Volunteers also would be required to be functioning at a relatively high level, working or in school, and in stable relationships. This would help assure me that they were grounded enough in everyday reality to handle what would be a rigorous and demanding study. I wanted them to have support from sources other than the research team to whom they could turn if they needed help outside of the sessions.
There would be careful medical and psychological screening of the volunteers. Women must neither be pregnant nor likely to become pregnant, and we would test urine for recreational drugs before every study day.2
In reviewing the techniques for measuring psychedelics’ psychological effects, I concluded that all previous questionnaires presumed their effects to be unpleasant and psychotic. A newer scale with less of a bias, based on responses in people who liked psychedelics, might provide a broader perspective on their effects. I proposed interviewing as many recreational DMT users as I could for this purpose. These individuals would provide a broad overview of DMT’s effects, which would form the basis of a new rating scale. As the research progressed, I could appropriately modify the questionnaire.
It also was necessary to develop an assay, or method of measuring, for DMT in blood. There were several older assays from which to choose, and we would try our hand at whichever seemed easiest and most sensitive. The most likely method was one used by researchers at the National Institute of Mental Health, the same group that had written the “decent burial” paper on DMT.
Based upon a 1976 study describing hormone effects of DMT in humans, we calculated that twelve volunteers were enough to show statistically significant differences between doses of DMT and an inactive saltwater placebo. Most dose-response studies of any new drug give volunteers one “high” dose, one “low” dose, and one or two “medium” doses in order to describe the entire spectrum of effects. I wanted to give as much DMT as possible, so I decided that each volunteer in the study would receive a placebo and four doses of DMT—one high, one low, and two medium.
Volunteers would receive the different DMT doses in a randomized and double-blind manner. Randomized means that the sequence of doses is in no particular order, as if a roll of the dice determined which day would involve any particular dose. Clifford Qualls, Ph.D., the University of New Mexico General Clinical Research Center’s biostatistician, generated a random sequence of the required doses on his computer, sealed it in an envelope, and delivered it to the pharmacy for their use. Double-blind means that neither the volunteers nor I would know which dose any volunteer was to receive on any particular day. Only the pharmacist possessed the list detailing the unique ordering of doses for each person.
The purpose of randomized double-blind studies is to reduce the role of expectation in affecting results. In chapter 1 I referred to the classic study demonstrating the power of expectation in determining drug effects. Similarly, if volunteers knew when they were going to get a low dose of DMT, their responses might be biased. They might react in a way consistent with what they expected a low dose to be like, rather than what actually happened, be it in reality placebo or a medium dose they received that day.
In addition, before entering into a complicated double-blind study, we thought it best to begin a volunteer’s involvement in the research by first giving them two “non-blind” doses of DMT. An introductory low dose of 0.05 mg/kg would let people settle in to the research setting without having an effect so strong that it might disorient them. A subsequent high dose, 0.4 mg/kg, would let volunteers experience the greatest level of intoxication they would ever reach on any subsequent double-blind day. We called this the “calibration dose.” If someone received their first high dose in the middle of the full study but didn’t know it was the most they’d ever get, they might drop out for fear of getting even more of an effect on another dose. With a non-blind high dose, volunteers had the option of dropping out of the study right away, before we had begun collecting a lot of data on them. So subjects actually would receive six doses of DMT—two non-blind and four double-blind.
Tests of new drugs always include a placebo, and our study would, too. Placebo-controlled studies further help tease apart the effects of anticipation from those of the drug. Placebo comes from the Latin, meaning I shall please, or to paraphrase, I shall meet your expectations. Most of us think of a placebo as an inert substance, what we refer to as inactive placebo. Sugar pills are the best-known example of inactive placebos. In our DMT studies, the inert placebo was sterile saltwater, or saline.
Practically speaking, it is extraordinarily difficult to keep doubleblind, placebo-controlled studies “double-blind.” Effects of active drugs are usually much more obvious than those of inactive saltwater or sugar, and both research subjects and staff almost always can tell the difference.
However, in this first dose-response DMT project, we wanted to use a placebo to see if volunteers and we could distinguish between the lowest dose of drug and none at all. In that capacity, the placebo day served a valuable function.3
There were drawbacks to this design. Volunteers usually felt substantial anxiety before getting their first double-blind dose. Was today going to be another shattering high dose? Or could they relax? If it was apparent that the first few double-blind sessions did not involve the large dose, anxiety also built up before later sessions in a way that didn’t for those who got the high dose out of the way on an earlier day. While the randomized order in which all volunteers received their full complement of doses probably statistically “evened out” this factor, at a human level there was a price to pay.
I also addressed how we would manage psychological and physical adverse effects. The first line of response to a panic reaction would be talking people down using reassurance and support. If this didn’t work, we would use a minor tranquilizer, such as injectable Valium; we would use a injection of a major tranquilizer, like Thorazine, if anyone got completely out of control. For allergic reactions, such as wheezing or a severe rash, an intravenous antihistamine was available. If blood pressure went up too high, nitroglycerin tablets under the tongue, much like the way people with angina heart pain use them, would be effective.
I attached a list of several dozen references supporting the ideas I had laid out. These included papers from the first wave of human psychedelic research. There were articles describing what we knew about psychedelics’ effects on animals and on serotonin receptors. Anticipating concerns about safety, I pointed to my previously published review of adverse effects of psychedelics. In it, I suggested that if people were mentally healthy, well prepared, and closely supervised before, during, and after the experience, the chances of serious and prolonged psychiatric side effects were extremely low.
Copies of the proposal went to all the boards that had control over human drug abuse research, including the Human Research Ethics Committee at the University of New Mexico, the U.S. Food and Drug Administration, and the U.S. Drug Enforcement Administration. The study would occur at the University of New Mexico Hospital’s General Clinical Research Center, so I sent a copy of the proposal there as well. The Research Center might cover the costs of measuring the large number of blood samples for DMT and hormone levels, so I also submitted a budget to their laboratory.
Now for the hard part: Getting everyone responsible for overseeing and funding this project to agree it was safe, was worth doing, and deserved money.
6
Labyrinth
In the United States, the Controlled Substances Act of 1970 exists to protect the public from potentially harmful drugs. This law also is a barrier preventing access to those drugs by the clinical research community. It is the labyrinth through which anyone who wishes to perform human research with psychedelic drugs must pass.
The Controlled Substances Act placed all drugs into “schedules,” depending on their “abuse potential,” “currently accepted medical use,” and “safety of use under medical supervision.” Schedule I drugs, the most restricted, are “highly abusable, l
ack medical utility, and are unsafe under medical supervision.” Over the objections of dozens of high-level psychiatric researchers, including Dr. Daniel Freedman, Congress placed LSD and all the other psychedelic drugs into Schedule I.
Schedule II includes drugs like methamphetamine and cocaine. They possess high abuse potential but some medical utility—cocaine as a local anesthetic for eye surgery, and methamphetamine for the treatment of hyperactive children, for example. Codeine is in Schedule III, because this commonly used painkiller has abuse potential “less than” Schedule I and II drugs, as well as fewer and less severe adverse consequences when used under medical supervision. Schedule IV drugs like Xanax and Valium possess abuse potential “less than” Schedule III and have “limited” problems associated with their medical use.
In the case of the psychedelics, the high abuse potential that lawmakers noted was not the compulsive, out-of-control use commonly seen with drugs like heroin and cocaine. Psychedelics don’t cause craving or withdrawal. In fact, one of their hallmarks is that they produce almost no effects after three or four daily doses, and abruptly stopping them causes no withdrawal. Rather, it was their acute effects that were so profoundly disruptive and at times disabling. Because of those highly destabilizing effects, Congress decided psychedelics must be tightly regulated.
Clinical research scientists in the 1950s and 1960s recognized and usually took into account the unique dangers of LSD and other psychedelics. By doing so, they could successfully prevent or quickly deal with any adverse psychological reactions to these drugs. However, uncontrolled public use, and media-intensive breaches in research protocols by Leary and his colleagues at Harvard, brought the expected responses. These drugs were causing highly publicized problems, and the door had to be shut for damage control.
In order to turn this tide of abuse, Congress emphasized psychedelics’ negative properties at the expense of their positive or neutral ones. What one day was “safety under medical supervision” became “lack of safety under medical supervision” the next. “Medical utility” as research and training tools and aids to psychotherapy quickly changed into “no currently acceptable medical use.”
It was into this black hole I peered as I prepared to shepherd the DMT protocol through the regulatory system.
The process began in December 1988. I kept a log during the next two years of every phone call, letter, meeting, fax, and discussion related to 89-001, the DMT protocol. From my notes, I summarized and extracted the most relevant information obtained from these interactions and wrote them up in 1990, immediately after getting permission to begin the study. I referred to this article as the “what if I’m run over by a bus?” paper. It was important that other people knew how to wind their way through this maze. It was possible, and there was a route through it. If nothing else came of the DMT project, I wanted to leave behind this map for success.1
The initial guardians of the regulatory realms were two University of New Mexico School of Medicine committees: the Research Center’s Scientific Advisory Committee and the Human Research Ethics Committee.
The General Clinical Research Center Scientific Advisory Committee dealt with the science behind my proposal. Fellow researchers on the panel looked at the scientific merit of the study and offered remedial suggestions. They also decided whether to allow its performance at the Research Center, and whether to pay for the many blood tests I requested. Because I had spent the last two years running the human melatonin project at the Research Center, I was a member of this committee at the time.
The Human Research Ethics Committee dealt with the safety of my proposed study. Its duties were to make sure the project had an acceptable safety profile, and that the informed consent document clearly spelled out the nature of the study and its risks.
It was incredibly fortunate that the chairman of the crucial ethics committee was a firm believer in libertarianism; that is, that the individual takes precedence over the state. He believed that educated people could make up their own minds. His motto, as head of one of the first and most important review panels, was great encouragement: “We’re not here to play God.”
The informed consent document is a crucial element of human research. In it, the researcher describes the objectives of the protocol, and why he or she is performing it. The consent states exactly, and in mind-numbing detail, what to expect from participating. It lists the potential risks and benefits associated with volunteering, details how the research team will manage risks, and notes that volunteers will receive all necessary treatment for adverse effects free of charge. The consent reminds the potential research subject that participation is totally voluntary and ongoing. He or she may withdraw at any time, for any reason, with no penalty or withholding of necessary care. In case a volunteer feels unfairly treated, the informed consent document provides names and phone numbers of people he or she can contact in order to complain.
While negotiating with the university committees, I also began working with the two United States federal agencies that formed the final, and more formidable, regulatory barriers. They held in their hands the ultimate decisions.
The first was the U.S. Drug Enforcement Administration (DEA). They had a local Albuquerque office, but their headquarters were in Washington, D.C. The DEA would decide if I would be allowed to possess DMT. If granted, this permission would take the form of a Schedule I permit.
The other federal regulatory agency was the U.S. Food and Drug Administration (FDA), which also is based in Washington, D.C. The FDA would decide if it was safe and worthwhile to give DMT to human research volunteers in my study. If granted, the FDA’s permission would take the form of an Investigational New Drug (IND) permit.
When submitting the protocol to the university committees, I told them the study would not begin until the FDA and DEA both gave their permission to administer DMT. However, these federal agencies first required local approval.
The informed consent document would be a major hurdle, and I was direct with the ethics committee about the expected effects of DMT. I did not want to lull volunteers into thinking it would be an easy day, but I also did not want to scare them away by emphasizing potential negative effects. On page two of the consent, this is what the volunteer read:
I understand that the primary effects of this drug are psychological. Visual and/or auditory hallucinations or other perceptual distortions may occur. My sense of time may be altered (short lengths of time passing slowly or vice versa). I may experience very powerful emotions, pleasurable or unpleasant. Opposite feelings or thoughts may be experienced at the same time. I may be extremely sensitive and aware of the environment; on the other hand, I may not notice anything at all in the environment. It may feel like my body and mind have separated. Feelings of impending or actual death or confusion may occur. Euphoria is very common. The onset of the experience is rapid, the experience being very intense with the higher doses within 30 seconds. It peaks within 2 to 5 minutes and is usually felt as only a mild intoxication within 20 to 30 minutes. I will quite likely feel like my normal self within an hour after the injection.
Regarding risks, the consent form was brief, but honest:
The main effects of DMT are psychological and have been described above. These usually last less than 1 hour. Rarely, emotional reactions to these effects may last longer (i.e., 24 to 48 hours). I can stay at the Research Center as long as necessary to regain my equilibrium, including overnight if desired. . . . DMT is physically safe. Mild to moderate brief increases in blood pressure and heart rate occur.
It would have been premature and inappropriate to suggest in the informed consent that participation in the DMT study offered any potential benefits. While I knew volunteers probably would enjoy their DMT experiences, this was different from suggesting that I was providing treatment for a diagnosable condition. Thus, the consent went on to say:
There are no benefits to me personally as a result of participating in this research. However, the potential benefits
are a greater understanding of the mechanism of action of hallucinogenic agents.
Within a week of submitting the DMT study, the ethics committee asked me to include the phrase “no currently accepted medical use” in the informed consent’s introductory paragraph. I replied by suggesting this phrase would unnecessarily frighten off prospective volunteers. In addition, if I ever did get permission to run the study, the phrase would no longer, strictly speaking, be true. It then would have currently accepted medical use; in this case, as a clinical research tool. They accepted this answer.
Confidentiality and anonymity were important issues I had to work out with the ethics committee, the Research Center, and the university hospital administration. Nearly all the DMT volunteers had jobs and families, neither of which they cared to endanger by admitting to the use of illegal drugs. Confession to having broken the law was a prerequisite for enrolling in the study, since only experienced psychedelic drug users could participate. I met with staff from the hospital’s medical records department and admitting offices, the head nurse and administrator of the Research Center, and the hospital’s attorney. Together we worked out a complicated but effective arrangement.
Records of the medical screening performed in the outpatient clinic of the Research Center would hold important medical information. This might be extraordinarily helpful if the volunteer at some future date developed health problems for which the treating physician needed baseline values, for example, regarding heart function. Therefore, we placed the volunteer’s real name on the chart containing results of the physical examination and screening laboratory tests. In this chart was no mention of drug use, nor a linking of the volunteer to my drug studies.
DMT: The Spirit Molecule: A Doctor's Revolutionary Research into the Biology of Near-Death and Mystical Experiences Page 11