in the placebo group. In 2006, MAPS' second Phase 2 pilot study was conducted in Switzerland (MP-2) with Peter Oehen, M.D., as the primary investigator and Verena Widmer as the co-therapist-another husband/wife team. The study enrolled 12 subjects. Published results in Journal of Psychopharmacology suggest clinically significant improvements in PTSD symptoms with a trend toward statistical significance, with an effect size similar to that of the U.S. study (Chabrol 2013). Twelvemonth follow-up data suggested that therapeutic benefits continued to increase in this subject population. In 2010, Dr. Mithoefer's study was completed and results published in Journal of Psychopharmacology showed clinically and statistically significant improvements in PTSD severity from the 20 subjects treated in this first pilot study in the U.S.). In addition, a long-term follow-up of people in the study suggested that therapeutic benefits were sustained over an average of 41 months post-treatment. Three subjects did experience relapses due to following stressful life events, and these individuals were eligible to enroll in a "relapse study" using a single, additional, open-label, MDMA-assisted psychotherapy session along with several non-drug psychotherapy sessions. The relapse subjects again experienced significant decreases in CAPSscores. After investing over $1.5 million and 25 years of dedicated effort, MAPS had completed two "Proof of Principle" pilot studies of MDMA-assisted psychotherapy in subjects with chronic, treatment-resistant PTSD. Both studies had average reductions in PTSD symptoms larger than that obtained in the studies of Zoloft or Paxil, and were conducted without producing any serious adverse events (SAE) or evidence of harmful effects. MAPS also negotiated several protocol amendments with the FDA and IRB. These changes increased from two to three the number of MDMA-assisted psychotherapy sessions, which were scheduled about three to five weeks apart with weekly non-drug psychotherapy for integration and preparation. We obtained permission to administer a supplemental dose of MDMA, half the initial dose given about two hours afterwards, to prolong the plateau of optimal therapeutic effects. MAPS also obtained permission to offer placebo subjects the option to enroll in the study a second time (Stage 2) with open-label, full-dose MDMA, starting after the two-month follow-up in the randomized study. This enables subjects to become their own controls in a cross-over design and helps with recruitment and retention of placebo subjects throughout the entire four-month treatment program. All of MAPS current phase studies are now designed to use supplemental dosing and include the option for placebo subjects to enroll in an openlabel Stage 2 after the primary end in point in Stage 1 is complete. In Stage 2, full-dose MDMA is administered. In 2013, we received approval to amend the protocol and use clinical titration in Stage 2 allowing either 100 mg or 125 mg doses; the decision is based on the experience of the subject and the opinion of the therapists. The appropriate supplemental dose is also offered during the session. With the completion of these studies, MAPS had the foundation of the Phase 2 program and a growing clinical department to support the work of conducting studies. PTSD, as a clinical indication and worldwide health problem, became our top priority for treatment with MDMA, in part because MDMA possesses unique pharmacological and psychological properties that make it well-suited for use as an adjunct to psychotherapy with PTSD patients. During the time since the studies first started, concerns about toxicity decreased. Toxicity concerns were further minimized as the therapeutic model was developed, and we were able to show that MDMA would be administered only a few times within a threeto four-month period, and only under the direct supervision of the co-therapist teams. This model is in contrast to existing medications, which are administered daily for months, or often indefinitely for PTSD, which is a chronic illness associated with high rates of psychiatric and medical co-morbidity, disability, suffering, and suicide. A significant minority of PTSD patients fail to respond adequately to established PTSD medications or psychotherapies, or respond in ways that are statistically significant but clinically inadequate. The completed studies demonstrated that the combination of pharmacotherapy and psychotherapy is more effective in treating PTSD than either pharmacotherapy or psychotherapy alone, and paved the way for the approval of further MAPS sponsored Phase 2 studies in Canada, Israel, and in the U.S. Progress in the Phase 2 program was slow. The Canadian MDMA/PTSD study was submitted to Health Canada in 2008, followed by many years of delay trying to meet Health Canada requirements for drug storage in the pharmacy. In order to move the Phase 2 program forward, and to focus our attention on the increasing numbers of U.S. soldiers returning home with PTSD after serving in Iraq and Afghanistan, MAPS again turned attention to the U.S., starting a study in 2010 conducted by Dr. Mithoefer and focusing on veterans. This study was the first to use three dose groups to increase knowledge of dose response while also improving study blinding. We extended the treatment population to veterans with war-related PTSD to see studies in different patient groups who differ in the cause of PTSD, specifically war-related PTSD as compared to PTSD resulting from sexual assault or childhood sexual abuse. It was quickly approved by the FDA and IRB, and our third study of 24 veterans with chronic treatmentresistant PTSD was under way, while the study in Canada remained stalled.
In January 2007, MAPS expanded its research when Dr. Peter Gasser submitted his protocol to the Swiss Ethics Committee for a MAPS-sponsored study to evaluate the safety and efficacy of LSD-assisted psychotherapy for subjects with end-of-life anxiety secondary to life-threatening illness. By November 2007, the study had received approval from the BAG (Swiss DEA), Ethics Committee (Swiss IRB equivalent), and SwissMedic (Swiss FDA equivalent). It was the first study to evaluate LSD's therapeutic applications in over 35 years. The study was also submitted to the FDA and in September 2008 the FDA issued a letter saying MAPS had resolved all the outstanding issues in the IND application to evaluate LSDassisted psychotherapy in the Swiss end-of-life/anxiety pilot study. The FDA was finally open to the possibility of the therapeutic potential of LSD-assisted psychotherapy and, with the IND in place, they would accept data from the Swiss study. This LSD study marked the culmination of the first phase of the psychedelic renaissance. It had taken several
History and Future of MAPS years for MAPS to reach this milestone with the FDA. LSD is the most controversial of all the psychedelic drugs, due to its association with the cultural rebellion of the 1960s, the implications of which are both celebrated and feared. The FDA had previously approved research with MDMA, psilocybin, DMT, ketamine, and mescaline. LSD was the last of the classic psychedelic drugs to be accepted as a research tool again. Acceptance by the FDA of the Swiss LSD protocol was a transformative moment. The first subject was enrolled on April 23, 2008, and in May 2011 the twelfth and final subject was treated. In August 2012, the last longterm follow-up was completed. On November 14, 2013, the results of the study of LSD-assisted psychotherapy for anxiety associated with life-threatening illness were submitted for publication in a peer-reviewed scientific journal. During this same period, MAPS became interested in supporting observational studies of ibogaine as a treatment for drug addiction. People with problem substance use have found that larger doses of ibogaine can reduce withdrawal from opiates and temporarily eliminate substancerelated cravings. The project started in Canada with Iboga House through the efforts of Sandra Karpetas and Valerie Mojeiko. The study was completed with clinics in Mexico, where 30 subjects were enrolled. Principal investigator Valerie Mojeiko and co-investigator Thomas Kingsley Brown, Ph.D., collected observational data from the opiatedependent subjects one year after ibogaine-assisted detoxification to evaluate the long-term outcomes of ibogaine treatment using the Subjective Opiate Withdrawal Scale and the Addiction Severity Index (ASI). Results highlight the need for follow-up after treatment. MAPS anticipates the data will be published in 2014. In 2011, a new observational investigator-sponsored study of ibogaine treatment for addiction began in New Zealand under the direction of Geoff Noller, Ph.D., at the University of Otago, NZ, conducted with assistance from MAPS. In 2012, additional progress on the MDMA/PTSD Phase 2 program was made when a study in Israel under Moshe Kotler, M.D., at Be'er Ya'akov Mental Health Center conducted with multiple co-therapist teams was started. In 2013, another U.S. study in Boulder with multiple co-therapist teams, led by Marcela Otalora, M.A., L.P.C, was started to reproduce results obtained in the initial studies. Both of these studies were approved and planning was under way when MAPS received news that all of Health Canada's requirements had been met by the pharmacy and the study was approved. The study in Canada is led by Ingrid Pacey, M.D., a psychiatrist and certified Grof Holotropic Breathwork practitioner, with cotherapist Andrew Feldmar, M.A., a Hungarian-Canadian psychologist. In 2013, 13 years from the first MDMA for PTSD protocol submission, all studies MAPS anticipated requiring to complete the Phase 2 MDMA/PTSD program, as well as progress in other indications with new psychedelics, were underway. In 2013, MAPS expanded research of MDMA into a new area, a Phase 2 study of MDMA as a treatment for social anxiety in adults on the autism spectrum. Social anxiety is characterized by fear of scrutiny and avoidance of social interactions, and frequently compounds the considerable social challenges experienced by adults on the autism spectrum. There are currently no FDA-approved pharmacological treatments for adults on the autism spectrum with social anxiety, and conventional anti-anxiety medications lack clinical effectiveness in this population. Based on anecdotal reports, MDMA-assisted therapy may be a suitable intervention for the treatment of social anxiety in adults on the autism spectrum, and warrants further investigation in a randomized controlled trial. Under the direction of Charles Grob, M.D., and Alicia Danforth, Ph.D., MAPS has received FDA and IRB approval and is preparing to conduct the randomized, double-blind, placebo-controlled exploratory pilot study with dose escalation to assess the safety and feasibility of MDMA-assisted therapy to treat social anxiety in 12 MDMA-naïve adults on the autism spectrum. Working on these studies, MAPS has grown and established itself as a non-profit pharmaceutical company actively developing and funding clinical trials with human subjects in accordance with guidelines set forth by the U.S. FDA, the European Medicines Agency, and the International Council on Harmonization (ICH/GCP). We have been impressed with and grateful for the supportive nature of the staff with whom we've worked at the FDA. The FDA will require research in accordance with the rigorous standards of scientific methodology that apply to all pharmaceutical drug development research, and will not obstruct studies because of irrational fears or political considerations. This is in line with how we pursue our research mission, by sponsoring scientific research using the same high standards of Good Clinical Practice (GCP) as any traditional pharmaceutical company but without the backing of their billions of dollars for drug development. In 2009, to further the development of the clinical research group, Amy Emerson, with over 15 years of experience in the pharmaceutical industry and a long-time MAPS volunteer, was hired to guide MAPS' expanding clinical research program. Past experience managing Phase 1, 2, and 3 clinical trials and regulatory know-how to work with the FDA helped to facilitate the growth of MAPS' clinical research program. MAPS' clinical team now implements the many complex and interlocking tasks necessary for conducting multiple clinical trials under the jurisdiction of multiple regulatory agencies. Standard Operating Procedures (SOPs), data collections procedures, compliant databases, site and employee training programs, and monitoring processes have been implemented. The clinical group has grown and now includes two part-time medical
History and Future of MAPS monitors, an experienced lead Clinical Research Associate (CRA), contract CRAs, and a data management group. In 2013, web-based data collection and remote monitoring capabilities including eCRF technology were added through a collaboration with Medrio to bring MAPS in line with data collection procedures at traditional, for-profit pharmaceutical research companies. Creating a clinical research department with the same format and procedures as a for-profit corporation allows MAPS to plan the independent multi-center international studies necessary for drug development without the concern of maximizing profits or being confined to a university setting. MAPS is able to select independent qualified investigational sites, design double-blind randomized protocols, obtain governmental approvals, raise funds, oversee study conduct, monitor all data and procedures, and produce reports on our psychedelic research. In addition to the standard monitoring required in GCP, we have also established a standardized treatment manual and training program for the therapists, as well as a video adherence program to ensure required elements of our manualized psychotherapy are applied across teams during the study visits. During the process of conducting our Phase 2 studies, we are in parallel training therapists to administer psychedelic drugs in therapeutic settings in preparation for Phase 3 studies, expanded access studies and, ultimately, post-approval treatments. To further the training of the co-therapist teams, a Phase 1, placebo-controlled, doubleblind, randomized cross-over study that allows MAPS to administer a single MDMA-assisted psychotherapy session to up to 20 therapists as part of their training was submitted to the FDA. After making requested FDA protocol changes, including evaluations of the psychological effects of MDMA administered to healthy volunteers in a therapeutic context, the study was allowed to proceed. This study, designated MT-1, is now underway. Today, we have a drug development infrastructure that is solid and flexible enough to take us through Phase 2 and 3 clinical trials of MDMA for PTSD, and to research additional disease indications and drugs. We have a clinical team of 17 staff, including interns and contractors, four active MDMA/ PTSD sites conducting five studies, with another site for MDMA in adults on the autism spectrum with social anxiety coming starting early in 2014. Since 2007, there have been 11 FDA-approved protocols across three clinical programs (two MDMA programs, LSD and marijuana, though our marijuana research has been blocked by NIDA, which has refused to provide the required DEAlicensed marijuana). Over the next year, we may have seven studies at six sites running simultaneously in the MDMA program for multiple indications, including PTSD, end-oflife anxiety and pain related to cancer, and social anxiety in adults on the autism spectrum. Much is needed before we complete the work on the MDMA/PTSD program. Phase 2 trials gather preliminary information on the safety and efficacy of the drug to treat the condition under investigation in populations of 12 to 200 subjects, and Phase 3 trials gather conclusive evidence regarding efficacy and safety in larger populations of 250 to 2000 subjects. At least two Phase 3 studies are typically required to prove safety and efficacy before permission for prescription use can be approved. While working to complete the Phase 2 studies, Phase 3 planning will start, including work to identify a GMP (good manufacturing process) manufacturer of MDMA, as well as training of Phase 3 investigators. We anticipate completing the primary end points in our Phase 2 studies in late 2015. At this point, we will apply to FDA for programs that may help accelerate the development of MDMA through Phase 3 and prioritize the final review for approval. The FDA has four programs for which we can apply. The programs are in place to facilitate development and review of new drugs that address unmet medical needs in the treatment of a serious or life-threatening condition. These programs are fast track, breakthrough therapy designation, accelerated approval, and priority review. We are not sure which of the programs we will qualify for, but based on the guidance for programs, a case can be made that chronic treatment-resistant PTSD meets the requirements. The programs were put in place to ensure that therapies for serious conditions are approved and available to patients as soon as it can be concluded that the therapies' benefits justify their risks. They are designed to provide the sponsor more access to FDA, including early consultation to generate efficient trial design, potentially relying on smaller, well-controlled studies for evidence of effectiveness. The regulations recognize that patients and physicians are generally willing to accept greater risk (and uncertainty about benefit) for a treatment for a serious condition where there is an unmet medical need. If MAPS is able to obtain designation in one or more of these programs, it could shorten the overall time to approval. We plan to have our End of Phase 2 meeting with the FDA in 2016 and, at that time, we will know if we have been accepted to any accelerated development programs and will finalize our Phase 3 strategy with FDA. Protocol design and cost estimates are refined following the End of Phase 2 meetings; however, we estimate that there will be two Phase 3 studies with 200 subjects per study across multiple sites, and the studies will be conducted in a staggered fashion from 2016-2021. Ideally, one Phase 3 study would take place in about 15 sites in the U.S. and Canada, and one in about 15 sites in Europe and the Middle East. In parallel with Phase 3, MAPS will request FDA permission to conduct Expanded Access (Compassionate Use) studies with cost recovery for people who do not qualify for the Phase 3 program. To meet the needs of the Phase 3 program, consisting of two Phase 3 protocols as well as an expanded access program, we will need to train about 300 therapists in 2015 through 2019. The main training is a five-day intensive with experienced therapists from our Phase 2 program. After completing the five-day training, some therapists will have the option of enrolling in MT1, our Phase 1 MDMA versus Placebo crossover safety study that is done in a therapeutic setting and is limited to therapists who have completed the training. If a drug proves to be safe and efficacious in two Phase 3 studies, the sponsor of the studies submits a New Drug Application (NDA) to the FDA and/or the European Medicines Agency (EMEA), which reviews the application for possible approval as a prescription medicine. We anticipate the decision regarding MDMA as a prescription medication in 2021. Should approval be granted, the addition of MDMAassisted psychotherapy as a treatment option for PTSD could make a major contribution to improved mental health for PTSD patients around the world and would facilitate the development of MDMA and other psychedelics for a wide range of other psychotherapeutic uses.
Every year, millions of individuals use psychedelics outside of supervised medical contexts, many of them for the first time. Many psychedelic users are unprepared to tend to a psychedelic-induced difficult experience if one were to arise. As part of our efforts to minimize risks related to the non-medical use of psychedelics, MAPS began offering support at events in 2001 for anyone having a difficult psychedelic experience who might benefit from a supportive space with trained volunteers. These harm-reduction services have helped to reduce the number of psychedelic drug-related arrests and hospitalizations. We also provide training at the beginning of each event, and by bringing together volunteers with different levels of experience, we create an environment analogous to a teaching hospital. These trainings have become a valuable opportunity for many aspiring psychedelic therapists who don't otherwise have opportunities to practice their skills sitting for someone in a psychedelic state. MAPS' efforts first began at an event called Hookahville in Ohio in 2001, followed by the Boom Festival in Portugal in 2002. The Portuguese government decriminalized all drugs in 2001, after which MAPS helped establish KosmiCare. Today, BOOM's KosmiCare is the world's closest model to a post-prohibition world, with on-site, thin-layer chromatography pill testing and a centralized space sponsored by both the festival and the local government. KosmiCare works with the local hospital, fire department, paramedics, security, and regional harm-reduction teams to provide compassionate support for anyone having a difficult psychedelic experience. In 2003, MAPS volunteered at Burning Man with Black Rock Rangers who were sympathetic to the need for harm-reduction services. We trained many Sanctuary volunteers, and the collaboration grew over the five years that followed. Unfortunately, as the U.S. Drug War continued to escalate, so did the perverse criminalization of harm-reduction services and, over time, MAPS' involvement in Sanctuary at Burning Man came to an end, while KosmiCare, in Portugal where drugs are decriminalized, has flourished. During this time, MAPS released a short film entitled Working with Difficult Psychedelic Experiences that gives an introduction to the principles of psychedelic therapy and harm reduction. The educational video teaches psychedelic drug users how to minimize psychological risks and explore the therapeutic applications of psychedelics. The video demonstrates examples of when and how to help another person make the most out of a difficult experience with psychedelics. The second iteration of MAPS' harm-reduction program, the Zendo Project, began in the summer of 2012, in our own village at Burning Man in the Nevada desert. With volunteer support, it became obvious that the Zendo provided a much-needed service amongst all of the lights, art, and music of the 65,000-person, week-long event. After our successful efforts in 2012, we expanded our services to a circuit of international events including Envision (Costa Rica), AfrikaBurn (Tankwa Karoo, South Africa), and Bicycle Day (San Francisco), as well as smaller events in California and Colorado. We returned to Burning Man in 2013 to see the project expand as we collaborated with the Full Circle Tea House, a sister harm-reduction space founded by Annie Oak. The Tea House provides a quiet space that supports conversation and integration, while the Zendo is better equipped to handle more serious cases. We shuttled volunteers and guests between the Zendo and Tea House in our art car, Rainbow Bridge, donated by MAPS Board Member David Bronner. Various Burning Man Rangers, medical staff, and local police visited the Zendo throughout the week to find out more about our services and thank volunteers for their efforts. As MAPS' research program has expanded, so has our obligation to educate the community about the risks and benefits of psychedelics, and to help mitigate risks involved with psychedelic use at events. MAPS has also helped support organizations like Erowid and Bluelight, which provide honest drug education through their websites, both of which receive over 100,000 visitors daily. We strive to reduce the public's fear of psychedelics and encourage honest and responsible conversations about their use. Psychedelic harm reduction is an exercise in selfreliance at the level of the community. As we show that we can help one another, we also reduce public fears surrounding psychedelics, a crucial step in reintegrating these tools and the experiences they can engender back into society.
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