Human Hallucinogenic Drug Research in the United States; A Present-Day Case History and Review of...

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Human Hallucinogenic Drug Research

in the United States

A Present day Case History

and Review of the Processf

RickJ. Strassman, M.D.*

Abstract - Legi timate human research wi th ha llucinogenic drugs, al though of great the-oretical and practical interest, involves daunting regulatory hurdles that have discouragedinvestigators from attempting such work. Using the example of the author's own application

for and receipt of federal permission to administe r N,N -dimethyl tryptamine (DMT) tohumans, thi s article reviews the application process, obstacles and thei r solutions, andthe local and federal issues involved. Further human research with hallucinogens is possibleif a persi stent and collaborat ive effort i s made with the relevant inst itut ions that overseethe performance of this type of research.

Keywords - dimethyltryptamine, hallucinogens, human research, public policy

When I first considered initiating a human researchproject with N .N-dimethyltryptamine (DMT), an endoge-nous hallucinogen that has also been a drug of abuse, Iwas reminded by many professional associates of the pit-falls involving research with drugs in Schedule I of the

Controlled Substances Act of 1970 (CSA). One leadingauthority on hallucinogen structure-activity relationshipsremarked to me in half jest that the sole paper he saw com-ing out of this attempt would be one describing the im-possibility of such work in the present climate of waragainst drug abuse. The psychedelic research community,especially those whose orientation focuses on the use ofthese drugs as catalysts of the psychotherapeutic and/orcreative process, is uniformly pessimistic with regard tohuman studies ever proceeding with Schedule I com-pounds, such as LSD, mescaline, psilocybin or DMT.

The CSA placed all medications and drugs of abuseinto five categories or schedules, depending on their

t Supported, i n part , from grant s r ecei ved from the Scotti sh Ri teFoundation for Schizophrenia Research, NMJ; the Nat ional Insti tu te onDrug Abuse G rant No. R03-DA06524; the U .S. Publi c Healt h Service- General Cli ni cal Research Center Grant No. RR0091-13; and a grantfrom the Psychiatric Research Committee of the Department ofPsychiat ry, Univers ity of New Mexico School o f Medicine.

Assistant Professor, Department of Psychiatry, University of NewMexico School o f Medic ine, 2400 Tucker Avenue NE, Albuquerque,New Mexico 81131.

Journal of Psychoact ive Drugs

medical utility, abuse potential, and safety of useunder medical supervision. Schedule I is the most restric-tive category into which drugs with no known medical use,high abuse potential, and a lack of demonstrated safetyunder medical supervision are placed. The CSA also pro-

vided a mechanism for the movement of drugs into andout of various categories. For example, tetrahydrocannabi-nol (THC) was rescheduled in the 1980s from ScheduleI to Schedule II, after evidence of its efficacy in treatingnausea and vomiting following cancer chemotherapy wasconvincingly demonstrated. However, methaqualone'srescheduling from Schedule III to Schedule I occurred asa consequence of its widespread abuse.

The placement of hallucinogens into Schedule I wascontroversial because studies had clearly demonstratedtheir safety under medical supervision (Strassman 1984).Although their medical therapeutic utility in several patho-logical conditions had not been irrefutably demonstrated,

their use in research elucidating brain-consciousness issueswas very promising. Nevertheless, further study of theirpotential utility for a variety of conditions could not beconducted after the CSA was passed; consequently, inves-tigators were required to return their supplies of thesedrugs.

The abuse potential of these drugs was clearly high;it was this characteristic that seems to have been the majorfactor in their placement in Schedule I. Fortunately, animal

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research continued unabated, providing the focal pointfor the recent explosion of information about the neuro-transmitter, serotonin, and its receptor subtypes in thebrain. These receptors playa role in sleep, aggression,mood, sexuality, and psychosis, as well as the mechanismof action of the hallucinogens. Schedule I drug researchwith animals is signi ficantly easier, and high-purity hal-lucinogens are available to quali fied investigators fromthe National Institute on Drug Abuse (NIDA). The pri-mary hurdles in the case of animal research are those in-volving Drug Enforcement Agency (DEA) requirementsfor securi ty of the storage and/or disposal fac ilit ies, andmaking certain that those who will be handling these drugsdo not have a criminal record.

THE RESEARCH PROPOSAL

For clinical studies wi th humans, one needs to beginwith a research protocol in which the ra tionale for hal lu-cinogenic drug administ ration is described in detai l. Theprotocol requires a clear statement of why one is interestedin giving hallucinogens to people and what one hopes tomeasure or observe. One must be careful not to put thecart before the horse in this type of work. Psychiatric re-search workers sometimes spend excessive effort in ap-plying drugs or other treatments of unknown mechanismof action to psychiatric disorders of tremendous hetero-geneity, even within single diagnostic categories.Furthermore, basic psychophysiological mechanisms areinferred from research in psychiatrically ill patients beforea clear understanding of the normal physiology of the vari-able under invest igat ion is known. It i s important to sys-tematically investigate in normal subjects how hormones,drugs or other factors work before explaining pathophys-iological states and treating or studying psychia tric pa-tients.

Similarly, before suggesting that psychedelic drugscan cure everything from neurosis to hangnails, one isbet-ter served by first applying current tools of psychophar-macologic research to shed light on the basic effectsof these drugs, both psychological and biological.Subsequent ly, these drugs could be prudent ly appl ied todisorders whose etiology or symptomatology interfacewith the known effec ts of hal lucinogens. This approachseems more like ly to provide useful data than a more seat -

of-the-pants approach.In my case, I approached the task of beginning a new

human psychedelic drug research study from two angles.The first was from the vantage point of schizophrenia. Inthe 1960s and 1970s, DMT had been considered a primecandidate for the so-called endogenous schizo toxin . Onetheory suggested that overproduction of DMT might berelated to the psychotic process seen in schizophrenic dis-orders (Gil lin et a l. 1976). Failure to demonstrate differ-


Drug Research in the United States

ences in DMT levels in several body fluids between nor-mals and schizophrenics prompted the discontinuation ofstudies either giving DMT or measuring DMT levels.However, newer data concerning the role of serotonin inboth endogenous and drug-induced hallucinations has pro-vided a new approach to understanding the etiology of hal-luc inogenesis (Fischman 1983). At the most basic level,one might suggest that drugs that could block the hallu-cinations of DMT might a lso be antihalluc inogenic in pa-tients with schizophrenia. Thus, understanding how DMTworked in normals had relevance to a major public healthproblem.

I also approached a clinical study of hallucinogensfrom the drug abuse perspective. Hallucinogens continueto be used and abused by people in the United States, par-ticularly in college-age populations (18-25 years), at aboutthe same rate now as 20 years ago (Pope et al. 1990). Inspite of the tremendous advances in understanding hal lu-cinogens' effects and pharmacology in lower animals, thenecessary interface of human psychopharmacology andanimal neuropharmacology requires human studies. Thehuman biology of these compounds has relevance to morespecific t reatments for acute adverse effec ts (e .g. , the badtrip), understanding the effects of chronic use, and eval-uating the effects of newly synthesized designer com-pounds as they appear on the street.

An important e lement of both of these approaches in-volved the development of a new rating scale for the ef-fects of DMT, one that has less pathology-orient ed ratingsthan previous scales. The Addiction Research CenterInventory (Haertzen, Hill Belleville 1963), more or lessthe benchmark for assessing subjective effects of drugsin humans, contains what is known as the LSD Scale,which is commonly known as the dysphoria scale.Certainly hallucinogens can produce unpleasant effects,but they can be distinguished from other drugs by morethan that quali ty. It seemed important to describe in moreneutral phenomenological terms what actually is observedin the psychedelic state , p articularly for subjects who seekout these drugs.

Both of these research direc tions also required basicdose-response invest igat ions. Is there a relationship be-tween dose and the effect of DMT, subjectively and bio-logically? Building on older clinical literature, interviewswith experienced DMT users, and newer animal data , one

might anticipate which experiences and biological effectswould be seen. Dose-response studies could then be ini-tiated. The biological factors I decided to examine involvedhormonal (neuroendocrine) effects ofDMT as downstreammarkers of effects on central serotonergic neurotransmis-sion. I also specula ted that serotonin receptor act ivat ionwould be reflected in effects on basic vegetative variables,such as core body tempera ture, blood pressure, heart rate,and pupillary diameter . Subjec tive effec ts would be mea-

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sured by the newly designed rating scale. This basic humanresearch could provide the foundation for more detailedexperimental interventions. Follow-up studies might in-clude differential effects of DMT in selected patient pop-ulations with presumed abnormalities of serotonergic neu-rotransmission (e.g., schizophrenia, affective disorders,posttraumatic stress disorder), selective blockade of sub-

types of serotonin receptors to begin assessing receptorsubtypes responsible for specific neuroendocrine and sub-jective effects, and experiments in which repeated dosesof DMT are administered in an attempt to develop acutetolerance to the drug.

A research protocol needs to provide an adequate dis-cussion of background information (i.e., what is and is notknown about the area to be investigated), hypotheses (find-ings that one hopes will be derived from the study and howthese data will answer specific questions), a plan of in-vestigation (what one will do and why), a considerationof risks and benefits to the subjects involved and how therisks will be managed (with plans to deal with adverse re-actions), sample size determination, data management,references/bibliography, and an informed-consent doc-ument. Sample size determination and data managementare relatively simple issues, if one has read the literature,has some idea of the direction and size of expectedchanges, and can consult with a qualified biostatistician.

University research offices have copies of U.S. PublicHealth Service Form 396, which is used in federal grantapplications. This form contains an outline covering allthe aspects of a research protocol, with clear explanationsof what each area should include. It is the model researchproposal format used by most nonfederal agencies as well.

Most institutional review boards (IRBs), local committeesthat review the relevant human-risk issues, like to haveproposals written in a similar format (although generallyin less scientific detail).

In order to decrease the risks involved in this projectmy protocol involved using only experienced hallucino-genic drug users. Administering a drug like DMT to naivesubjects seemed to be a high-risk venture. Level of expe-rience was determined by an informal interview focusingon extent of psychedelic drug use as well as negative andpositive effects experienced by prospective subjects.Special attention was paid to assessing the presence of de-fenses characteristically known to be associated with neg-

ative reactions to hallucinogens, specifically denial andprojection (Barr et al. 1972). Furthermore, experiencedsubjects are better able to report on subjective effects andto compare and contrast their past experiences with DMTand/or other psychedelics. Finally, from a purely legalpoint of view, litigation claiming long-term brain or per-sonality damage or subsequent problems with drug abusewould be less sustainable in subjects with extensive pastuse of psychedelics.

]O UM of Psychoactive Drugs

Drug Research In the United States

LOCAL ISSUES

The Institutional Review BoardOnce the research protocol has been written (and

hopefully reviewed and critiqued by knowledgeable col-leagues), it must be reviewed and approved by the localIRB. This is a requirement for any research involving

human subjects. The function of IRBs is to assure thesafety of participating human subjects and, depending onthe particular IRB, the scientific merit of the study. Thelatter element almost always is given greater attention bythe scientific review committee of the research site inwhich the study will actually take place. The IRB may alsorecommend changes in and approves the informed-consentdocument that accompanies the protocol. Once approvalby the local IRB and performance site is obtained, the pro-cess of obtaining federal approval can begin.

Issues with the IRB can be complex if one does notwork within a university/medical school setting. The U.S.Food and Drug Administration (FDA) has publishedguidelines for uni versity- and nonuni versity-affiliatedIRBs. This information is available through the FDA'sOffice of Health Affairs. Nonuniversity IRBs may be localor may not be if local ones do not have the requisite ex-pertise and/or it is a multi site study and the relevant IRBis at a different site. One can even hire an IRB that maywork with nonuniversity-affiliated investigators, but theymay charge exorbitant fees. If one is interested in creatingan IRB, the requisite composition of an IRB is clearly de-fined in FDA guidelines. However, this is not recom-mended because it would create an unnecessary bureau-cratic nightmare, independent of the major goal of receiv-

ing IRB approval. Itis preferable to use an IRB that alreadyexists.From the outset, I had to explain to the IRB that even

if I received their approval, I could not initiate any studiesuntil the FDA and the DEA review processes were com-pleted and their approvals obtained. Local approval wasthe necessary first step before I could submit my requestto the federal review process.

The IRB at the University of New Mexico was mostinterested in the nature of the informed-consent documentThey requested two things that were somewhat difficultto address. The first issue was that of Schedule I drug usein humans. If a drug has no medical use and cannot be used

safely under medical supervision (the criteria for place-ment into Schedule I), how could I justify human researchwith it? They requested that I add the phrase this drughas no known medical use to the informed-consent doc-ument I responded by referring to the hundreds of articleson the human use of LSD and nearly a dozen on DMT be-fore the drugs were scheduled, demonstrating that theycould be used safely under medical supervision, and thatin many ways the Schedule I placement was not a medical

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but a legal definition. I asked to be able to state only thatit had no current medical use, which they agreed to.Ultimately, I was able to remove even that phrase by ar-guing that if FDA approval was obtained, no current med-ical use was no longer true, as I would have demonstratedits utility as a tool for medical research.

The IRB's second concern was that I describe in theinformed-consent document what the subjects might ex-perience on the drug. Clearly, one can choose from themost hellish to the most beatific descriptions of thepsychedelic drug-induced state, with a strong biasing ef-fect on the subjects. I opted for a balanced description ofeffects of the range of symptoms, with a slight emphasison pleasurable and interesting effects. I justified this moresanguine view by summarizing the results of my inter-views with over 20 essentially normal DMT users, all butone of whom described theirDMT experiences in an ex-tremely positive light. There also were no published re-ports of serious psychiatric sequelae (e.g., psychosis last-ing more than 24 hours) in normals given the drug. I didsuggest the possibility of serious emotional reactions tothe experience induced by DMT, and that in the most ex-treme case, psychiatric hospitalization was available.However, I was able to assuage the IRB's concerns slightlyby emphasizing that these were quite experienced hallu-cinogen users, many of whom had had bad trips that hadbeen informative and developmentally useful in their abil-ity to manage subsequent experiences with psychedelics.

The Performance Site Scientific Review CommitteeMore or less parallel to the IRB process is that of sci-

entific review by the committee that oversees studies in

the research center. My project was to take place in theGeneral Clinical Research Center (CRC) of the Universityof New Mexico Hospital, funded by the National Institutesof Health to provide beds and nursing as well as laboratoryand statistical support for CRC-approved human researchproposals. Projects are submitted to the CRC AdvisoryCommittee and need to follow the same general guidelinesas do submissions to the IRB, with a naturally greater em-phasis on the scientific rationale for the proposed project.There was less difficulty in obtaining CRC approval thanIRB approval, as the CRC assumed that the IRB wouldaddress the overriding issues of risk and informed consent.The CRC requested an additional literature review to sup-

port my requests for measurements of the hormones I wasinterested in evaluating. They also wanted urine drugscreens taken on the morning of every study day. This wasnot to disqualify people from participating in the study,but to be able to assess the effects of a positive urine onthe parameters under scrutiny. Would a less robust pro-lactin response, for example, be associated with a positiveurine screen for marijuana? The Advisory Committee alsowanted me to impress on subjects the importance of not

Journal of Psychoact ive Drugs 32


taking any other drugs of abuse during the project to keepthe data as clean as possib le.

ConfidentialityOne of the thorniest issues of the project was that of

anonymity and confidentiality. Admitting to the use ofSchedule I compounds is admitting the commission of a

federal offense and being liable for prosecution. All of thesubjects in this project are professionals, with spouses,families, reputations, and careers. Therefore, strictanonymity and confidentiality were required. Severalmeetings were held with the Medical Records Department,Legal Counsel for the University Hospital, AdmittingOffice, and Head Nurse of the CRC to discuss how to as-sure strict confidentiality and anonymity. Furthermore, itis usually required that the signed informed-consent doc-ument be attached to the subject's medical records, a sit-uation impossible in this case. The final solution was com-plex but appears to be working well. A subject coming infor an admission medical history, physical examination,and laboratory work (i.e., blood count and chemistr ies,electrocardiogram, thyroid functions, urinalysis) has achart made up with his or her real name. This is neededif at any time in the future the subject happens to visit theemergency room or clinics, then baseline medical data willbe available for comparison. However, subjects' chartsare not associated with my DMT protocol number. As Ihave run several projects through the CRC over the years,my being their physician of record is not in itself partic-ularly incriminating. (I just as easily could have had an-other physician sign these forms; if th is were the only pro-ject I had ever performed at the CRC, having me sign their

papers might be seen as their admitting to the use of illegaldrugs). The subjects' screening psychiatric examinationas well as every admission for the project occurs under acode name and hospital chart number. Ultimately, theMedical Records Department allowed me to be the onlyperson with the code. The more people who have confi-dential information, the more likely it will be compro-mised. I was also the sole possessor of the signed in-formed-consent documents and had to state that clearlyon every admitting form.

The informed-consent clauses regarding confidential-ity went through some evolution as the process unfolded.I had previously run a study giving melatonin, a pineal hor-

mone and an experimental nonscheduled drug, in a clinicalresearch setting that required FDA approval. In that case,I had stated that the FDA and the manufacturer of mela-tonin could have access to participants ' medical records.In my first informed-consent document for the DMT ex-periment, I originally indicated that the FDA, DEA (as alsoinvolved in the regulatory process), and the manufacturerofDMT (at that time undetermined) might, under extraor-dinary circumstances, have access to the medical records.

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This met with universal alarm, The following was the [malsolution to the issue of informed consent: if the FDA orthe manufacturer was interested in interviewing subjectsand/or having access to their medical records for scientificpurposes, they would need to go through me, who thenwould determine whether or not individuals were indeedwilling to do this. Records theoretically could be subpoe-naed, but that would be vigorously fought. And, as I amthe only one with the key to the code, I w ould refuse todivulge the key if this should occur.

State Pharmacy Board Schedule I PermissionThe last local issue was getting my state of New

Mexico Schedule I permit, which is necessary before theDEA will process a Schedule I request. This varies fromstate to state, and the state board of pharmacy and/or thelocal DEA office knows if a state permit is necessary be-fore applying for DEA approval. This was relatively easy.I submitted the appropriate form, including an abbreviatedversion of the protocol and approval letters from the CReand IRB. This permission was granted at the board 's nextmeeting.

FEDERAL ISSUES

One should never send anything important to any fed-eral agency by regular mail; always send itby express mailor with a return receipt requested. Also, always take de-tailed notes whenever speaking with anyone at any federalagency. Get names and phone numbers because one rarelygets the needed person the first time; he or she is often atthe end of a long chain of in- house transfers from exten-

sion to extension. Write down as much as possible fromevery conversation. Refer to these phone calls in your mailcorrespondence to let the relevant agency know you aretaking notes and to ensure accurate communication.

One will need to deal with at least two federal agen-cies in the application process: the DEA and the FDA. Attimes, their responsib ilities overlap in vague and poorlydefined ways. By going through the application processin a methodical and persistent manner, defects in this two-tier system became clearer and gradually worked them-selves out. My overall impression of the process is thatthe difficulties I encountered were not due to intentionalmalicious roadblocking but uncertainty regarding who had

final authority in a particular matter and what were theproper channels through which my request should be fun-neled. This, combined with generic bureaucratic ineffi-ciency, resulted in a 21-month process from the date ofapplication to final approval to begin the study. Even so,with my initial expectations, I was pleased that the processeven went that quickly.

Journal of Psychoactive Drugs

Drug Research In the United States

Funding: An _Aid to Obtaining Federal ApprovalI submitted a research grant proposal to a nonfederal

granting agency, the Scottish Rite Foundation forSchizophrenia Research, at approximately the same timeI began the FDA-DEA approval process, which was in thespring of 1989. I would encourage all potential investi-gators in this field to consider a similar course. First of all,one's scientific reasoning is sharpened by the grant reviewprocess, and if the FDA and/or DEA review turns out tobe inordinately long, the feedback obtained from the grant-ing agencies' review boards may anticipate objectionslikely to originate at the federal regulatory level. If sucha grant is approved, this enhances the likelihood ofFDA/DEA taking note of the scientific credibility of theproposed work. I received a one-year award from theScottish Rite Foundation torecruit subjects, develop a wayto measure DMT in blood (the DMT assay), interview sub-jects who had smoked DMT in the past in order to drafta DMT rating scale, and pursue FDA-DEA approval. Asecond year was approved pending FDA approval. An ap-plication for aNIDA grant was made in June 1989. Thiswas approved and funding started in May 1990, essentiallyat the end of the first year of the Scottish Rite grant. TheNIDA grant then took over where the Scottish Rite grantleft off, a fortunate case of good timing. Both these awardswere extremely helpful in prompting the FDA and theDEA to pay more attention to my request to get startedwith the experiments.

The Drug Enforcement Administration:The Schedule I Permit

DEA approval, although slow, was not particularly

complicated. There is an application form specifically forSchedule I drugs (DEA Form 225: Application forRegistration Under Controlled Substances Act of 1970)that is available from Washington or the local DEA branch.This is different from the routine Schedules II-V form thatall medical practitioners use to obtain approval to routinelyprescribe controlled substances (e.g., opioids, benzodiaz-epines). There is a four-digit code number for all scheduleddrugs that needs to be placed in its respective box on theform. Not everyone at the DEA knows these numbers. Idid not realize it at the time but the back of the front pageof form DEA 225 has a list of many scheduled compounds(including DM1) with their respective drug codes. Should

there be any difficulty in determining the correct drug codenumber, one can call the Registration Branch of the DEAin Washington. I was inadvertently given the NationalDrug Code number for DMT by the DEA in Washingtonover the telephone. My entire application packet was re-turned to me a month after I submitted it with a requestfor the right number, accompanied by a piece of paper withall the appropriate numbers for my information. Alongwith this properly completed form an abbreviated version

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of the protocol needs to be included, along with IRB andscientific review committee letters of approval. One alsoneeds to describe the security arrangements for storing andhandling a Schedule I compound, which the pharmacy canprovide on their official stationery.

After several months of phone calls, inquiring as tothe status of my application, I learned it had been sent tothe regional DEA office in Denver. From there, it was sentto the local DEA office in Albuquerque. The local DEAagent assigned to my case then came out to the Universityof New Mexico a couple of times. She inspected the se-curity system in the pharmacy (and found some weak-nesses in the system that required correction), instructedthat a special freezer with its own lock be purchased thatwas to be placed in the controlled-substances vault in thepharmacy (which was already kept locked and guarded24 hours a day), interviewed me and the manager of thepharmacy, and requested the names, addresses, social se-curity numbers, and phone numbers of all the people whowould have access to the DMT and/or have keys to thefreezer (several laboratory personnel and pharmacists, pri-marily; I do not have a key to the freezer). She then ransecurity checks on me and all those whose names wereprovided to check for any criminal records. After beingsatisfied with the security checks, locked freezer, and im-provements in the security system, she described to methe consequences of poor record keeping and unexpectedlosses of drug supplies. She wrote an approval letter to theDEA office in Washington . After a month or two of keep-ing track of this letter, I encountered another unexpecteddifficulty.

My project required laboratory-grade DMT for the

assay, which I could purchase from Sigma Chemical with-out difficulty once I received my Schedule I order forms.This form ofDMT did not need to meet the many require-ments necessary for human administration. It could betaken off the shelf of a chemical supply house and useddirectly for laboratory or animal work. The project alsorequired getting permission to obtain and possess clinical-grade DMT for human administration. This form of DMTneeds to be certified by the FDA as safe for human use.However, the DEA had no recent experience processinga request for administering a Schedule I drug to humansand had difficulty in differentiating the two requests. Theywere reluctant to let me order laboratory-grade DMT until

I had received FDA permission to go ahead with thehuman study. However, FDA approval for this could notoccur until I found a source for, and established the safetyof, a clinical-grade DMT. I asked the FDA for their helpin interfacing with the DEA's pharmacist, and finally suc-ceeded in getting the DEA to distinguish between the tworequests. Soon thereafter, I was issued my Schedule I per-mit, with order blanks, and could order DMT from SigmaChemical for the laboratory. Once I received FDA ap-


Drug Research Inthe United States

proval to begin human administration of DMT (from, atthat point, an unknown source) I was to notify the DEAof this but no additional paperwork was required.

The Food and Drug Administration:The Investigational New Drug Applicationand the Drug Master File

The application process with the FDA involved twosteps. Usually, if a drug is used for a purely experimentalstudy, an Investigational New Drug ( ND) applicationneeds to be submitted. This was quite simple in the caseof my previous melatonin study in 1985. At that time, Iworked with Sigma F D, a division of Sigma Chemical,who had a Drug Master File (DMF) for melatonin on fileat the FDA. After I spoke with and wrote to Sigma theyauthorized the FDA to access their DMF on melatonin onmy behalf. The FDA looked at the manufacturing data,chemical purity tests, and other information on melatoninin the DMF and then gave me permission to order themelatonin. After the pharmacy prepared it in a solutionappropriate for injection , I tested the sterility and pyro-genicity (ability to cause fever), sent in this information,and shortly thereafter received permission to proceed withthe study.

Since 1985, and particularly since the early 1970s,when a group at the National Institute of Mental Health(NIMH) received permission to give DMT to humans, reg-ulations have become much stricter at the FDA, particu-larly regarding injectable drugs. DMF requirements aremore elaborate and require a full pedigree of the compound(i.e., statements regarding the source and purity of all pre-cursors, assessment of purity and identification of con-

taminants in all intermediary synthetic compounds, andmore documentation regarding the composition and char-acteristics of the final product that would ultimately begiven to subjects). Therefore, when I submitted my INDapplication for DMT, I again believed that Sigma F Dwould be able to provide the drug and that the processwould be analogously simple. I spoke with and wrote toSigma F D, who agreed to set up a DMF for their DMT.I sent in my ND application forms, along with copies of

the IRB and scientific committee approvals, a copy of theinformed-consent document and a brief description of thestudy, hoping that the FDA would accept Sigma F D'sinformation.

The forms used to apply for an IND are FDA 1571and 1572, each of which is two pages long. Form 1571contains an interesting clause that might be of use whentrying to study drugs that have been previously investi-gated. This clause, which can be checked as part of an ap-plication procedure, is a request for reinstatement of anIND that is withdrawn, inactivated, terminated or discon-tinued. DMT had been studied by a group of investigatorsat NIMH in the 9 7 s (Gillin et a1. 1976) and another

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group in Chicago had used the NIMH IND for a series oftheir own studies somewhat later (Meltzer et al. 1980). Ithought that I might be able to use information from theold IND to speed the approval process for my own appli-cation.

Documents sent to the FDA enter via the DocumentsRoom, and from there letters are routed to the appropriate

division. In the four years since my melatonin IND wasissued, a new division has been formed for Pilot DrugEvaluation, to which my DMT IND application was re-ferred a week or two after its arrival in Washington. TheFDA then sent me a standard form letter acknowledgingreceipt of the application , the name of the drug for whichthe application was made, and the IND number. It wassigned by the responsible Consumer Safety Officer (CSO)with a phone number and routing address. (Never fail towrite the IND number on the top of any future correspon-dence with the FDA. Without it, letters wi11languish for-ever in the Documents Room awaiting someone who hasthe time to figure out what the IND number is and, by de-fault, where it needs to go.) This letter stated that unlessI heard from the FDA within 30 days of the date stampedon the top of the form letter (generally 10-15 days aftersending the application) I could proceed with the study.This is standard procedure for the FDA on receipt of anyIND application.

At this point, it is necessary to begin intensive tele-phone contact with the review section staff. I began callingas soon as I received the name of my project manager(PM). Of course, the main problem with the IND appli-cation was that I had no source of drug, and the FDA couldnot grant me permission to begin a study without the DMT.

It was therefore on Hold (an official FDA term) fromthe outset. However, I needed to begin finding out whocould make the drug, and what information I would needto send to the FDA concerning the compound. Within acouple of months, I received a detailed letter from the FDArequesting the necessary information regarding preparationof the bulk drug, and the characteristics of the clinical formof the drug that I actually planned to administer.

The two primary contacts one first works with on thesection staff are the CSO (or PM) and the chemist. TheFDA has two charges in a case like this: the first is to as-sure the safety of human subjects, and the second is to givesome scientific guidance to optimize the chances that the

experiments with humans will provide valid and valuabledata. A chemist is involved because no drug companymakes Schedule I drugs for human use anymore. My re-quest was linked to the finding of a source for the actualdrug; the chemist needed to help me with this process.Even if a drug company was making the drug, the FDAchemist would still be involved in assessing and examiningthe DMF to assure that the drug was safe for human use.Safety in this context means assuring that the drug is in

lOWTUll of Psychoactive Drugs


a high state of purity (99+%) and contains no toxic im-purities. The chemist must evaluate the manufacturing pro-cess and analytical data (the chemical pedigree) for thedrug in order to certify these requirements. The PM, onthe other hand, interfaces with the scientific staff at theFDA regarding scientific matters.

I was aided in the area of scientific concern by virtue

of having received IRB and CRC input and approval. I alsowas fortunate to have received the Scottish Rite and thenNIDA funding for the project. The review processes in-volved in these grants sharpened the science of the project,and funding from outside agencies greatly enhanced mycredibility.

The Search for Clinical-Grade DimethyltryptamineAcquiring the DMT for the study was a complex pro-

cess, and at one point in time I began to fear that the wholeproject would come to a dead end because satisfactoryDMT could not be obtained. When a drug has been madefor human use, be it by a pharmaceutical company or a pri-vate concern, the FDA has a DMF on it, containing de-tailed information regarding synthesis of the drug and itspedigree. Drug companies have large chemistry labora-tories that provide this information to the FDA, and theyare familiar with the process of setting up a DMF for anyparticular compound. The DMF also contains informationregarding animal and human toxicity data, when relevant.Fortunately, in the past, DMT had been given in numerousanimal studies and nearly a dozen human studies.Therefore, the toxicity issue did not concern this particulardrug.

My IND application was complicated by the fact thatit was necessary to establish a DMF for the DMT, in ad-dition to acquiring permission to give the drug for an ex-perimental purpose. If a study was designed to use a drugcurrently in use (e.g., morphine) for research on a nonindi-cated use (e.g., to control high blood pressure in an emer-gency setting), a drug company could simply authorizethe FDA to access their DMF on the researcher's behalf.However, no DMF existed for DMT. One hope I held outwas that I might acquire DMT from some source, and ifit were not pure enough, I could purify it to the requiredlevel. However, at a very early stage in the negotiationsit was clear that this was not satisfactory to the FDA. Thepedigree and detailed synthetic information had to be pro-

vided.With the aid of the FDA chemist, I was able to track

down (in the Federal Archives Building) the old IND forDMT that was used at NIMH in the 1970s. Recall that Iwas hoping to reactivate an expired IND, using data ac-quired by NIMH researchers. However, the informationin that IND was wholly inadequate for current FDA re-quirements: there was no DMF in their IND. The IND mesaid that Aldrich Chemical in Chicago had made the DMT

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for the NIMH study. I contacted Aldrich, but they hadnever compiled a DMF for the drug nor did they distributethe compound anymore. The NIMH group, whom I sub-sequently contacted, no longer had either their IND recordsor any information regarding the drug.

Sigma F D, as described previously, was willingto supply the FDA with as much information as it hadavailable regarding their DMT in order to set up a DMFon the compound. However, they did not actually man-ufacture the drug; a source in Europe supplied it to them.The European source was unwilling to provide detailedinformation regarding their synthesis of the drug.Therefore, Sigma F D was ruled out as a source ofDMTthat could set up a valid DMF.

NIDA has made scheduled drugs available for animalstudies, and has in fact supplied investigators with a non-hallucinogenic LSD analogue for human positron-emis-sion tomography studies (Wong et al. 1987). However,NIDA's DMT that was on the shelf was relatively old anddid not have the pedigree and required synthetic informa-tion that the FDA required.

However, NIDA has a contract with the ResearchTriangle Institute (RTI) in Research Triangle Park, NorthCarolina. RTI provided the THC for the marijuana/I'HCprotocols in the 1970s that investigated the effects of thesedrugs on nausea and vomiting induced by cancerchemotherapy. However, when I contacted RTI on NIDA'sreferral, they initially claimed they could not make drugsfor human use because of liability concerns, but I was toldby NIDA that not one suit has ever been brought againstNIDA for the marijuana/fHC study. Although NIDA ex-pressed their general concern about the lack of any reliable

source of high-quality drugs of abuse for human studies,they stated that research with DMT was not of sufficientpriority for them to pay RTI to make the drug to the spec-ifications required by the FDA, even ifRTI did agree tomake it. Therefore, I would have to pay for the preparation.These discussions with RTI and NIDA took place beforemy grant from NIDA was approved and funded. Aftersome negotiating , RTI agreed to prepare high-qualityDMT and send me the information necessary to set up myown DMF for the drug. They estimated the cost of sucha synthesis, including the record keeping, to be in thethousands, which was quite out of the range of my abilityto pay. Thus, RTI and NIDA were also effectively ruled

out as sources for clinical-grade DMT.Next, I tried NIMH, which has a Chemical Synthesis

Program to make obscure research drugs for investigators.Again, their contract stipulated that their drugs, even ifprepared to the most exacting specifications, could not beused in humans. However, the director of this programstated that he was considering changing the wording oftheir contract when it was up for renewal to be able to pro-vide drugs for human studies. This might be a source of

Journal of Psychoactive Drugs

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such drugs for future investigators and should be pursued,but NIMH also had to be ruled out as a source of DMT formy own study.

I then asked a colleague with experience in synthesisof hallucinogens within a university setting if he wouldconsider making the DMT for my project. He declined,referring to the difficulties involved in acquiring a man-ufacturer's license through the DEA to distribute sched-uled drugs. I approached another colleague with similarexperience within a university setting. He had been keep-ing abreast of my futile search and was aware that I hadabout exhausted all possible avenues. He finally agreedto consider making DMT to FDA specifications at cost,and thereby considerably less than the RTI quote.However, manufacturer's licensing procedures are muchstricter than regulations concerning indi viduallaborato-ries' research use and he wanted assurance that makingthe drug for me would not break any DEA regulations.After some effort, I found a division within the DEA, theOffice of Drug Research Registration, that regulates reg-istration issues for researchers. They informed me of the coincidental activities clause within their regulationsthat allows registered researchers to prepare small batchesof scheduled substances for collaborative research effortsrather than the sale-for-profit context of a manufacturer-purchaser relationship.

At this point, when asked whether or not this wouldbe a satisfactory arrangement from the FDA's point ofview, the FDA chemist referred me to a physician on thedrug abuse staff in the FDA's Pilot Drug Division. He be-lieved such an arrangement would be satisfactory. He alsoquickly became my most important, responsive, and re-

liable liaison within the FDA.My colleague who agreed to manufacture the DMTand I then submitted brief amendments to each of our DEAapplications that would justify the preparation and pos-session of adequate amounts of DMT for a collaborativeresearch effort. We needed to provide the DEA with thereason for requesting this amendment, the amount ofDMTinvolved, and a statement to the effect that this was a re-search, not a fiduciary, relationship. A tremendous numberof phone calls was required to keep this amendment mov-ing through the maze of sections at the DEA. One majordelay was the DEA's request that the FDA approve thisamendment. The FDA did not believe this was necessary,

although the DEA would not proceed past a certain pointuntil they received, in writing, FDA approval of thisamendment. I do not know where the truth actually liesin this case, although the FDA complied with the DEA'srequest.

DEA approval was thus obtained for my colleague toproduce DMT. Several months later, I received eight gramsofDMT-fumarate (a form ofDMT that FDA has approvedfor human use) and all the supporting documentation of

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orative relationship with someone who can manufacturehallucinogens may be necessary. Drug companies, if theydo make the drug, might be inclined; however, it is betterto have a first-class medicinal chemist with a universityaffiliation. Again, outside funding and the possibility thatthe project might dead-end without my colleague's assis-tance were very important factors in persuading him totake on this daunting task.

For researchers interested in studying the use of hal-lucinogens to enhance the psychotherapeutic or creativeprocess, I believe that using the same approach, tediousand plodding as it is, might be similarly applied. Therehave been well-validated advances in psychotherapyand cognitive science research in the past 20 years.Standardized treatment protocols and testing proceduresare effective in teasing apart salient issues in psychopatho-

Drug Research Inthe United States

logical states. Carefully blending the relationship betweenthe effects of hallucinogens on cognitive, emotional, andinterpersonal variables with the processes involved in stan-dardized psychotherapy techniques (or creative problemsolving) could be combined in attempting to use thesecompounds for such purposes.

ACKNOWLEDGMENTS

I would like to express my gratitude to MargaretBrophy, F. Ivy Carrol, Daniel X. Freedman, BernhardtFunk, J. Stephen Kennedy, Betty Lee, Corinne Moody,David Nichols, Dottie Pease, Juanita Ross, AlexanderShulgin, Marion Strassman, Robert Walsh, and CurtisWright for advice and help along the way.

REFERENCES

Barr, H.; Langs, R.; Holt, R ; Goldberger, L. Klein , G. 1972 . LSD:Personality and Experience New York: Wiley Interscience ..

Fischman, L. 1983. Dreams, hallucinogenic drug states, and schizophre-n ia : A psychological and b io logical comparison . SchizophreniaBulletin Vol. 9: 73-94.

Gillin, J.; Kaplan, J.; Sti llman, R. Wyatt, R. 1976. The psychedelicmodel of schizophrenia: The case of N,N-d imethyl tryp tamine .American Joumal of Psychiat ry Vol. 133: 203-208.

Haertzen , C.; Hill, H . Belleville, R. 1963. Development of theAddiction Research Center Inventory (ARCI) : Selection ofitems that are sensitive to the effects of various drugs .Psychopharmacologia Vol. 4: 155-166 .

Mel tzer, H.; Wii ta, B.; Tricou, B .; Sirnonov ic , M . Fang, V . 1980 .Effects of serotonin precursors and serotonin agonists on plasma hor-


monelevels. In: Ho, B.; Schoolar, J. Usdin , E. (Eds. ) Serotoninin Biological Psychiatry New York: Raven .

Pope, H .; Ionescu-Pioggia, M Aizley, H . Var ma, D. 1990. Drug useand l ife s ty le among col lege undergraduates in 1989 : A comparisonwi th 1969 and 1978 . American Journal of Psychiatry Vol. 147: 998-1001.

Strassman, R. 1984. Adverse react ions to psychedelic d rugs: reviewof the literature. ournal ofNervous and Mental Disease Vol. 172:577-595.

Wong, D.; Lever, J .; Hartig, P .; Dannals , R.; Vil lemagne , V.; Hoffman ,B.; WIlson , A.; Raver t, H .; Links, J.; Scheffel, U Wagner, H. 1987.Local iza tion of seroton in 5-HT. recep to rs in l iving human bra in by

positron emission tomography using N,-([UCl-methyl)-2-Br-LSD .Synapse Vol. 1 : 393-398.

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