The following is an excerpt from an article, MDMA Research: A New Beginning by Rick Doblin which the will appear in the forthcoming 2nd. Edition of Ecstasy: The MDMA Story by Bruce Eisner. It is an account of what seems to be an amazing change in attitude toward psychedelic research.

For the first time in fourteen years, on July 13 and 14, 1992 in Bethesda, Maryland, the National Institute on Drug Abuse (NIDA) convened a Technical Review meeting on “hallucinogens”. In an impressive display of interagency synchronization, NIDA's Technical Review immediately preceded the July 15 meeting of the FDA's Drug Abuse Advisory Committee. The FDA Committee reviewed general policies regarding “hallucinogenic” research and specific issues concerning the MDMA research protocol of Dr. Charles Grob which MAPS helped to develop.

The consensus of the experts at these two meetings was that there were significant scientific benefits to be gained by administering psychedelics to human subjects in order to research the brain's basic physiological mechanisms and their psychological correlates. Most importantly, the experts thought that these scientific benefits outweighed the estimated risks to subjects and society from conducting the research. The FDA's Drug Abuse Advisory Committee recommended that psychedelic research protocols be required to meet the rigorous scientific standards that the FDA applies to studies involving any other drugs.

A brief review of these meetings is important to help explain why the FDA finally approved human studies with MDMA.

The NIDA Meeting

Fourteen years had elapsed since NIDA had last scheduled a Technical Review on “hallucinogens.” This lengthy hiatus was largely due to the paucity of scientific advances, since human studies had been essentially prohibited by the government. There were, however, several important reasons for NIDA to have convened a Technical Review at this time. Unlike human studies, animal studies had been permitted all along and had yielded some tantalizing clues about the basic functioning of the brain, in particular of the serotonin neurotransmitter system. Furthermore, out of a frustration with the success rates of traditional drug treatment methods, NIDA's Medications Development Division was beginning to investigate the possible use of psychedelics, specifically the African root ibogaine, in the treatment of drug addiction. NIDA was also concerned about the use of psychedelics outside legal contexts which had not disappeared under ever tougher drug laws but is reported instead to be on the increase, according to NIDA's Household Survey data and DEA reports.

On July 13 and 14,1992, NIDA gathered together almost twenty scientists for a two-day meeting. Among these were three researchers familiar to many MAPS members: Rick Strassman, a psychiatrist at the University of New Mexico who has conducted basic research with DMT, Sasha Shulgin, an independent researcher who co-authored with his wife Ann the book PIHKAL, and David Nichols, a medicinal chemist at Purdue University who manufactured the MDMA that was used in the pre-clinical animal studies used by MAPS to open its FDA Drug Master File on MDMA at the FDA.

Rick Strassman focused on findings from his work with DMT in eleven human volunteers. He reported that it took him about two years of effort to receive final FDA approval to evaluate DMT's physiological effects and develop a questionnaire to measure the psychological effects of DMT and other hallucinogenic drugs. His groundbreaking research clearly demonstrated that human studies with psychedelics could be conducted safely and that valuable scientific data could be generated.

Sasha Shulgin's presentation reviewed the work he and his wife Ann have written about in PIHKAL in which he synthesized hundreds of novel psychoactive compounds and tested them for activity in himself and a team of twelve research associates. He emphasized the incredible subtlety and unpredictability of the relationship between the structure of a compound and its psychoactivity. He cited instances where data from animal studies was contradicted by data from human reports and made an impassioned plea for more human studies. He mentioned the use of psychedelics to produce experiences of a religious, mystical nature and asked the assembled researchers and government officials to tell him how they would ever get rats to provide sufficient data on those matters. The response was, of course, only laughter. One subsequent speaker, however, prefaced his talk on the effects of psychedelics in animals by acknowledging the courage of Sasha Shulgin and Rick Strassman in gathering human data, which he felt provided essential clues in interpreting the animal data.

At the conclusion of the meeting, Dr. Geraline Lin, the chairperson of the meeting, asked the group for a summary of their sense of the current state of research and of future directions to explore. The scientists felt confident that animal models were useful in helping to predict the psychoactive characteristics of novel compounds and in understanding the structural and functional aspects of the brain's serotonin neurotransmitter system. However, most scientists felt that animal studies had limited relevance unless correlated with human data and they were generally supportive of further studies in humans.

The FDA's Drug Abuse Advisory Committee Meeting

Since the Federal Advisory Committee Act of 1972, the FDA has used expert advisory committees to provide guidance and advice on important matters coming before it. Such matters include the final review of data concerning the approval of a drug for marketing (called a New Drug Application or NDA) and more rarely on the approval of a research protocol (called an Investigational New Drug application or IND). The FDA has created about 17 different advisory committees, each composed of eleven members who serve for several years and meet about once or twice a year. The meetings are always tape recorded, often filmed, and transcripts are made of all comments. Though the FDA retains final authority to make decisions, the recommendations of the committee are almost always taken. The most widely publicized recent use of an FDA Advisory Committee concerned the review of the safety of breast implants.

After almost two years of preparation, Dr. Charles Grob had submitted to the FDA's Pilot Drug Evaluation Staff (PDES) a protocol designed to investigate the use of MDMA in the treatment of pain and distress in end-stage cancer patients. The PDES suggested several significant changes in the protocol design and choose to present the IND, along with their critique and Dr. Grob's response, to its Drug Abuse Advisory Committee.

The PDES also gave the Advisory Committee the task of considering policies for “hallucinogenic” research in general. Within the last year, the PDES has approved several applications for psychedelic research with DMT and LSD and will soon be presented with applications to research ibogaine and psilocybin. Since there is renewed scientific interest in the field of psychedelic research, the PDES felt a need for the guidance and backing provided by the Advisory Committee.

Procedurally, the Committee met in open session to discuss general policies toward psychedelic research. It then went into closed session for the discussion of the MDMA protocol, allowing in only other government officials from NIDA, DEA and the White House Office of Drug Control Policy (the Czar's office) and participants specifically invited by Charles Grob.

To aid the Committee in its deliberations, the PDES arranged for six expert witnesses to address the committee in open session. These included MDMA neurotoxicity experts Dr. Lewis Seiden (U. of Chicago) and Dr. George Ricaurte (Johns Hopkins), esteemed researchers Dr. Reese Jones (UCSF) and Dr. Murray Jarvik (UCLA), and Rick Strassman and David Nichols, both of whom were also at NIDA meeting. Charles Grob was given an opportunity to address the Committee during the closed session concerning details of the MDMA protocol design.

From the opening moments of the meeting to the conclusions reached at the end, the participants were privileged to witness the triumph of science over ideology. The first person to address the Committee was NIDA's Dr. Geraline Lin. She reported on the Technical Review meeting and indicated that the participants had reached consensus on the need to conduct human studies with “hallucinogens” for two basic purposes, to investigate their biological correlates and therapeutic utility. She stressed the need for well-controlled, objective human studies that would enable regulators to balance therapeutic uses with risks, toxic and otherwise.

The real star of the meeting was, however, Dr. Reese Jones. He began cautiously by pointing out the problems involved in obtaining genuine informed consent from research subjects. He recommended that the therapists conducting the studies not conduct the initial subject screening because the delicate nature of any therapeutic relationship they might develop with the potential subject could give them undue influence. He pointed out the difficult issue of ensuring that training psychiatrists conducting psychedelic research be properly trained in the administration of psychedelics.

He then switched gears and reminded the Committee that psychedelic researchers are pioneers without the large resources of pharmaceuticals companies behind them. He urged the Committee not to demand that they conduct the ideal protocols the first time out, but rather let them begin by conducting more limited but nevertheless scientifically rigorous studies. He strongly criticized alarming interpretations of MDMA neurotoxicity data. He conjectured that since MDMA-related serotonin depletion in animals was seemingly without harmful behavioral and physiological correlates and human users reported beneficial effects from MDMA, serotonin depletion, if it even occurred, could as easily be considered advantageous as dangerous. He quipped that a pharmaceutical company with a drug that produced beneficial effects that people desired with possible permanent brain changes would prominently feature the brain changes in advertisements and make them a major selling point.

Rick Strassman spoke briefly about his DMT work, summarizing the data that he reported more fully at the NIDA meeting. He primarily made the point that human studies could be safely conducted.

When George Ricaurte discussed some of his concerns about neurotoxicity, he was aggressively questioned by Reese Jones who opined that MDMA neurotoxicity reminded him of the LSD chromosome damage scare of the 1960's which helped generate fear of LSD and contributed to the cessation of LSD research but was later proved groundless. This interchange was rather dramatic, a snippet of which was broadcast around the world in CNN's television news story on the meeting. The MDMA Protocol Discussion

The meeting then went into closed session. It began with a presentation by Charles Grob. His sincerity and his careful preparation were evident to the Committee. He had chosen to strongly rebut some of FDA's protocol critiques, a delicate task. In addition, he was asking to make a major change in the protocol and proposed separating the study into two parts, a neurotoxicity safety study in normals and an efficacy study in cancer patients. Though he was willing to conduct spinal taps on cancer patients if the FDA insisted (the oncologist working on the study had no objections to this), he much preferred not to. He argued that the neurotoxicity data would be better in any case if he eliminated the confounding effects of the patient's terminal illness and instead used healthy normals for that study.

Dr. Curtis Wright, the FDA official directing the review of the protocol, asked George Ricaurte what he thought of the extent of the neurotoxic risk to the proposed subjects from MDMA. After considered reflection, George Ricaurte stated that the doses called for in the experiment would not pose a large risk to the subjects, either in the cancer patients or the normals.

The Committee then discussed various aspects of the protocol and suggested several changes. Curtis Wright suggested that the Committee not get bogged down in details, which the FDA staff could better handle at a later time, but should consider two basic questions. First, should human studies with MDMA and other psychedelics be conducted? And if so, was psychedelic research sufficiently unique such that a new set of standards and procedures needed to be created to evaluate the studies?

The Committee decide that the benefits of gathering scientific information about MDMA and other “hallucinogens” through the use of human studies warranted the risks to subjects and society of conducting such research. The Committee also felt that research into the medical uses of “hallucinogens” was most appropriately regulated in the same manner and held to the same rigorous scientific standards for safety and efficacy as medical research with any other drug that the FDA would be asked to review. Finally, the Committee suggested that the FDA assist Charles Grob in the design of two studies, a standard Phase 1 study to investigate the safety of MDMA in healthy subjects and a standard Phase 2 study to investigate the efficacy of MDMA in the treatment of pain and distress in end-stage pancreatic cancer patients.

THE PHASE 1 MDMA RESEARCH PROTOCOL

In late October, 1992 the FDA informed Dr. Charles Grob that his application to conduct a basic Phase 1 human trial of the physiological and psychological effects of MDMA had been approved. This decision of the FDA marked the first time that it had ever approved human studies with MDMA, five previous applications had all been denied citing concerns over MDMA's neurotoxic risk.

The FDA's historic decision to permit human volunteers to be a dministered MDMA in an experimental context was based on several key factors. Foremost among them was the July, 1992 recommendation of the FDA's Drug Abuse Advisory Committee to approve human studies with MDMA. Also of critical importance was recent scientific evidence suggesting that the risk of MDMA neurotoxicity from therapeutic doses was smaller than previously feared, coupled with the record of safety established by the small group of Swiss psychiatrists who had legally administered MDMA to their patients without observing any evidence of MDMA-related harm. Finally, the FDA was influenced by the scientific interest in MDMA research which had not diminished since MDMA had been made illegal but rather had grown stronger and more vocal.

As the FDA's Drug Abuse Advisory Committee recommended, MDMA research was to be held to the same rigorous scientific standards and procedures that were applied to any other pharmaceutical drug. In practice, that essentially meant that only data gathered from FDA-approved studies would be considered in assessing MDMA's risks and benefits. All of the knowledge gained by the therapeutic community prior to MDMA's scheduling in 1985 was basically to be ignored. In effect, researchers were instructed to design studies that would gather preliminary safety data before any therapeutically oriented studies could begin, regardless of the fact that tens of thousands of doses or more of MDMA had been already used safely in therapeutic contexts.

After FDA permission was in hand, Dr. Grob was still required to apply for three additional approvals prior to the commencement of the experiment. The first additional approval is from the UC Irvine Human Subjects Committee, which needed to review the revised experimental protocol. While it had approved the earlier study design of MDMA in the treatment of cancer patients, it also needed to specifically approve the Phase 1 study, notwithstanding the fact that it was a smaller and much less risky study than the cancer patient study. This approval was granted on December 11, 1992.

With FDA and UC Irvine Human Subjects Committee approval in hand, Dr. Grob was able to make the final two applications. The first is to the Drug Enforcement Administration, which checks to make sure the researchers themselves can be trusted to handle Schedule 1 drugs and checks the hospital's storage facilities for the drugs. The second is to the California Research Advisory Panel, which reviews all Schedule 1 research carried out in California. Only the State of California has this layer of additional review. Permissions from both these agencies are expected by mid-January, 1993.

Rick Doblin is President of the Multidisiplinary Association for Psychedelic Studies Maps, Inc. (MAPS), a membership-based non-profit and educational corporation that is working to develop MDMA’s medical potential as well as that of other psychedelics. Rick has a Masters Degree in Politics from Harvard University. He is an energetic young Irishman with a single minded goal: to promote research with psychedelic compounds in order to show their medical and therapeutic benefits.