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Substituted Amphetamine
Controlled Substance Analogues

David E. Nichols

Cocaine, Marijuana, Designer Drugs: Chemistry, Pharmacology, and Behavior: Chapter 14, pp. 175-186
Editors: Kinfe K. Redda, Charles A. Walker, Gene Barnett, 1989 CRC Press, Inc. Boca Raton, FL

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Table Of Contents

  1. Introduction
  2. Social Issues
  3. Hallucinogenic Amphetamine Analogues
  4. Toxicity
  5. MDMA
  6. Research Concerns
  7. References

I. Introduction

First and foremost, drug abuse is a social problem rather than a physiological one. It is not entirely clear that any solutions can be found by focusing attention on the drugs themselves, rather than on the societal conditions that lead to drug abuse. Therefore, it seems appropriate to consider some of the broader issues, rather than to deal exclusively with the chemistry or structure-activity relationships of hallucinogenic amphetamine derivatives.

The task is made doubly difficult by this author's belief that although controlled substance analogues of the hallucinogenic amphetamine type possess the potential for nearly unimaginable tragedy, at the same time, research with these substances holds hope for future advances in psychiatric medicine.

On the one hand, if hallucinogenic drugs can be seen as useful substances, they may serve as a potentially rich source of new psychotherapeutic compounds, which could catalyze a revolution in psychiatry and psychotherapy. However, virtually no approved clinical research is being carried out with hallucinogens, and this appears to be a continuing situation in the foreseeable future. And, while there may be no clinical research, "recreational" use of hallucinogenic controlled substance analogues continues pretty much unabated.

II. Social Issues

"It is becoming clear that a drug-free Eden, if it ever existed, will never return. The days when youth had no access or interest in the bewildering array of consciousness-transforming drugs will, in all likelihood, not be seen again."1 For some reason, the notion seems to be developing today that we can somehow achieve a "drug-free society". However, Cohen's opinion seems to be a more realistic assessment of the present state of affairs. As long as psychoactive drugs are available, young people will experiment with them. From 1962 to 1980, the number of 18- to 25-year-olds who had ever tried illicit drugs (other than marijuana) increased more than tenfold, from 3 to 33%. These data at first seem frightening, but are they really meaningful? Is it cause for serious alarm if a majority of young adults have "ever used" some illicit drug? Adolescence is a period of exploratory, risk-taking, sensation-seeking behavior, and in a highly technological society such as ours, chemical exploration now seems to be a part of that world. As Cohen has pointed out, a distinguishing feature of drug abuse is whether or not people go on to use drugs dysfunctionally.

Despite growing concern over drug abuse, any connections between illicit drug use and the social ills attributed to it are hard to prove. An excellent analysis of prospective studies of drug use concluded that, "few unfavorable outcomes of drug use, especially marijuana use, have been identified."2

The real issue is this: how can one come of age in America without becoming a casualty of the acute or chronic use of drugs that affect mood, thinking, and sensing in the process? When is a young person capable of making decisions about drugs that can impact on his or her health and future? Obviously, this will never occur unless sufficient accurate information about the drug is acquired. The approach that seems most reasonable is one of education.

As a society, we should believe that when facts are presented in an objective way, and if real dangers exist, that this information will be accepted. However, one should be wary of "crying wolf". For example, during the years of peak LSD use, one report suggested that LSD caused chromosome damage3. This research was widely reported by the media. However, we now know that LSD does not have such an effect4,5. The danger of genetic damage was disproven, no additional physiological hazards have been demonstrated, and use of this drug continues today.

When misinformation is supplied, this will eventually become evident. If the supplying of misinformation is seen as a "scare tactic" to keep persons away from drug use, the drug-using subculture will tend to ignore any real warnings of a genuine toxicity problem as just another repeat of earlier misinformation. How many young persons heard that smoking marijuana led inevitably to heroin use, only to discover for themselves that this was not the case? The movie Reefer Madness was originally produced to illustrate the destructiveness of marijuana, yet is not factual and today is viewed by marijuana users as a comedy. With such a past history of providing "educational" information, how seriously do marijuana-using persons take the warnings that marijuana can suppress the immune system or that marijuana smoke is heavily laden with carcinogenic hydrocarbons?

It is imperative that misinformation about drugs not be propagated. The less people know about the effects of recreational drugs, the more dangerous they consider the drugs to be6,7. However, the perception of danger is a motivating factor in risk-taking behavior. It is extremely important that when dangers associated with illegal drug use are identified, that the potential users have a complete understanding of the danger so as to avoid misusing those materials. Incredibly, this author has heard individuals who believe that anyone who uses illegal drugs is a societal menace and deserves any consequent health damage that occurs. It would be wise for those persons to consider that there must be millions of individuals who are now in highly responsible positions that at one time or another have experimented with drugs. As a nation, we should feel lucky that these persons did not suffer health damage as a result of their experimentation.

In some ways the recent concern over "designer drugs" parallels the situation that occurred with marijuana. While use of marijuana was confined to blacks and the lower socioeconomic classes in the U.S., it received little notice. It was not until marijuana was widely used by adolescents of the "middle class" during the 1960s that it was perceived to be a "problem". Similarly, although large numbers of opiate addicts suffer injuries related to intravenous administration of street drugs, it took the introduction of highly potent fentanyl analogues, and the resulting increase in overdose deaths, and MPTP-induced Parkinsonian symptoms to focus attention on this problem. Likewise, the popularity of MDMA was seen as a serious problem when college students and young professionals began to use it.

We know that to have the potential for abuse, a drug must have desirable pharmacological properties. Perhaps it is appropriate to discuss what it is about hallucinogenic drugs that makes them so attractive. Hallucinogens are an unusual class of drugs. The drug-induced state can be so like a spontaneous transcendental experience that an overwhelming feeling of significance accompanies it. The experience seems to have a value in its own right, which the nonuser can neither share nor understand8. There has been, and will probably continue to be, a good deal of human experimentation with hallucinogenic drugs. If one considers descriptions in the Rig Veda of the use of SOMA, there is evidence that these types of substances have been used for at least 4 millennia. It is the overwhelming sense of meaningfulness of the experience that causes these drugs to be rediscovered every few decades and leads people to coalesce around the idea that something of spiritual importance derives from their usage1.

Is the solution proscription and prosecution for use? As much as we as a society would like to believe that all the individual's needs can be provided by our system and our way of life, drug abuse is found at all socioeconomic levels.

It seems to be reasonably well documented that humans are particularly curious to experience altered states of consciousness9,10.

There are some who argue that this is a relatively recent phenomenon and that drug users "embrace a constellation of attitudes and values that reflect an openness to deviant behavior and nonconformity with respect to social institutions"11. However, the preponderance of evidence shows that drug abuse exists at every level of the society, and that virtually every society has found ways to alter human consciousness both with and without the use of chemical catalysts.

The conclusion that the occasional need to alter one's state of consciousness is one of man's basic drives seems inescapable10. Whether this state be obtained as the result of a formalized religious service, in the form of a "runner's high", through a variety of relaxation or meditative techniques, through the use of alcohol or marijuana, or any of a number of other methods, there is some driving force that leads humans to desire altered states of consciousness. There seem to be two different approaches to this. Some "...commend the sober mind...", with the admonition that with sufficient training, it (the mind) can achieve even that which is inconceivable1. The alternate approach seems to be to admit that all humans simply do not have the motivation or dedication to satisfy these needs through some form of mental discipline.

Misinformation and "scare tactics" have not proven to be adequate deterrents to drug abuse. Furthermore, research with hallucinogens suggests that they have therapeutic value12-14. Also of importance are the results of an early pilot study with prison inmates, where hallucinogens were employed in successful rehabilitation efforts8. Rather than using evidence of illicit use or abuse of these drugs to assess their value or therapeutic potential, further formalized and systematic research is needed.

III. Hallucinogenic Amphetamine Analogues

Since most hallucinogenic amphetamine derivatives were synthesized in efforts to understand the mechanism of action and structure-activity relationships of this class, rather than to circumvent the law, this author greatly prefers the term "controlled substance analogues" to the one adopted by the media, "designer drugs". This is especially true in the present case. Even though a few of these compounds have become popular as recreational substances, they were all outgrowths of legitimate research, and were not "designed" in clandestine laboratories by "renegade chemists" in some attempt to thwart the drug laws.

The current problem with the growth and spread of socially unacceptable uses of drugs was anticipated more than 10 years ago by Shulgin15, in an article entitled "Drugs of Abuse in the Future". Although most of the discussion in that paper was directed toward potential stimulants and opiate-type drugs, Shulgin noted that the hallucinogenic agents that are the most likely candidates for future abuse are those that are totally synthetic and have a sufficiently simple structure for synthesis. He identified three potential types of compounds: tryptamines and carbolines, phenethylamines, and choline analogues related to atropine and scopolamine. The latter group of compounds are more properly classified as deliriants and have not proven to be popular; hence, the tryptamines and phenethylamines shall be the focus of our present attention.

As it happens, there are relatively few tryptamines with significant biological activity, when compared with the variety of possible phenethylamine derivatives. First, the tryptamines are sensitive to ring substitution, with activity being limited to an unsubstituted indole, a methoxy in the 5-position, or a hydroxy in the 4-position. Other substituents, or other substitution locations, give compounds that lack hallucinogenic activity. Within these constraints, activity seems to lie within a fairly narrow range of amine substitutions, including N,N-dimethyl, diethyl, diisopropyl, di-n-propyl, or methylisopropyl16.

However, perhaps even more important to this issue is the fact that substituted indoles, the required precursors to tryptamines, are generally difficult to synthesize, and require a high level of skill on the part of the chemist. It appears that novel synthetic tryptamines with biological activity that would make them attractive for abuse generally will not be economical to manufacture. These compounds are unlikely to appear as serious drug abuse problems. The carbolines are prepared from tryptamines, so the possibility is even more remote that these will appear as problems.

On the other hand, phenethylamine derivatives are relatively easy to synthesize. Mescaline serves as the prototype of this variety of analogue. Although mescaline is a naturally occurring alkaloid, it possesses relatively low potency. Thus, it is only very rarely that mescaline has been seen on the illicit market, and then only at a high price. It is simply not economical to manufacture mescaline. However, a fairly wide range of structural variation within the phenethylamine class leads to compounds possessing psychoactive properties. Ring substitutions at the 4-, 2,4-, 2,4,6-, 3,4-, 3,4,5-, and 2,4,5-positions can all give rise to active compounds.

Either a two-carbon ("phenethylamine" or three-carbon ("phenylisopropylamine") side chain leads to activity. The latter type of structure is referred to as a "substituted amphetamine hallucinogen".

For a drug to gain popularity on the illicit market, at least two criteria must be fulfilled. First, and most fundamentally, the drug must have some pharmacological property that is considered desirable to potential users. Second, it must be economical for manufacture by clandestine laboratories. Generally, this means that the compound must have a fairly high potency. One might assume, for example, that if the active dose of mescaline was 10 mg, rather than 300 mg, then mescaline would have become a very popular drug on the illicit market.

Also included in this latter consideration are not only cost, but the ease of obtaining starting materials. Thus, while some phenethylamines can be prepared from commercially available benzaldehydes or benzoic acids, others require a tedious multistep synthesis from some accessible precursor. Whether or not this starting material has a low cost, unless the final compound is extremely potent, substances that require complicated synthetic schemes are unlikely to attract the attention of clandestine laboratories.

As a result of research over the past 20 years, a great deal is known about which compounds have desirable properties, which are easy to synthesize, and which ones could likely prove to be problems in the future. It is fortunate that the structure-activity relationships are fairly restrictive, as contrasted, for example, with drugs that have opiate-type activity.

IV. Toxicity

The typical hallucinogens have rarely caused death. Lethal overdoses of LSD and mescaline and chronic organ toxicity are unknown. When death does occur, it is most often accidental and usually associated with the drug-induced mental aberrations, (see for example Reference 18). Suicides have occurred during the postdrug state when depression or fear of remaining psychotic may occur. Very few homicides have been reported1.

Adverse reactions to typical hallucinogens usually are treated by support, reassurance, and a quiet environment in the company of family or hospital staff members. However, most hallucinogenic experiences never receive medical attention.

In contrast to the opiate-type drugs, which produce genuine physical dependence and addiction, hallucinogens do not have this capability. Whereas chronic use of opiates produces a pharmacological "need" for the drug, hallucinogens are typically not used on a chronic basis, since repeated use leads to rapid development of tolerance and reduced drug effect.

The National Commission on Marijuana and Drug Abuse19 suggested that drug use can e divided into five classes. Experimental use is defined as trying a drug once or twice to find out what it is like. Recreational-social use is the pattern of ordinary social drinkers or marijuana users, and also that of many non-addicted heroin users. Situational use is use for special but nonmedical purposes. This would include the use of stimulants for work or study, tranquilizers for public speaking, and psychedelic drugs for religious or personal insight. Most people are probably capable of using these types of drugs only in these ways, which produce relatively little harm. The other two categories, intensive use and compulsive use, cause most of the "drug problem"20, yet are rarely associated with use of hallucinogenic drugs.

The difference between usage patterns of opiates and hallucinogens has another practical consequence. One can imagine that toxicological problems will be more readily apparent with opiates, stimulants, or other drugs that are typically used on a frequent or chronic basis. For example, if a particular opiate analogue has some subtle toxicological property, this effect is more likely to become manifest, or amplified, in a population of drug users who administer that drug on a continuing, chronic basis.

It needs to be kept in mind that it is not just "designer drugs" that are the problem. Rather, it is simply the fact that users of illicit drugs obtain "street drugs". Such clandestinely manufactured materials typically are not pure and contain a variety of impurities that may in themselves be toxic. The recent tragedy with an MPTP-contaminated meperidine analogue would not have occurred had the drug been purified and freed of the MPTP contaminant. So the problem is not just with controlled substance analogues, but is a more general hazard associated with street drug use.

There are two types of toxicity that can be expected with hallucinogenic amphetamine analogues, or with any drug for that matter. The first is acute toxicity. With opiate analogues, the most serious form of acute toxicity would be death due to severe respiratory depression. Alone in this situation, an individual would become a casualty. However, hallucinogenic amphetamine overdose would not typically lead to rapid death. First, this type of substance, while it can be administered intravenously like the opiates, is more often taken orally. The pharmacokinetics of oral administration allow more time for medical intervention if it is apparent that an overdose has been taken. Hallucinogenic amphetamines do not cause respiratory depression, and do not typically lead to loss of consciousness.

The two analogues of this class that have caused the most deaths are paramethoxyamphetamine (PMA)21 and 3,4-methylenedioxyamphetamine (MDA)22. The toxic manifestations reported in overdose with these drugs include restlessness, agitation, sweating, rigidity, convulsions, high blood pressure, tachycardia, and extreme hyperpyrexia, all suggestive of excessive CNS stimulation. With these obvious symptoms the overdose victim or his companions are more likely to recognize that a problem exists and have more time to seek medical assistance than in an opiate overdose. Although there is presently no antidote recognized for poisoning with these agents, Davis et al.23 have shown chlorpromazine to be effective against a lethal dose of MDA in dogs.

Vascular spasm has been associated with excessively high doses of the hallucinogenic amphetamine 2,5-dimethoxy-4-bromoamphetamine (DOB). One case report describes effects of a dose of 75 mg of DOB that led to severe peripheral vascular spasm which was apparently improperly treated and eventually resulted in bilateral above-the-knee amputations24. Appropriate medical intervention can prevent such severe consequences25. Of course, a 75-mg dose of DOB must be considered massive, since the psychoactive effects of this drug can be detected in the sub-milligram range. Death due to DOB overdose has also been reported26.

The second type of toxicity that can occur is chronic. This is a toxicity that would be manifest over a long period of use. There are no toxicological studies with hallucinogenic amphetamines that would suggest what form such toxicity might take, since most hallucinogenic amphetamines are not used over long periods of time, or on a chronic or daily basis. Therefore, these concerns have not been addressed in the scientific literature.

Yet the dangers of hallucinogenic amphetamine use are real and present. Consider the consequences of the following scenario. A new drug hits the illicit market in large quantities. Its chemical structure is very simple and the starting material is present in most chemistry laboratories. One can envision widespread usage of the drug and, probably, a sort of cottage industry that would develop to manufacture the drug locally by persons with relatively little chemical expertise. Thus, not only would the drug proliferate, but much of the available drug would be impure or might not be the advertised drug at all. Suppose further that the drug or a common contaminant had a toxic effect that was not immediately evident, but was only manifest much later. It might be a neurotoxic action, for example, suggested as a possibility for MDA27 or MDMA28, or it perhaps might be a carcinogenic agent. In any event, large numbers, perhaps millions, of persons might have experimented with the drug before the toxic effect was observed. This would be a tragedy of a magnitude never previously encountered. This possibility should generate sufficient concern to force a serious search for ways to forestall such an occurrence.

To quote a statement made in 1978, "We cannot afford to wait until an enterprising illicit drug manufacturer successfully markets some new drug, one which might receive enthusiastic public acceptance. We need to be prepared to recognize the symptoms which might be seen in acute intoxication involving such a new drug"29.

Certain means have been suggested to remedy this situation29. First of all, ethical considerations should be reexamined with respect to psychoactive drug studies. It has also been suggested that a set of human research standards be developed for the study of drugs in acute trials, with specific focus on the mind-altering properties of these drugs. Clearly, the ethics of self-experimentation and informed consent need to be readdressed for such studies. ln other words, the issues that presently discourage clinical studies with hallucinogenic drugs should be reexamined.

V. MDMA

I have so far only alluded to the substance MDMA, also known as Ecstasy, which became popular in the past few years as a recreational substance. While hallucinogenic amphetamines have been used for many years, it was the sudden popularity of 3,4-methylenedioxymethamphetamine, MDMA, that brought to a focus concerns about controlled substance analogues of the hallucinogenic amphetamine type.

MDMA was patented in 1914, but was never marketed. In the 1970s it was rediscovered to be a mild psychoactive agent, which did not produce the striking changes in mental states that are characteristic of powerful hallucinogenic agents such as LSD or mescaline29. Sometime subsequent to this, MDMA was employed by a number of therapists as an adjunct to psychotherapy. George Greer30, a psychiatrist practicing in New Mexico, privately published a report of 29 case studies where he concluded that MDMA was beneficial to his patients.

In contrast, a study by Ricaurte et al.29, found that MDA, a structurally related compound, produced serotonin nerve terminal degeneration in rat brain. When MDMA was openly sold, and flagrantly advertised as "a legal drug", it was inevitable that government action had to be taken. With the power that Congress had recently granted to the Drug Enforcement Agency (DEA) to curb the tide of new, controlled substance analogues, the study by Ricaurte et al. was presented as evidence for the dangers of MDMA use, and the DEA invoked its emergency scheduling powers to place MDMA into Schedule I of the Controlled Substances Act of 1970.

Interestingly, although MDMA is chemically related to the hallucinogenic amphetamines, it is not itself hallucinogenic29-31. In rats, MDMA has pharmacological properties similar to both amphetamine and to hallucinogens. However, in man it has a psychoactive effect that seems distinct from other known classes of compounds. It has been suggested that MDMA, and substances with a similar pharmacology, are representatives of a completely new pharmacologic class that has been named "entactogens"32. One of the more powerful arguments for this new classification is the fact that it is the (+)-isomer of MDMA that is more biologically potent, while it is the (-)-isomer of the hallucinogenic amphetamine analogues that is more active.

It is not clear whether many other MDMA-like compounds will appear on the illicit market. At present, it appears that the 3,4-methylenedioxy aromatic ring substituent is required for MDMA-like pharmacology. In addition to the N-methyl derivative, MDMA, the N-ethyl derivative MDE has been available on the illicit market. Only one additional compound is presently known with an MDMA-like effect. This is the homologue where the alpha-methyl in the side chain of MDMA has been replaced with an alpha-ethyl. It is somewhat less potent in humans than MDMA32.

The acute toxicity of MDMA would appear to be low. However, a major concern developed after publication of the study by Ricaurte et al.27 , where administration of the chemically related compound MDA to rats caused serotonin nerve terminal degeneration. It is not known if this toxicity occurs in man, or if it does, what the consequences are. This issue will probably have to be resolved before extensive clinical research to study the therapeutic potential of MDMA can be approved.

VI. Research Concerns

There are no convincing arguments that it is a good idea to categorize hallucinogenic drug analogues with addictive or acutely toxic substances such as heroin or fentanyl analogues. While there are real dangers, there is no evidence that they are of the same magnitude as those associated with abuse of opiates, cocaine and other stimulants, or sedative-hypnotics (all of which are dwarfed, of course, by the public health costs of alcohol and tobacco use.) Indeed, Nicholi11 did not even treat the subject of hallucinogens when he considered the problem of non-therapeutic use of psychoactive drugs.

It is quite possible to develop psychoactive chemicals that could be safely used in a recreational context. Whether or not our society would accept the use of such substances is quite another matter. Certainly no drugs can be viewed as either "good" or "evil" in and of themselves; it is the context of drug use that must be viewed as positive or negative. Huxley, in his article "Criteria for a Socially Sanctionable Drug"10, has even discussed what pharmacological properties a drug must have that would allow it to be socially acceptable.

However, even though the evidence from many cultures suggests that humans need to experience altered states of awareness, the notion that drugs can or should be used by "well" people seems repugnant to our society. Nevertheless, enforcement has not succeeded in controlling recreational use of hallucinogens. Therefore, it is not clear how increased penalties for the use of hallucinogens will abolish the human desire to experiment with these drugs. Indeed, it seems axiomatic that making a substance illegal, and prohibiting its use, can actually encourage its use, engendering a sort of adventurism.

In the attempts to control the black market use of hallucinogenic drugs, a massive "overkill" in legislation has occurred. While the drugs are still widely available on the street, clinical investigators face a formidable array of paperwork and approvals to obtain them, one result being a disincentive to carry out research on hallucinogens. Although some readers may violently disagree with this supposition, a quote from a paper written by Szara, in 196733, is still relevant:

"Finally, there is a situation I feel compelled to comment upon. I am referring to the nonmedical use or abuse of hallucinogenic drugs. There is an obvious need for regulating the use of these powerful and potentially dangerous agents. However, we should not throw the baby out with the bath water. The recent run of unfavorable publicity in newspapers and national magazines has forced the Sandoz Company to stop manufacturing LSD in the United States, and the company has turned over its LSD supply to the NIMH as of April 15, 1966.

This publicity pressure threatens serious scientific research not only with LSD but with the entire class of hallucinogenic drugs. We cannot put blame on the drugs; we can only put blame on the manner and the ways they are being used. It is my belief that it would be most unfortunate if we were to permit undue hysteria to destroy a valuable tool of science and evaporate an eventual hope for the many hopeless."

What now exists is a situation where there is a real need for research with psychedelic and hallucinogenic substances, but society and its regulatory agencies refuse to permit clinical research to occur. Instead, one finds self-experimentation, with results that are unpublished and unavailable to the scientific community, with reports of drug effects that are anecdotal, anonymous, and completely unreliable. When a drug such as MDMA surfaces and gains popularity, it merely strengthens the resolve of enforcement agencies to proscribe any use, under any circumstances, of these compounds. This situation may be justified with opiate analogues, since nonmedical use of these substances does not constitute "research" and is rarely experimentation. These drugs have their representatives in the armamentarium of clinical medicine. The same can be said of CNS stimulants, which are widely abused, but which are also pharmacologically well-defined. It is only with hallucinogens that the situation seems unique. At present, no clinical counterpart exists, and no research is occurring to study them further.

While governmental agencies proclaim their desire to see more clinical research done, there is no suitable protocol for study of these drugs. Without widely recognized medical benefit, the benefit/risk ratios are perceived to be infinitesimally small. Without a significant benefit/risk ratio, no studies will be allowed. Even when an acceptable benefit can be demonstrated, the regulations are so cumbersome that they restrict research. I recall the story related by Dr. George Greer, concerning a patient of his in his 70s who had crushed vertebra secondary to multiple myeloma and was in severe chronic pain. Prior to the scheduling of MDMA, the only treatment that had given this patient significant and long-lasting relief was MDMA-assisted therapy. After MDMA was placed into Schedule I, Greer attempted to obtain a compassionate Investigational Exemption for a New Drug (IND) for this patient, in order to conduct another MDMA session. In spite of the fact that MDMA had been used recreationally on a widespread basis with no known significant adverse health consequences, and in spite of the continuing chronic pain of this patient, his age and terminal prognosis, approval of Greer's IND was postponed for lack of sufficient preclinical animal data.

Apparently, informed consent of the patient to utilize this experimental treatment was of no consequence. The patient has subsequently died, in pain, with his physician powerless to relieve his suffering.

It would seem that the use of hallucinogens or related psychoactive drugs to facilitate psychotherapy is just as valid a technique as any of the approximately 400 other forms of therapy that are currently available, none of which is superior to the others34. As long as the patient is properly informed as to the nature of the drug effect and possible adverse psychological consequences, his desire to use these treatments should be respected. The wishes of the terminal patient referred to above, who was in severe chronic pain, were ignored by the procedures that currently govern clinical drug studies.

Most classes of drugs are developed to be used daily, over a long period of time. By contrast, research with hallucinogens suggests that, if they found a place in medicine, they would be used intermittently and infrequently, as therapeutic catalysts to bring about some psychological transformation. Protocols for Phase I studies are not designed for drugs that are to be used episodically in this way.

Because of disincentives for research, scientists and clinicians who began research with LSD were unable to complete their efforts. Although feeling that they had gained an initial understanding of how to use LSD in a proper therapeutic context, so as to derive maximum benefit for their patients, clinical research with LSD, for all practical purposes, is now completely dead. Why? Because Schedule I classification is very restrictive, making it difficult even for medical treatment of the terminally ill. One hears time and again from regulatory officials how Schedule I classification is no impediment to research; yet if this is so, where is the clinical research with LSD today? The facts speak for themselves.

One hears the standard retorts that LSD was proven dangerous, or had no value, or was too tricky to use. There are many clinical reports to the contrary12-14. Like any new technology, it takes time to learn what can and cannot be done, and how to most effectively use new tools. Psychotherapeutic approaches using hallucinogens were just being developed when scheduling occurred and researchers pulled out of the field. However, LSD was found to be safe when used under appropriate clinical conditions35 and is probably one of the safest drugs known in terms of physiological toxicity. Nonetheless, there seems to be minimal interest on the part of government agencies to fund this sort of research, and clinical scientists are either afraid of the controversy that continues to surround LSD, or are unsure how to go about getting approval and funding to work with it. As a result, there is a whole new generation of uninformed clinical scientists who have dismissed any possible therapeutic value of LSD.

This author has commented extensively on the need for discovery of new types of psychoactive drugs, many of which, like MDMA, might arise from research with hallucinogenic amphetamine analogues36. Presently, regulations on clinical studies appear likely to thwart the discovery of such novel mind-altering substances. Unless there is a change in philosophy, psychiatric practice will remain limited by the types of psychoactive drugs which are now in use.

In order to assess properly both the potential for abuse and the therapeutic value of hallucinogens, research must be allowed, indeed, must be encouraged. It is only through education, armed with factual research results, that we can hope to control the use of hallucinogenic drugs. In our haste to control these substances, it is to be hoped that we will not, again, "throw the baby out with the bath water".

References

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