Drug Abuse

A.5 HALLUCINOGENS

INTRODUCTION

One of the most remarkable and controversial drugs known today is &lysergic acid diethylamide-25, also called lysergide, but better known as LSD or simply 'acid'. LSD is capable of producing profound and unusual psychological changes in almost infinitesimal doses, with relatively little other pharmacological effect. Along with related drugs it has exerted significant influence in a variety of aesthetic, scientific, philosophic, religious and social areas over the past two decades. LSD is often considered the prototype of the drug class we have called Psychedelic-Hallucinogens (or simply hallucinogens), which includes a great number of synthetic and naturally occurring substances with somewhat similar psychopharmacological properties. To date, several thousand articles on LSD and related drugs have been published.

LSD was developed in 1938 by Hofmann and Stoll, in Switzerland, as part of a research program investigating potential therapeutic uses of certain ergot compounds.129 LSD is a semi-synthetic derivative of lysergic acid, an ergot alkaloid produced by a parasitic fungus, or 'rust', sometimes found on rye or other grains. Closely related substances are also produced in the seeds of certain varieties of tropical morning glory. Most ergot alkaloids are not
particularly psychoactive, although some may have a variety of powerful, and often toxic, physiological actions, and have been used for centuries for medical purposes.

Since LSD appeared to be relatively uninteresting in early animal physiological studies, it received little attention until Hofmann unwittingly
ingested a minute quantity some pars after its original synthesis.'3° He subsequently described his experience as follows:

In the afternoon of 16 April 1943, when I was working on this problem,
was seized by a peculiar sensation of vertigo and restlessness. Objects, as well as the shape of my associates in the laboratory, appeared to undergo optical changes. I was unable to concentrate on my work. In a dreamlike state I left for home, where an irresistible urge to lie down overcame me. I drew the curtains and immediately fell into a peculiar state similar to drunkenness, characterized by an exaggerated imagination. With my eyes closed, fantastic pictures of extraordinary plasticity and intensive colour seemed to surge towards me. After two hours this state gradually wore off.

To confirm his suspicion that LSD was responsible for this effect, Hofmann investigated further:

However, I decided to get to the root of the matter by taking a definite quantity of the compound in question. Being a cautious man, I started my experiment by taking 0.25 mg of d-lysergic acid diethyl amide tartrate, thinking that such an extremely small dose would surely be harmless, and bearing in mind that the natural ergot alkaloids produce toxic symptoms in man only with doses exceeding several milligrams. After 40 minutes I noted the following symptoms in my laboratory journal: slight giddiness, restlessness, difficulty in concentration, visual disturbances, laughing.

And later:

I lost all count of time. I noticed with dismay that my environment was undergoing progressive changes. My visual field wavered and everything appeared deformed as in a faulty mirror. Space and time became more and more disorganized and I was overcome by a fear that I was going out of my mind. The worst part of it being that I was clearly aware of my condition. My power of observation was unimpaired.... Occasionally I felt as if I were out of my body. I thought I had died. My ego seemed suspended somewhere in space, from where I saw my dead body lying on the sofa .... It was particularly striking how acoustic perceptions, such as the noise of water gushing from a tap or the spoken word, were transformed into optical illusions. I then fell asleep and awakened the next morning somewhat tired but otherwise feeling perfectly well

Since various aspects of the LSD experience were later thought to resemble symptoms of naturally occurring schizophrenia, many investigators became interested in using LSD as a tool for producing an artificial or 'model psychosis' in the laboratory. The possibility of gaining insight into psychiatric disorders by the study of the LSD-induced state stimulated considerable activity in medical and scientific communities and the terms psychotomimetic (psychosis mimicking) and psychotogenic (psychosis producing) were coined. The subsequent discovery that the LSD experience is, in fact, generally different from natural psychoses has lessened interest in this aspect of its use. The descriptive label hallucinogenic (hallucination producing) has gained wide acceptance, although there is some controversy regarding the importance or frequency of hallucinations in the LSD experience. The term illusinogenic (illusion producing) is probably more appropriate.

In the 1950s, the exploration of LSD as an aid to psychotherapy began. Much of the early investigation of the use of LSD in the treatment of alcoholics was conducted in Canada under the direction of Abraham Hoffer at the University of Saskatchewan. In 1957, after reviewing the various descriptive names given LSD and related drugs, Humphrey Osmond, then Superintendent of the Saskatchewan Hospital, suggested the terms psycholytic (mind releasing) or psychedelic (mind manifesting) as more appropriate general labels.228 For various reasons the latter has gained worldwide usage, although its common application has strayed considerably from its original context, and the word psychedelic may now denote general styles of art, fashion and music which are, in some sense, felt to reflect, enhance, or substitute for the psychedelic drug experience.

In this report, the labels "psychedelic", "hallucinogen" or "psychedelic-hallucinogen" are used interchangeably to refer generally to LSD and LSD-like drugs and, for practical purposes, are considered synonymous.

Non-medical interest in LSD, psilocybin and mescaline began to grow during the 1950s, although such use was apparently largely restricted to a few professional, academic, and artistic experimenters. The drug gained continental notoriety in the early 1960s as a result of experimentation by two Harvard University psychology professors, Richard Alpert and Timothy Leary, who invited other 'explorers' to "Turn on, tune in, and drop out" of the existing social institutions. Their unorthodox religious orientation to the LSD experience is presented in The Psychedelic Experience, (a 'trip' manual based on The Tibetan Book of the Dead), which became one of the 'bibles' of the psychedelic drug movement.'77. 18° Another significant influence, with considerably less religious orientation, was writer Ken Kesey's group, the adventures of which are well documented in The Electric Kool-Aid Acid Test.325

Since 1963, the Canadian Government has controlled the medical and scientific use of LSD, and in 1969 the possession of LSD without governmental authorization was made a criminal offence. Regulation of the legal supply of LSD has apparently had little effect on 'street' use, however, since essentially all of the drug illicitly used has come from clandestine laboratories. Since LSD is odourless, colourless and tasteless in solution and active in almost invisible quantities, effective legal control of its transportation, distribution and use has been extremely difficult. (See also Appendix B Legal and Illegal Sources and Distribution of Drugs.)

MDA (methylenedioxyamphetamine) and STP (DOM, dimethoxymethylamphetamine) are synthetic drugs, intermediate in structure between mescaline and amphetamine with some pharmacological properties of each. Closely related compounds which are rarely found on the illicit market include MMDA, TMA and DOET. Relatively little information is available regarding the non-medical use of these drugs and the effects produced by such use.

MDA was originally explored medically for its amphetamine-like properties, and has been shown to have some anti-depressant and appetite-suppressing effects, but it is currently legally available only for experimental purposes. MDA is in some respects similar to, but more potent than mescaline.m. 113, 288 The non-medical use of MDA has increased considerably in Canada during the past few years.

STP first appeared on the illicit market in California in 1967, where it was heralded as a "megahallucinogen"—a drug "one hundred times as potent as LSD", which was capable of producing an hallucinogenic 'trip' lasting for several days. The label STP is presumably a satirical reference to a commercial automobile engine oil additive (Scientifically Treated Petroleum). Later the words "serenity, tranquility and peace" were appended to the initials. The chemical identity of STP was uncertain for some time and it is likely that the label has been applied to several different drugs and drug mixtures in the past. A number of illicit samples were finally identified as DOM, an experimental compound originally developed by the Dow Chemical Company of California. Since then the letters STP have generally been taken to refer to DOM. In this report STP and DOM are considered synonymous. In spite of the "megahallucinogen" reputation, DOM is considerably less potent than LSD, and 'trips' of long duration are only achieved with unusually large doses. 214, 235, 281

Phencyclidine or PCP (Sernyl®, Sernylan®) is sometimes called 'the peace pill', 'angel dust' or 'hog'. It was developed in the late 1950s for use as a sedative, general anesthetic and analgesic. After considerable clinical testing its use in humans was discontinued, in part because it often produces agitation and psychotomimetic effects at moderate to high doses. Phencyclidine is still marketed for veterinary purposes, and is the 'animal tranquilizer' often noted in mass media reports of illicit drug use. It has some subjective effects in common with LSD, but PCP is typically much more sedating, and produces a different pattern of physiological response. Some investigators feel that PCP is pharmacologically more similar to the general anesthetics or volatile solvents than to LSD. The use of PCP in Canada has become significant in the last few years. There is a significant body of clinical data on PCP, but relatively little scientific information exists regarding its non-medical use and associated consequences.78, 79' 234

While LSD has had a rather short, and somewhat stormy history, numerous naturally occurring substances with apparently similar psychological effects have been used in the Western Hemisphere for centuries. Perhaps the most widely known are mescaline, from the peyote cactus (Lophophora Williamsii) and psilocybin (and psilocin), the active principles in certain `sacred mushrooms' (teonanactl or Psilocybe mexicana). The subjective effects of LSD, mescaline and psilocybin are almost indistinguishable, except that psilocybin has a much shorter duration of action. 4, 140, 324 Other related plant materials include the Mexican morning-glory ololiuqui (Rivea Corymbosa), and DMT (dimethyltryptamine) which is found in special snuffs used for centuries by certain South American Indians. Harmine and harmaline occur in the caapi plant, which is used in the form of a drink by Amazonian natives. Some of these botanical substances were considered divine by the ancient Aztecs and played an important role in religious ceremonies long before the Spanish invaded the land. In spite of the Conquistadors' attempts to destroy the culture and its historical and religious underpinnings, the sacramental use of peyote, for example, spread to the Mexican Indians and, later, in the 19th century to certain North American tribes. Today, peyote is used in religious ceremonies by the Native American Church which has over 200,000 Indian members from 82 tribes in Canada and the United States. 3, 64, 172, 186, 261

The ritual use of hallucinogenic substances by a contemporary Yaqui Indian sorcerer or 'man of knowledge' in Southwest United States has recently been documented in detail by an anthropologist, Carlos Castaneda, in three monographs.53, 54' 55 These books record the events which took place during Castaneda's period of apprenticeship to Don Juan, and describe his experiences with peyote, Jimson Weed (Datura stramonium) and psilocybin mushrooms.

The Amanita muscaria or fly agaric mushroom grows wild in many areas of the world. Its use for psychotropic purposes is best documented, in recent times, in parts of Siberia. Gordon Wasson has conducted a remarkable investigation of Amanita muscaria and has proposed that it is the divine soma described in the earliest Hindu literature some 3,000 years ago.318 Recently, in The Sacred Mushroom and the Cross, John Allegro presented the thesis that this mushroom played a significant role in early Christianity." Although Amanita muscaria and several varieties of psilocybin mushrooms grow untended in many areas of Canada, it would appear that these mushrooms have been ingested by only a few exceptional experimenters in this country. There is no evidence that the native Indians of Canada have used these mushrooms.

The common spice nutmeg (and mace) has had a long history of medical and non-medical use as a drug which parallels in many respects that of cannabis. The effects of nutmeg and cannabis are remarkably similar, although the nutmeg 'trip' is considerably longer in duration. The nutmeg tree (Myristica fragrans) is cultivated in many tropical areas of the world. The active principles of nutmeg are structurally very similar to amphetamine, mescaline and MDA. The use of nutmeg for its psychotropic properties has often been noted in certain groups in North America, but such use has apparently never been extensive.97, 266, 302, 319

Certain belladonna alkaloids, such as scopolamine, and other anticholinergic drugs which produce sedation in low doses, but hallucinogenic effects with larger quantities are discussed below in A.8 Minor Tranquilizers and Non-Barbiturate Sedative-Hypnotics. There is also some discussion of drugs with certain hallucinogenic properties in A.9 Volatile Substances: Solvents and Gases.

Until relatively recently, psychedelic drugs received little general public attention, even though some had been intensively explored over the past century by various writers, scientists and adventurers. Based on his mescaline experimentation, Aldous Huxley presented, in his twin volumes The Doors of Perception and Heaven and Hell, one of the most lucid and perceptive analyses of some of the possible personal, philosophical and social implications of the psychedelic experience.138

The pharmacological classification of cannabis is the subject of much controversy. Cannabis has certain characteristics in common with a wide variety of drugs; under various conditions and doses it has been shown to have stimulant, sedative, analgesic and psychedelic properties. Many investigators feel that cannabis should have a separate and unique category. As it is most commonly used in North America, cannabis in low doses resembles alcohol in some subjective effects. Larger doses are more psychedelic, and with very high doses certain LSD-like experiences are reported. It is clear that any attempt to completely specify a pharmacological classification for cannabis must include a clear delineation of dose, as well as the set and setting of use. The Commission has classified cannabis with the psychedelic-hallucinogen drugs. Since cannabis has already been dealt with in great detail in a separate final report, little further reference will be made to cannabinoid drugs in the present discussion.47

LSD is the best studied and most frequently encountered psychedelic-hallucinogen in Canada (excluding cannabis), although in recent years, significant quantities of PCP and MDA have been identified. STP is only occasionally found. The use of other LSD-like drugs appears to be rare in this country. Although one frequently hears fascinating stories of exotic drugs created by 'hippie chemists', there is no evidence that such compounds are used significantly. The general discussion which follows focusses primarily on LSD, with references to other related drugs, including PCP, MDA, mescaline, and psilocybin, where distinctions are appropriate and data are available.

MEDICAL USE

There is currently no widely accepted medical use of LSD, although it may be employed experimentally for therapeutic purposes. There have been numerous impressive reports of LSD successes in the treatment and rehabilitation of alcoholics, opiate narcotic dependents, criminals and various psychiatric patients.105, 126, 178, 267 LSD has also been used with patients dying of cancer, to alleviate their anxiety and pain, and to help them adjust to the prospects of death?". 230 Many of these leads have not been followed up with adequate scientific investigation, however, and several recent controlled studies have not substantiated the claim that LSD adds to the effectiveness of conventional psychotherapy 75, 171,198, 272

Two basic forms of psychological treatment with LSD have developed: psycholytic therapy, which uses small or moderate doses on repeated occasions, sometimes over a period of several months; and psychedelic therapy which calls for higher doses and a more profound acute effect and is, as a rule, given only once or twice. While some investigators claim that LSD, itself, is more effective than psychotherapy, others claim that its usefulness is mainly limited to the removal of therapeutic 'blocks' which may occur at times in the course of psychotherapy. Still others feel that LSD has no useful contribution to make to psychiatric treatment. Most clinicians who have had experience with this form of therapy stress the need for a careful selection of patients and for special qualities and experience in the therapist.

More sophisticated scientific investigations of possible therapeutic uses of LSD are underway and may help clarify some of these issues. It seems justified to say at this time, however, that the general medical effectiveness of LSD has not been adequately demonstrated.

Phencyclidine (PCP) is no longer employed as a sedative-anesthetic in humans, although it is available for veterinary purposes. Various forms of MDA (e.g., MER-22, SK&F 5 and SK&F L-5) have been evaluated in the treatment of schizophrenia and depression, and were investigated for their anorectic (appetite-suppressing) effects. MDA is not used medically at the present time, however.24, 78, 79, 80, 100, 113, 134, 222

CHEMICAL ANALYSIS OF ILLICIT SAMPLES IN CANADA

Illicit drug samples submitted to authorized laboratories for identification are often those suspected of being adulterated, some other drug than it was alleged to be, or the cause of adverse or unusual reaction. Even though such samples cannot be considered representative of the available illicit drugs, some useful general information can be obtained from an examination of the data from these laboratories. The Commission's national survey of drug analysis facilities in Canada during 1971-72 and our own collection of illicit samples provide considerable data on LSD and related drugs.218.[c] These two sources of data are considered together in the following summary.

Of 162 samples alleged to be primarily LSD:
69% were LSD alone
9% contained LSD and other drug(s)
9% were other drug ( s )
5% were primarily products of faulty or incomplete LSD synthesis 8% contained no drug

Of ten samples presented specifically as LSD mixtures, only one was the alleged combination, and the remainder contained LSD only. In addition, LSD was frequently found in samples represented as other drugs. A total of 45 LSD-PCP combinations were found, only one of which was presented to the analyst as such. Seven samples of LSD-barbiturate mixtures were reported, but no other specific LSD combination occurred more than a few times each in these data. A total of 208 relatively pure LSD samples were found, and of 183 for which some alleged identity had been specified, 111 (61% ) had been presented as LSD.

Of 64 samples alleged to be primarily MDA:
42% were MDA alone
20% were MDA and other drug(s) 27% were other drug(s)
11% contained no drug

Of 12 samples presented specifically as MDA mixtures, none had the alleged composition and seven contained only MDA. A total of 52 samples of unadulterated MDA was found, and of the 42 for which an alleged identity had been specified, 27 (66%) had been presented as MDA. MDA combinations included LSD, PCP or amphetamines. No evidence of faulty synthesis of MDA was noted in these data. Two samples of MMDA and 17 STP (DOM) samples were reported. All of the STP-containing samples had been presented as some other drug.

Forty-seven samples of PCP alone were found, as well as 57 PCP combinations (45 with LSD and 9 with methamphetamine). No indications of faulty or incomplete PCP synthesis were noted. In spite of the fact that PCP was detected in a total of 104 samples, there were only two cases which were presented as PCP or PCP mixtures. In every other instance the drug was either alleged to be something else or its identity was not specified. Eighteen of 26 alleged tetrahydrocannabinol (THC) samples were actually PCP, and none contained THC.

There were 171 samples alleged to be mescaline, but only five (3% ) contained any trace of that drug. One hundred and thirty-five (79%) were other drug(s) and 31 (18%) contained no drug. The samples erroneously presented as mescaline included 43 LSD, 33 LSD and PCP, 18 PCP, 11 STP, 9 methamphetamine, and a variety of other drugs.

Thirty-two samples were alleged to be psilocybin. This drug was tentatively identified in only one case. Twenty (63%) of the samples were other drug(s) and 11 (34%) contained no drug. Fifteen of the samples were actually LSD.

In an earlier study, Marshman and Gibbins of the Addiction Research Foundation reported on the composition of 621 illicit drug samples collected and analysed in Ontario between January 1969 and February 1970.201 The data reported is generally similar to that presented above. Of 176 alleged LSD samples, 56% were relatively pure LSD. None of 58 alleged mescaline samples contained any of that drug (about half were LSD). The analysts were unable to detect the presence of a second drug in any of 46 samples which had been presented as combinations. There were 29 samples of MDA submitted for analysis, of which 62% had been presented as that drug. Only a few PCP samples and PCP-LSD mixtures were identified at that time.

The Federal Health Protection Branch (HPB) has informed the Commission of the quantitative analysis of several hundred hallucinogen samples selected from among those seized by the police during June 1971—October 1972.114,[b] Many of these samples had been chosen for this special analysis because of previously detected impurities and, consequently, they cannot be considered representative of either the drugs on the street or of police seizures in general. Of 229 samples containing LSD, 166 (73%) contained no impurities or other drugs, 34 were LSD-PCP mixtures, and 16 contained LSD and methaqualone. No other mixture occurred more than a few times. Products of faulty or incomplete LSD synthesis were sometimes noted. Because of the frequency of LSD-PCP mixtures in police seizures, HPB officials considered this combination as a separate category rather than as an incidence of adulteration. Excluding the LSD-PCP mixtures, the 117 unit doses of LSD-containing samples analysed ranged from a mere trace of LSD up to 305 mcg of pure LSD, with a median of 141 mcg. Only 8 of 73 PCP-containing samples did not include another drug in combination. These eight PCP samples contained between 1.7 and 49.0 mg PCP each with a mean of 10.9 mg. Median quantitative values for 26 unit doses of LSD-PCP mixtures were 41 mcg of LSD and 1.8 mg of PCP. There were also 10 PCP-ephedrine mixtures, in which a mean of 4 mg PCP was present. No products of faulty or incomplete synthesis of PCP were noted.

Of 126 seizures of MDA analysed by HPB in this series, only 7 contained other drugs (heroin, methamphetamine or PCP). Sixty-one unit dose samples ranged from 0.6 to 107 mg pure MDA, with a median of 37.5 mg. The 57 samples found in powder or bulk form were between 0.1% and 91.3% pure MDA, with a median of 36.6%. Fifteen seizures of LBJ (methylpiperidylbenzilate) were analysed, of which only three did not include other drugs. These samples typically contained a little over one milligram of LBJ per unit dose. By-products of synthesis were found in 11 cases.

Overview

Subject to the sampling restrictions noted, the data available on the analysis of illicit drugs allows some tentative conclusions regarding the hallucinogenic drugs used non-medically in Canada. Excluding cannabis, LSD is the most frequently encountered of these drugs. For example, LSD alone or in combination with other drugs was detected in 292 (66%) of the 445 hallucinogen (non-cannabis) samples in the Commission study. PCP was found in 104 (23%) and MDA was identified in 72 (16%) of these samples. (Note that because of drug mixtures, these categories are not mutually exclusive.) In total, LSD, PCP, MDA, or combinations involving these drugs made up 94% of such samples. Data from the Addiction Research Foundation and the Health Protection Branch provide generally similar pictures. STP and LBJ have been identified on only a few occasions. Other LSD-like drugs, including mescaline and psilocybin, have rarely been documented in Canada. The Commission's data is particularly significant in this regard since special effort was made to obtain information on rare or unusual drugs or combinations, yet on analysis, samples of such substances were almost invariably found to contain only common drugs. It is obvious from the data that misrepresentation often occurs in the illicit market and that the LSD and related drugs available are highly variable in both purity of the material and the quantity contained in a unit dose. The user has little objective basis for assessing the identity, quality or dose of such drugs prior to use.
Drug combinations are not uncommon, but with the exception of PCP, most samples contain only a single active compound. The present studies are biased in favour of collecting and identifying mixtures and unusual drugs and consequently exaggerate the frequency of their occurrence in the general illicit market. While a few unusual combinations of several different substances have been identified, the vast majority of mixtures are made up of only two common drugs. Samples which are represented as mixtures on the illicit market are rarely as alleged and typically contain only one active substance.

In Manitoba, a poisoning was attributed to an overdose of the stimulant strychnine, which had reportedly been sold as MDA.217 In all of the data reviewed here, strychnine was not found in any of the combinations where it was alleged to occur, but was reported in 4 other instances. Strychnine was not found in any of 2,000 police seizure drug samples analysed by the HPB in 1971,114 nor has it ever been identified in the analyses conducted at the Addiction Research Foundation of Ontario.

It would appear that most of the LSD available on the illicit market is of reasonable quality, although evidence of crude manufacture is present in some samples. Available data suggest that 140 mcg is a typical unit dose in Canada. Concern has been expressed regarding the possible toxic properties of ergot alkaloids present in a few samples as a result of faulty or incomplete LSD synthesis. Since there has been no direct testing of the biological activity of such samples, firm conclusions can not be drawn. Serious toxicity would seem unlikely at typical LSD doses because of the small quantities of ergot compounds generally involved, although unusually large doses of poorly synthesized LSD may involve some risk.

It would appear that PCP is rarely identified as such on the illicit market, but instead is sold alone or in mixtures, primarily represented as mescaline, THC or, less commonly, other rare drugs. Consequently, epidemiological data involving self reports by users, as well as clinical data of adverse reaction or poisoning, are likely to grossly underestimate the involvement of PCP. Chemical identification of the drugs used in such reports is almost nonexistent at the present time. Any PCP cases are likely to be erroneously attributed to other drugs. Reports involving the illicit use of mescaline or psilocybin are likely to actually represent LSD and/or PCP cases.

There has been some concern in the literature that the illicit production of PCP carries a special risk of `missynthesis', the by-products of which may be highly toxic.237 Although the original source of the illicit PCP is uncertain, no evidence of products of faulty or incomplete synthesis of this drug has been found in Canada.

It is interesting that PCP is the only drug in these data which occurs less often alone than in combination with other drugs (primarily with LSD). This is especially significant for the discussion of drug effects which follows, since there is virtually no experimental information available on PCP-LSD interaction in humans.

ADMINISTRATION, ABSORPTION, DISTRIBUTION AND PHYSIOLOGICAL FATE

LSD and most related drugs are usually taken orally, but may be sniffed in powdered form or injected in solution. Some can be effectively smoked. While LSD is available in ordinary capsules or tablets, it is often impregnated in such innocuous substances as sugar cubes, candies, biscuits, and cloth or blotter sections for oral use. LSD is well absorbed from the gastrointestinal tract, is distributed rapidly in the blood and easily diffuses into all tissues including the brain, and in pregnant females crosses the placental barrier into the fetus. LSD does not have any particular affinity for neural tissues and approximately one per cent actually reaches the central nervous system. Essentially all of the LSD in the body is metabolized in the liver and excreted in the urine in the form of inactive compounds. Likewise, MDA and PCP are primarily excreted in the urine in the form of metabolites 9, 84, 78, 79, 234, 281

Recently developed radioimmunoassay techniques allow the rapid detection of minute quantities of LSD in body fluids and tissues 71, 812 PCP, MDA, STP, mescaline and psilocybin can be detected in body fluids and
tissues by standard analytic methods. 19, 57, 58, 156, 288, 294

PSYCHOLOGICAL EFFECTS

LSD is one of the most potent biologically active substances known and can exert noticeable psychological effect with 20-30 mcg (millionths of a gram)—an almost invisible quantity of pure LSD. Taken orally, LSD effects typically occur within an hour and peak at 2 to 3 hours, but may be much faster; response to intramuscular injection usually appears within ten minutes; and if the intravenous route is used, the latency may be only a few minutes or less. Intraspinal injection produces an almost instantaneous effect. The duration of the action depends to a certain extent on the amount taken, and with typical doses, major effects usually last 6-10 hours with gradual recovery over a similar period. Peak effects correspond with blood levels of
LSD 9,84

Depending on dose, the duration of major effects of mescaline, MDA, STP and PCP may be comparable to those of LSD. The main effects of Psilocybin dissipate very rapidly, and usually last only a few hours, and DMT is even shorter acting. The following figures represent typical oral doses of these various drugs as noted in the scientific literature, but cannot be taken as precise quantitative equivalents.4,78,127,140, 244,266,324

LSD    0.1-0.2 mg (thousandths of a gram)
Psilocybin    5-10 mg
STP (DOM) 5-10 mg
PCP    5-10 mg
MDA    75-150 mg
Mescaline    250-500 mg

The psychological effects of LSD and related drugs are not readily predictable, and are determined to a considerable degree by various personality factors in the individual; his past history and experiences; his attitudes, expectations, and motivations; the general setting in which the drug is taken; persons accompanying the `trip'; and external events occurring during the experience. While the psychological response to LSD is to some extent dose-related, certain effects appear to be relatively independent of dose over a considerable range. Increased quantities often seem to affect the duration more than the intensity or quality of the 'trip', although with very high doses confusion and disorientation are more likely to occur. 6, 61, 98, 127, 141, 239

Subjective psychological effects of LSD and LSD-like drugs are extremely difficult to describe and many scientists are quite pessimistic about the possibility of presenting an objective list of responses which in any way communicates the essence of the experience. The intensely personal nature of the effects further limits description and generalization. Pahnke and Richards232 have described several major types of psychological experience which have been reported with psychedelic drugs. The outline presented below is based on that proposed by these researchers. While the list is certainly not exhaustive and does not describe necessarily discrete or non-overlapping categories, it provides a convenient basis for the discussion of LSD-like effects. It should be noted that not all of the experiences listed happen in all sessions or in all individuals, although several may occur in varying degrees, in sequence or simultaneously, during a 'trip'. The relative frequency of these various experiences is not indicated by the order in which they are presented here.

First is the psychotic adverse reaction, or 'freak-out' which may be characterized by an intense negative experience of fear or 'nightmarish' terror to the point of panic, complete loss of emotional control, paranoid delusions, hallucinations, catatonic features, and, perhaps, profound depression and sense of meaninglessness. Such states are usually of short duration, although prolonged reactions have been noted.

Second is the non-psychotic adverse reaction in which the person may experience varying degrees of tension, anxiety and fear, unpleasant illusions, depression and despair. Inappropriate or disordered social behaviour may occur. This kind of reaction may differ from the first in the intensity of the experience and in the degree of control and 'reality contact' expressed by the individual. Such unpleasant experiences are commonly labelled 'bad trips' or `bummers'.

Third is the psychodynamic psychedelic experience characterized by a dramatic emergence into consciousness of material which had previously been unconscious or suppressed. Strong emotional feelings can accompany what may be experienced subjectively as a reliving of incidents from the past or a symbolic portrayal of important conflicts. Such effects are often sought in LSD psychotherapy.

Fourth is the cognitive psychedelic experience characterized by an impression of astonishingly lucid thought. Problems may be seen from a novel perspective, and the interrelationships of many levels of meaning and dimensions may be sensed simultaneously. The relationship between this experience and naturally occurring insight and creativity has been the subject of considerable interest and speculation.

Fifth is the aesthetic psychedelic experience characterized by a change and intensification of all sensory impressions, with vision often most affected. Fascinating alteration in sensation and perception may occur; synesthesia or crossing-over of sensory modalities may be produced (music and other sounds may be "seen", for example); objects such as flowers or stones may appear to pulsate or "become alive"; ordinary things may seem imbued with great beauty; music may take on an incredible emotional power; and visions of beautiful colours, intricate geometric patterns, architectural forms, landscapes and "almost anything imaginable" may occur.

The sixth type of psychedelic experience has been called by such names as psychedelic-peak, cosmic, transcendental, or mystical. Some of the psychological phenomena which are said to characterize this experience, are: a sense of unity or "cosmic oneness" with the universe; a feeling of transcendence of time and space; a deeply felt positive mood of joy, blessedness, love, and peace; a sense of sacredness, awe and wonder; a feeling of profound theological or religious awareness; a feeling of insight into reality at an intuitive, non-rational level; an awareness of things which seem logically contradictory and paradoxical; and a belief that the experience is beyond words, non-verbal and impossible to describe. The full peak experience, in its entirety, does not occur in the majority of individuals, is usually transient, and does not last for long in its full intensity, although it may have persisting effects on attitudes and behaviour.

With few exceptions, little general information can be given as to the relative frequency of occurrences of these various types of psychedelic drug reaction since the response is largely determined by such variable factors as the particular individual involved, his set and the setting. As is often the case in science, techniques designed to measure the effects of these drugs may greatly influence or distort the phenomenon under study. Savage has pointed out, that unless the LSD experience takes place

. . . in a secure setting, with sufficient emotional support where S (the subject) feels safe to encounter the bizarre and often powerful manifestations of his own mind unharassed by tests, interpretations, and the coldly precise scientific analytic attitudes, the only result can be confusion and paranoia.'

Reports of "objective study" of LSD's subjective effects vary considerably in content and often appear to be as much a function of the individual scientist's conceptual orientation and experimental method as they are of the subjects and the drug itself. Some researchers report that LSD experiences in their subjects are definitely unpleasant and anxiety-ridden, and that subsequent sessions are uniformly avoided, while other scientists claim that anxiety is infrequent and that subjects generally enjoy the sessions and are eager to participate further.122, 269, 304 Experiences in non-supervised and indiscriminate settings are undoubtedly even more variable.

It is generally reported that LSD has deleterious effects on performance on tests requiring a high degree of attention, concentration or motivation. It is often difficult to get meaningful data from such measurements, since subjects frequently become engrossed in the subjective aspects of the drug experience and lose interest in the tasks presented by the investigators. Psychological tests are often seen as absurd or irrelevant by the subjects. After the drug, performance on standard tests of intelligence, learning, memory and other cognitive functions, as well as certain psychomotor tasks generally show temporary impairment, sometimes lack of change and, more rarely, some
improvement.67, 127, 131, 150, 170, 247, 276, 322

In some situations gross impairment of judgment may occur, but this is not common under experimental conditions. Later recall of events occurring during the drug experience is generally good, and amnesia is rare. PCP produces more disorganization of thought and confusion than the other LSD-related drugs. Delirium, agitation and other features of alcohol-like inebriation are commonly reported with high doses of PCP, but not with the other drugs discussed in this section.78

Effects on driving skills have not been systematically investigated, although related experimental data, reports by users, and certain eye witness accounts, suggest that driving ability would usually be drastically reduced by the acute effects of LSD. There is no evidence that the drug has been a significant factor in automobile accidents or traffic violations, however.163, 204, 227, 315 Apparently few LSD users drive while under the influence of the drug. Further research in this area is needed—especially the investigation of persons involved in traffic accidents. Recent advances in the detection of LSD and related drugs in body fluids and tissues enable a more sophisticated approach to such study.71

Changes in visual perception usually play an important role in the psychedelic drug experience. Colours often appear clearer, brighter and more vivid, and alterations in the form or size of objects are typically noted. Subjects report that afterimages last longer, and tinges of colours or "halos" may be seen around the edges of certain objects. The sense of visual depth is usually enhanced but may be decreased, perspective is often altered, and stationary objects may seem to undulate and change in contour and shape.33,
46, 112, 127, 141, 164, 202, 246 Profound changes in visual imagery are among the most characteristic effects of drugs of this class. 67, 138, 169, 186, 267 The stimulation of visual imagery is most pronounced in the dark when the eyes are closed, although the sensations may also occur to lesser degrees when the eyes are open and, more rarely, under normal lighting conditions.232 Visions of luminescent colours, flashes of light, gem-like objects, intricate geometric and kaleidoscopic patterns, landscapes, and architectural forms are commonly reported. Stimulation of other sensory modalities such as hearing may induce changes in these visual phenomena.112, 117, 165 Kluver has suggested three general perceptual forms which typically occur: spiral-like; tunnel- or funnel-like; and grating or lattice-type forms. 168 Commission research has confirmed the existence of these visual form constants and other LSD-like visual imagery effects with THC and marijuana.216, 268 MDA is apparently less likely than the other LSD-like drugs to produce these visual effects. 222

Some subjects report that LSD enhances certain subjective qualities of other sensory modalities as well. Music may be especially beautiful, and some persons report that the taste of food and drink becomes more vivid, and the sense of smell more acute after the drug. Evidence of objective changes in these areas are limited, however, and many individuals do not experience significant alteration in auditory, gustatory or olfactory perception.77, 112.124
Changes in the perception of one's body and limbs (often called body-image) commonly occur with psychedelic drugs. Subjects regularly report that body parts feel strange or unusual, as if shape, size, weight and various bodily sensations were altered or distorted.

Changes in tactile perception are typical and include numbness, increased sensitivity to textures and shapes, and a tingling feeling in the skin. Parts of the body or mind may feel as if detached or floating free. Dreamy, floating sensations are very common, but
often come and go in wave-like fashion.33, 61, 112, 150, 187, 189, 199, 202

One of the most uniformly cited and significant effects of LSD and related drugs is the alteration of ordinary time perception or time sense. Subjective time is almost invariably faster than objective "clock time" with psychedelic drugs, and subjects typically overestimate the passage of time. Moments may seem like hours, and time may seem to be transcended. Pleasant experiences may extend indefinitely, or, on the other hand, an acute 'bad trip' may seem like an interminable horror. PCP, in contrast to the other drugs discussed here, tends to produce an underestimation of time. Time perception effects may be related to changes in short-term memory or may reflect an alteration in the general speed of an "internal clock" in the
brainy, 35, 73, 161, 202

It has been frequently reported that PCP is much more likely than other LSD-like drugs to produce feelings of isolation and apathy in users. The disturbance in sensory input produced by PCP is considered by some investigators to resemble sensory deprivation, and is quite distinct from the general sensory effects of LSD.78, 194, 212

There is some controversy regarding the extent to which LSD and related drugs produce hallucinations. This question is primarily a problem of semantics. There are many definitions of the word hallucination, and there is little agreement in scientific circles regarding its specific delineation. Some investigators would subsume under the general label of hallucinations the various alterations in visual perception and other sensory changes described above. Others have suggested that some of these effects might better be called illusions, and still others feel that neither term is appropriate and that these phenomena should be considered, in a broader context, as altered states of consciousness and perceptual awareness. Many investigators restrict the use of the word hallucination to false sensory impressions which are believed to be real by the person experiencing them. In this sense, LSD and related drugs rarely produce hallucinations, since subjects are almost always aware that the perceptual changes are due to the drug and, typically, do not attribute to them significant independent existential reality.61, 66, 127

Contentions are often made that LSD can elicit new levels of spontaneity, insight, problem-solving and creativity. These claims are very difficult to assess scientifically, since the effects described are often highly subjective and personal, and are hardly amenable to empirical validation. The problems of studying creativity in the laboratory are considerable, and little is known of the basic psychology of such cognitive processes. A generally agreed upon definition of the concept of creativity has eluded investigators so far, and few meaningful tests are available. Studies of the effects of psychedelic drugs on allegedly creativity-related interests and behaviours have produced inconsistent results.36, 116, 145, 206, 289, 301, 327 Often performance does not reflect the subjective impressions of the drug experience. Sophisticated scientific investigation in this area is only just beginning, and the question of subtle effects on creative processes in certain individuals must be answered by future research.

Current arguments as to whether LSD is truly 'consciousness expanding' as its proponents contend or 'consciousness constricting' as its opponents assert, will probably not be resolved by science in the near future, since it seems unlikely that such hypotheses can be put to adequate empirical test given the current state of technology.

Most authorities agree that LSD does not have a specific aphrodisiac or sex-drive stimulating effect. Some users indicate an enhanced appreciation of sexual experience, while many others report a total disinterest in sex while on a 'trip'. Some increase in sexual behaviour may occur as a result of a lessening of inhibitions and an increase in emotionality, tactile appreciation, and interpersonal contact. LSD has been used in the treatment of sexual disorders of psychological origin (e.g., frigidity and impotence), although its general usefulness has not been clearly demonstrated in this area.

The possible religious significance of psychedelic drug experiences has been the subject of heated controversy for centuries. While many authorities have pointed out basic similarities between drug-induced feelings of transcendental or mystical awareness and the satori or kensho of Zen Buddism, the samadhi of Hinduism or the beatific vision of Christianity, others have been outraged by the suggestion that such 'instant mysticism' could be produced chemically. It is quite apparent, however, that a considerable degree of religiosity pervaded the psychedelic drug movement of the 1960s and has played a major role in the use of such drugs in other cultures. The major theoretical positions and scientific research in this area have been reviewed by several investigators and these reports provide experimental support for the notion that drug-evoked experiences may have religious significance for certain individuals.11, 202, 279

Perhaps the most rigorous scientific evidence comes from Pahnke's controlled psilocybin experiment with seminary graduate students, conducted in the setting of a Good Friday religious service.232 He notes that: "Those subjects who received psilocybin experienced phenomena which were indistinguishable from, if not identical with, the categories defined by our typology of mysticism." The religious aspects of the psychedelic experience apparently depend a great deal on the individual, his values and expectations, and the setting involved, and do not normally occur with great intensity in most persons or in most situations. Masters and Houston report that 6 out of 206 of their subjects attained a mystical experience,202 while other researchers report no such events and still others, a much higher incidence. Differences in semantic meaning, definition and criteria may account for part of these discrepancies. The "objective validity" of drug-elicited religious experiences, however, is by nature untestable in the scientific sense, and the area will doubtless remain in a storm of controversy.

Adverse Psychological Reactions [i]

As noted in A.1 Introduction the term adverse reaction, as traditionally applied to the medical use of drugs, refers to significant undesirable or negative side effects of the drug. The distinction between main or desired effects and the multitude of other side effects which the drug may have is not absolute in any sense, and the application of these terms generally depends on the conditions of drug use. In the medical use of drugs, the desired and undesired effects are relatively easy to define in a specific treatment context, although the labels may change with the aims of the therapy.

In the area of the non-medical use of drugs, defining adverse reactions becomes considerably more complicated. With hallucinogens, for example, personal and social attitudes and norms often dominate in the interpretation of drug effects.'" What may be a desirable or pleasurable effect to one individual in a certain situation may be considered an adverse response or a side effect in another situation or to another individual. In a survey of physicians regarding adverse reactions to LSD, one respondent stated, "From my understanding of the effects, I would consider all reactions to LSD as 'adverse' regardless of the immediate subjective response."307 Clearly, not all LSD users or other observers share this opinion. As Bialos indicated, in discussing some of the difficulties with defining marijuana adverse reactions:

. . . drug users, the non-drug user friend, the professional clinical observer, the researcher, the law enforcement official, and the middle-aged, middle-class citizen may all have different criteria for defining the syndrome.

Tart has proposed two criteria for selecting what he believes would be unequivocally negative effects : 298

(1) the effect is clearly unpleasant to the user;
(2) it has no redeeming value, other than as a possible lesson to the user.

While most observers might agree in principle with the approach, considerable conflict among individuals would undoubtedly arise in the application of these criteria in many practical situations. Even if agreement were reached as to whether a particular drug-associated condition is positive or negative, determining cause and effect relationships can be a formidable task. It is often very difficult to isolate the alleged effects of LSD from the possible influence of cannabis, since LSD users are almost invariably users of marijuana and hashish as well. Other drugs are also involved in many cases where possible chronic effects are a major issue.

In spite of these ambiguities, a number of rather specific concerns have developed regarding possible adverse psychological reactions to hallucinogenic drugs. Some of these alleged effects include acute adverse reactions such as depression, anxiety, panic or psychotic-like, short-term responses; augmentation of pre-existing neuroses, character disorders and adjustment problems; functional psychoses, in which drugs might serve as a precipitating or complicating factor; long-term changes in personality, behaviour or life style associated with chronic use (for example, the so-called "amotivational syndrome"); specific psychoses or dementia of a chronic nature caused primarily by the drug; and "flashbacks" or recurrences of previous drug effects.

In the past decade there have been numerous clinical reports of adverse psychological reactions to hallucinogen use in North America. The majority of these reports display considerable methodological problems which impose severe limits on their usefulness. Pre-drug personality, cause and effect relationships, and details of both the general patient group and the overall catchment population from which the subjects were drawn are rarely adequately explored and presented. Some well-documented reports have appeared, however, and certain recurring patterns are becoming apparent.

An LSD-induced 'bad trip' is typically a self-limiting reaction of short duration, lasting only a few hours. Although much more prolonged responses sometimes occur it may range from a mildly negative or ambivalent experience to an episode of intense terror and nightmarish panic. Such adverse reactions often seem to focus on the fear of death, fear of permanent insanity, basic sexual conflicts, and fear of legal repercussions in illicit users, or may be precipitated by an objective 'hassle' or problem of real or imagined significance. Under the influence of LSD, it is often difficult to cope with immediate problems which arise, and emotional vulnerability may be increased. Sad trips' seem to occur most often when the individual has had little experience with hallucinogenic drugs, is poorly prepared, alone, or in an otherwise unprotected or unsupervised setting. While an experienced 'guide' or therapist can often help prevent or alleviate negative reactions, this is no guarantee against an unpleasant experience. Neither are earlier positive experiences—severe 'bad trips' have been noted in individuals who had previous long histories of unequivocally pleasant psychedelic experiences.

Illicit users of LSD commonly voice the opinion that 'bad trips' are caused by bad drugs and that 'pure acid' is relatively free from adverse reactions. These claims are rarely based on chemical analysis. Although contaminants and other drugs occasionally found in illicit market LSD can undoubtedly affect the experience, it seems unlikely that a large proportion of the negative reactions reported can be accounted for by adulterants. It is well-documented that 'freak-outs' do sometimes occur with pure LSD.

Becker has proposed an explanation for the occurrence of anxiety reactions to hallucinogenic drugs, which is gaining considerable support.29, 30, 31 Hallucinogenic drugs produce effects which are qualitatively different from those a non-user is likely to expect or have experienced before. In many instances, it is the interpretation or meaning which the user attaches to these radically different experiences which determine the subsequent emotional response. Effects which are considered tolerable or even interesting or pleasurable to experienced users, may be frightening to a novice, who may fear a permanent derangement of his mind. Hallucinogens sometimes produce transient waves of mild anxiety or paranoia, which the regular user usually correctly attributes to the drug and has learned to control. These same effects may convince the novice that he is insane and bring on a severe panic. The response of others to this fear is of great importance—if they are not alarmed, and reassure him that the effects are not unusual or permanent, the anxiety reaction may be minimized. On the other hand, nonusers, including some police and medical personnel, may react with alarm, and reinforce the notion that the person is at least temporarily insane (psychotic), thereby adding to his distress. Becker's hypothesis predicts that as familiarity with the acute effects of hallucinogens in our culture increases, the frequency of short-term panic reactions among users will decrease.

The frequency of suicide among LSD users is not known, but a few cases have been documented. Suicidal thoughts have often been reported, but there is little indication that such notions are carried through. Some data on suicides among persons who have taken LSD in medical settings are discussed later. Attempts at self-mutilation have been reported on rare occasions. Accidental deaths associated with hallucinogen use have been reported and a number of fatalities or serious injuries have been noted as a result of a loss of critical judgment or attentional processes. For example, a few individuals have jumped from buildings or trees apparently under the delusion that they could fly or were indestructible.83, 127, 259, 272 Stories of persons who had become permanently blind while staring at the sun during LSD trips were generated by a state official in the United States and widely circulated in the public media. These reports were subsequently shown to be a hoax and no such cases are on record.224

Fear, panic and aggression may result from a 'freak-out', but homicides associated with LSD use are rare and only a few have been documented.'67. 238 Reports of violence resulting from the use of LSD have generally not been supported,89 although there may be some significant exceptions. The majority of non-drug arrests associated with LSD use in Canada seem to be on the order of "disturbance of the peace" offences251. 252 and there is little evidence that LSD plays a significant role in major crimes.

Recurrence of certain aspects of hallucinogen experiences ("flashbacks" or "echos") of varying duration and intensity have been reported over periods ranging from a few months to more than a year after the last (or only) LSD use.118, 249, 272, 305 The quality of these experiences, which usually last only a few minutes or less, may depend on as many factors as the original effects. They may be triggered or precipitated by drug-associated stimuli which were previously associated with drug experiences, by seemingly irrelevant stimuli or events, by other drugs, or they may appear spontaneously.

According to Keeler and associates the recurrence of a drug-like effect (or "flashback") is not necessarily an adverse reaction and should be classified as such only if it precipitates anxiety or interferes with function.'" "Spontaneous recurrences are tolerated by some and enjoyed by others." They note that the recurrence of clinical psychopathology that was present during the drug reaction is not a spontaneous recurrence of the drug effect.

Discrete recurrences may be on a continuum with more subtle effects of drug use. For example, some subjects claim that their perceptual awareness was increased by hallucinogen use and that some degree of this enhancement remained with them after use. Perhaps also related is the 'contact high' --the experience reported by some users of feeling somewhat 'high' without the drug when in the presence of others who were 'high'. Although these various post-intoxication responses may be in some respects related psychologically and physiologically, in most situations they cannot be considered the same phenomena. The lack of clear agreement as to essential definitions in these areas prevents simple interpretation of the very limited data available. Definitions of "flashbacks" or "spontaneous recurrences" rarely accompany clinical reports in the literature.

There is little agreement regarding the frequency of these ill-defined recurring phenomena. In a recent survey of metropolitan Toronto high school students, 60% of LSD users reported experiencing "flashbacks" of some kind.274 Of students who had used the drug 21 times or more in the past six months, almost three-quarters reported such recurring experiences. In contrast, other surveys report that about one-quarter of LSD users have had "flashbacks".42, 290 Horowitz estimated that approximately 5% of repeated hallucinogen users have experienced "repeated intrusions of frightening images" in spite of volitional efforts to avoid them.135 Studies of persons who have been given LSD under medically controlled settings have rarely found evidence of significant adverse recurrences.65, 74, 121, 204 It is likely that these various studies are examining different phenomena and comparisons among them seem rather meaningless. Further research is needed, applying more rigorous definitions.

A number of clinical reports have appeared which suggest that the chronic use of hallucinogens may be causally associated with a variety of psychological problems of a more prolonged nature than the generally accepted acute reactions. Although most negative LSD experiences appear to be of short duration, prolonged psychotic episodes lasting months or even years have reportedly been elicited by LSD. Many investigators contend that such extreme experiences occur only in individuals already predisposed to psychotic reaction, and are simply precipitated by the stress of a 'bad trip'. In most of the cases described, considerable prior psychopathology existed, although this is reportedly not always the case, and there are numerous reports of significant adverse psychological effects in individuals without
obvious previous pathology.68, 69, 104, 120, 220, 259, 272, 307

A number of clinicians have described an "amotivational syndrome" in some chronic users of cannabis, LSD and other hallucinogens. McGlothlin and West report that clinical impressions suggest that heavy use of these drugs may contribute to some characteristic personality changes, including apathy, loss of effectiveness, reduced drive and ambition, diminished capacity or willingness to carry out complex long-term plans, to endure frustration, to follow routines or to successfully master new materia1.2" David Smith has described a similar condition in a small proportion of chronic users, "The picture in terms of social consequences is then similar to that of a chronic alcoholic, but without the physical deterioration."278

While an association between heavy hallucinogen use and an "amotivational" behaviour pattern in some persons is generally acknowledged, the complexity of untangling any causal relationship between the use of drugs and the general life style has resulted in considerable controversy regarding the essential etiology of the syndrome. The role of drugs in such cases may often be more symbolic than pharmacological. Some investigators have suggested a definite organic basis. Unwin contends that "the so-called amotivational syndrome" may in most cases, be a "masked depression".809 Lecker felt that such a syndrome might represent an "operant conditioning state" during which the chronic user aims at the quickest way to get pleasure, and may revert more and more to the drug for instant gratification.182 McGlothlin has suggested that drug use by persons appearing "amotivational" was perhaps continued and intensified when the drug effects were compatible with the users' natural personality characteristics and preferred life style. He indicated that separating the various social, psychological and pharmacological components would be an arduous task.

In contrast to reports of adverse personality change with hallucinogenic drugs, numerous claims have been made by various LSD users, psychotherapists and scientists that LSD can produce long-lasting beneficial effects on personality and behaviour. Both types of allegation are difficult to evaluate, since few adequately controlled investigations have been done on the long-term effects of either medically supervised or non-medical LSD use. Experimental data suggests that in most subjects, long-lasting effects (beneficial or harmful) of LSD administered under controlled conditions are minima1.2°4. 2" Less information is available on non-medical use. It would appear, however, that under some circumstances LSD can potentiate or facilitate attitude and behaviour change, the nature of which is strongly influenced by suggestion, expectation and other aspects of the set and setting, as well as the personality of the individual involved. The degree to which any personality or behaviour change is viewed as beneficial or adverse depends on personal and social attitudes and norms. What is considered positive by some individuals or groups may be viewed negatively by others. Additional research is needed regarding the psychological effects of chronic hallucinogen use-- especially in adolescents. Concern has frequently been expressed regarding the effects of regular hallucinogenic drug use on the maturation process in young people, but little systematic data are available.

Some observers warn that chronic hallucinogen use may cause prolonged disruption of cognitive functioning and school performance. While users of LSD and related drugs have been shown in several studies to have poorer academic records than non-users, this general pattern typically holds for all drugs including alcohol and tobacco, and is likely not a pharmacological
effect.15, 88, 107, 278, 274, 275, 816, 321

Prolonged psychoses are quite rare in clinical or experimental settings, even when psychiatric patients are used as subjects. In 1959 Cohen surveyed 44 investigators who had given LSD or mescaline to approximately 5,000 persons a total of about 25,000 times." He found that psychotic reactions lasting over 48 hours occurred in 0.18% of the psychiatric patients studied and 0.08% of the experimental subjects. Only a few "flashbacks" were noted. There were four suicides among the patients, all occurring months after the LSD experience, and none among the experimental subjects. Whether these deaths can be attributed to LSD use is not certain.

In 1970 Malleson surveyed 73 doctors known to have used LSD on human subjects in the United Kingdom.20° The data covered some 4,300 patients given a total of 49,000 LSD sessions, and 170 non-patient experimental subjects administered LSD on 450 occasions. There was a reported suicide rate of 0.07%, and a rate of 0.9% for psychoses lasting for more than 48 hours. The investigator concluded that:

. . . treatment with LSD does give rise to acute adverse reactions, but if there is adequate psychiatric supervision and proper conditions for its administration the incidence of such reactions is not great.'

In 1971 the Commission conducted a survey of researchers who had administered LSD (or mescaline or psilocybin) in clinical or experimental settings in Canada over the preceding 20 years.122 Twenty-four of the 29 investigators surveyed responded and of these, data from 18 research teams were adequate for the following analysis. A total of 3,515 individuals had been administered LSD alone or in combination with other drugs on 5,398 occasions. The vast majority of these subjects were psychiatric patients and were receiving the drug as part of a program of psychotherapy. Sixteen severe psychotic reactions were reported to have occurred in conjunction with LSD treatment (0.3% of drug sessions). The majority of the psychotic reactions lasted for several hours or less, but a few were more prolonged. Three occurred during the year following LSD treatment, and in one case a psychotic reaction lasting almost a year was precipitated three weeks after LSD was administered. Only a few "flashbacks" were noted. Six possible suicides (three confirmed) were reported in patients within a period of two years after LSD sessions. The role of the drug treatment in these deaths was not certain. As with the Cohen and Malleson studies, it is not clear whether the suicide rates found in these patients after LSD treatment were lower or higher than in comparable patients not given such treatment.

McGlothlin and Arnold conducted a ten-year follow-up study of persons who had been given LSD in a controlled medical setting.204 Some of these individuals also had some non-medical hallucinogen experience. Twenty-five per cent of 247 respondents had experienced a bad trip' at one time or another. Almost half of those reporting having had at least one unpleasant experience, viewed them as beneficial in retrospect. Few serious problems were associated with LSD experience.

It would appear, on the basis of these studies, that adverse reaction to LSD is not a prohibitive danger when the drug is administered in a controlled clinical setting. Many other investigators have also indicated that the experimental use of LSD in a medical setting is comparatively safe from a psychiatric point of view.74,127, 185 There is no evidence that clinical research with LSD or pharmacologically similar compounds should be restricted for reasons of subject safety. These findings do not provide a satisfactory basis for estimating the effects of illicit use, however, since set, setting, purity and quantity of drug, and consequently, the quality of the experience are all apt to be quite different in these situations.

There are no adequate data regarding the frequency with which various unpleasant or adverse effects occur in the illicit hallucinogen-using population as a whole. These various possible negative effects are rarely clearly defined in studies, but it would appear that a large proportion of regular hallucinogen users have experienced unpleasant effects of some kind. Very little is known regarding the incidence of the more severe reactions or 'freak-outs'.

In a recent survey of Toronto high school students, 53% of LSD users reported that they had experienced unpleasant effects or a 'bad trip' of some kind. Few reported more than one or two such experiences. As would be expected heavy users reported having had a greater number of unpleasant experiences. 274 Solursh reported that 24 'freak-outs' occurred out of 601 'acid trips' in a series of illicit users studied retrospectively.285 In the Commission's national surveys, approximately one-fifth of the respondents who reported that they had quit or decreased LSD use indicated having had a bad experience as a reason for this change in drug use.174. 175' 176

Smart and Fejer of the Addiction Research Foundation have examined the relationship between non-medical drug use and experience in psychotherapy among high school students in a semi-rural area of Ontario.87 For all drugs (including alcohol and tobacco) significantly more users than nonusers had received treatment for psychological problems. Non-users who had received treatment noted family or school problems most frequently as the reason for treatment. Users of illicit drugs most often gave depression as the reason for therapy. It is difficult to ascertain the role of hallucinogen use in these data since the incidence of psychotherapy generally increases with age, as does drug use. The investigators point out that age differences may be a confounding factor in the correlation between drug use and treatment. As well, we do not know whether the treatment preceded or followed hallucinogen use.

In a study of Harvard seniors, Walters and associates found more visits to a psychiatrist among those students who were users of hallucinogenic drugs. However, in half of these cases, the individuals were not users at the time they saw the psychotherapist. Few felt that drug use was related to their seeking psychiatric help.318 Similarly, a study of adults in the San Francisco area found that hallucinogen use was more common among those who had seen a professional psychotherapist.'"

A number of surveys of clinicians and treatment services have been reported. As noted in A.1 Introduction the interpretation of such studies is generally quite difficult.

In spite of various methodological problems, it is apparent from these surveys that a significant number of adverse reactions to hallucinogens come to the attention of medical authorities.115, 215, 223, 226, 307 Since most cases of adverse reaction are probably not brought to medical attention, accurate diagnostic and treatment statistics must be considered underestimates of the overall incidence of the less severe conditions. In any event, drug-related cases must ultimately be interpreted in terms of the overall patient population, and more importantly, in terms of the extent and patterns of drug use in the general population from which the patients were drawn.

The statistics collected by the Federal Poison Control Program provide some general information regarding adverse reactions and poisonings attributed to LSD and related drugs.48. 169, [f] However, it is generally not possible to distinguish between psychological adverse reactions and physical toxicity from these reports. Since physical reactions to LSD requiring medical treatment are rarely noted in the scientific literature, it is likely that the LSD cases reported are almost entirely psychological tad trips' of one sort or another. This may not be the case with MDA or PCP, since these drugs are more likely to produce signs of physical toxicity, which may account for some proportion of any adverse reactions associated with these drugs. For sake of convenience, all of the adverse reaction and poisoning reports are discussed here; physical toxicity and fatalities are dealt with later in the section on physiological effects.

The general increase in the number of hospitals participating in the Poison Control Program from year to year precludes accurate comparisons among the various years, but some interesting relative reporting trends are apparent. (See Table A.3.) The overall number of adverse reaction reports involving hallucinogens is levelling off. The proportion of these cases ascribed to LSD has markedly declined from 1969-1971, as the proportion of cases attributed to MDA, mescaline, and unspecified hallucinogens increased. The specific sub-categories must be interpreted with caution, however. Drug identification in hospital reports involving hallucinogenic drugs is nearly always based on the verbal report of the user, rather than on chemical analysis of the drugs involved, and erroneous classification of such cases frequently occurs. Samples of the drugs taken are not usually available for chemical analysis, and accurate screening for these drugs in body fluids is beyond the capacity of most hospital laboratories.

TABLE A.3
LSD AND OTHER PSYCHEDELIC-HALLUCINOGENS NOTED IN THE POISON CONTROL
PROGRAM STATISTICS
1969*        1970*            1971t
LSD        390 (93.5%)        885 (77.2%)        799    (62.2%)
MDA        7 (    1.6%)    53 (    4.6%)    151    (11.7%)
Mescaline        15 (    3.5%)    57 (    4.9%)    105    ( 8.1%)
STP        3 (    0.7%)    15 (    1.3%)    3    ( 0.2%)
PCP        0 (    0.0%)    0 (    0.0%)    0    ( 0.0%)
Psilocybin        1 (    0.2%)    0 (    0.0%)    0    ( 0.0%)
Unspecified        1    (    0.2%)    135 (11.7%)        225    (17.5%)
TOTAL•        417        1,145        1,283   
• Poison Control Program Statistics. 1969, 1970. (Table G-II)
t Unpublished information provided to the Commission by E. Napke (Head, Drug Adverse Reaction and Poison Control Section, Department of National Health and Welfare, Ottawa.)

There has been no mention of adverse reaction to PCP in the Poison Control Program reports. As discussed earlier, PCP is almost invariably represented as some other drug on the illicit market and is rarely acknowledged as PCP. If PCP adverse reactions occur, they would likely be mistakenly attributed to other drugs, or left unspecified. Although alleged 'mescaline'is not uncommon in Canada, as indicated earlier, samples of such materials have almost invariably been found upon chemical analysis to be some other drug—primarily LSD, PCP or both. Consequently, it is likely that most of the 177 'mescaline' cases reported actually represent adverse reactions to LSD and/or PCP. Many of the unspecified cases are probably attributable to these drugs as well.

Overall, males outnumbered females by almost three to one in these data, and the vast majority of the individuals involved were in their teens or early twenties. Of the 1,653 reports where the disposition of the case was specified, 15.6% were hospitalized for treatment and these patients received a median of 1 to 2 days institutional care169 Less than one-tenth of the hospitalized individuals (1.4% overall) were given more than two weeks of inpatient care. It would appear from these data most adverse reactions to LSD and related drugs are of short duration, not requiring hospital care; long-term hospitalization is uncommon.

In the Commission's national survey of psychiatric hospital diagnostic records, taken in the spring of 1971, LSD and related drugs were mentioned as factors in the primary and secondary diagnoses of 67 (0.3% ) and 14 (0.06%) respectively of the 22,885 patients in the hospitals surveyed.121, [6] In British Columbia, psychiatric wards in general hospitals were surveyed as well, and in this population, LSD-like drugs were mentioned in the diagnostic records of 10 (3.3% ) of 293 resident psychiatric patients. A follow-up examination of certain specific case histories was done, focussing primarily on cannabis, although other more general information was obtained as well. These case histories revealed that most of the hallucinogen cases had intense involvement with a variety of drugs, the most common being cannabis, alcohol, 'speed' and LSD. In many instances drugs were apparently considered causal factors primarily because of general information that the patient had been a user, either in the past or at the time of hospital admission. The inclusion of such cases would likely give an inflated estimate of the role of the drugs in psychiatric disorder. On the other hand, many patients have drug-related problems which are not detected in the admitting diagnoses, and can only be identified by intensive subsequent exploration.162 Consequently, diagnostic record sampling is bound to miss certain valid drug-related cases. Almost half of the patients in the follow-up study had been diagnosed schizophrenic at some time, and a high proportion of personality problems and adolescent adjustment difficulties were also noted. In many cases, these problems preceded hallucinogenic drug use. (See also Table A.7 in the Annex to this appendix.)

In the 1970 national mental health data provided to the Commission by Statistics Canada, 226 (0.44%) of the first admissions and 71 (0.14%) of the readmissions to psychiatric wards and institutions were attributed to drug dependence involving LSD and related hallucinogens (ICD-304.7).51' 243, [e] For 1971 the corresponding figures were 142 (0.26%) and 62 (0.12%) for first admissions and readmissions respectively. The apparent reduction in hallucinogen cases is striking; however, only limited between-year comparisons can be made with the available data. Some additional toxic reactions to these drugs are undoubtedly included in other undifferentiated general diagnostic categories (e.g., ICD-294.3, 309.149). In the available data, males outnumbered females by approximately three to one. (See also Tables A.5 and A.6 in the Annex to this appendix.)

The Commission psychiatric hospital survey and the national mental health statistics can only provide a general picture regarding the extent to which these drugs are involved in hospital admissions. Detailed follow-up of individual cases would be necessary to ascertain the nature of the role of the drugs in these patients.

While the psychiatric hospital statistics do not allow firm conclusions regarding the causal role of the drugs in the cases described, the data indicate, however, that hallucinogens do appear as a complicating factor in a significant number of psychiatric admissions in Canada. However, such cases apparently represent a very small proportion of hallucinogen users in general, and of the psychiatric hospital patient population in particular.

In studying psychiatric patient populations we have a priori defined the group under study as pathological. Consequently, only limited information can be gained from tabulating the pathology within such groups. Such studies provide little information regarding the frequency of adverse reactions in the general population of hallucinogen users. Few controlled studies exist of hallucinogen users who were selected on some non-pathological or non-deviant basis. It would be preferable to compare a cross-sectional sample of hallucinogen users with a control group of non-users with similar social, economic, and educational backgrounds. Even this type of investigation can only demonstrate factors which are associated with drug use and cannot indicate causality.

Although good epidemiological data are lacking, many observers feel that the frequency of psychopathology in the chronic hallucinogen-using population is higher than would be expected by chance. If this were true, at least three reasonable explanatory hypotheses might be adequate, each with some supporting evidence:

(1) Pathological persons may be more likely to use hallucinogens (or to use them heavily). This might, for example, represent acting-out or rebellious behaviour, attempted self-treatment, poor judgment, or an inability to find pleasure by other means.
(2) Hallucinogen use may lead to an increased incidence of psychopathology. This could be a direct neurological effect, or, for example, the drug might conceivably precipitate or complicate a schizophrenic reaction in a predisposed person.
(3) Other factors may influence both psychopathology and drug use. Social alienation, adverse socio-economic conditions, or poor family environment might play such a role.

In summary, mild transient phases of anxiety and paranoia occur in some inexperienced and regular users of hallucinogens in North America. More severe panic reactions, especially among inexperienced users have been reliably reported. The notion that LSD and related drugs may, under certain circumstances, precipitate a more prolonged psychotic reaction in predisposed individuals is gaining some support in the clinical literature, although there is no consensus as to the exact nature of the predisposition or its prevalence in the general population. Other more prolonged adverse psychological reactions to chronic use (including personality changes and an "amotivational syndrome"), in some instances in apparently previously normal individuals, have been cited, but there is considerable controversy as to the validity and general applicability of many of the clinical reports presented. It is not yet certain what role the drugs play in such chronic syndromes or the frequency with which they occur in the hallucinogen-using population. Additional epidemiological research will be necessary to clarify these issues. (Further discussion of theoretical and methodological issues relevant to hallucinogen adverse reactions appears in Chapter Two of the Cannabis
Report.")

PHYSIOLOGICAL EFFECTS

LSD exerts its most significant physiological effects on and through the central nervous system, although the exact mechanisms by which this occurs are not yet known. As a result of its potent general arousal or activation capacity, LSD may produce a variety of autonomic nervous system (sympathomimetic) actions, generally considered to be of little clinical significance at normal doses. Commonly noted are minor increases in heart rate, blood pressure, blood sugar level, body temperature and perspiration. Chills, `goose pimples', flushing of the facial skin, decreased or increased urination, headache, nausea and, more rarely, vomiting are reported. Nausea is more common with peyote than with LSD. LSD may produce a variety of changes in the visual system, including widening of the pupils, some disturbance of focussing and accommodation, an increase in intra-ocular pressure, and certain direct effects on the retina. It would appear that the profound changes in visual perception which typically occur reflect a combination of peripheral (perhaps retinal) and central neural mechanisms. LSD and most of the related drugs generally increase the activation of the brain (as indicated by the EEG), produce alertness, block sleep, decrease appetite, change respiratory patterns, facilitate certain simple reflexes, and may induce tremors and reduce coordination. A few rare cases of convulsions have been reported.21, 25, 27, 67, 131, 141, 142, 195, 255 Cold extremities are sometimes reported with LSD and are likely due in part to constriction of the blood vessels in the skin. There have been occasional rumours of gangrene in the extremities allegedly caused by the use of poorly synthesized illicit LSD (thought to contain other physiologically active ergot alkaloids). We have been unable to substantiate these rumours, but one case of gangrene was recently reported in which LSD and large doses of nicotine (a potent vasoconstrictor) were implicated.'39

Considering their close structural similarity with amphetamine, it is surprising that MDA and STP produce little amphetamine-like peripheral physiological change. Pupilary dilation is the only conspicuous effect of MDA at low doses. Larger doses may produce increased perspiration, dry mouth, tension, tremors, dizziness, indigestion and occasionally nausea. Appetite is usually suppressed. Amphetamine-like central stimulation and EEG changes occur. 12, 100, 134 Although the literature is inconsistent regarding the physiological effects of STP, it would appear to be similar to, but more potent than MDA in most respects.85, 96, 281

At moderate doses, PCP produces physiological effects similar to alcohol or barbiturate intoxication. Larger doses are increasingly anesthetic, but very high doses produce convulsions. Moderate doses typically result in numbness in the extremities, an increase in blood pressure, heart rate, perspiration and salivation, and dilation of the peripheral blood vessels in the skin. Unlike most LSD-like drugs, PCP produces a slowing of the EEG, generally decreases arousal, and does not affect pupil size. Muscular incoordination, ataxia, blurred vision, minor changes in involuntary eye movement, and dizziness are often reported. Nausea and vomiting may occur.24, 78, 79, 127, 234

There is no direct evidence of generalized brain damage due to the chronic use of LSD and related drugs, but indications of impairment on some behavioural tests have been reported which are suggestive of slight neurological dysfunction in certain LSD users.28, 39, 70, 205, 326 The evidence is not consistent in this regard, and further research is needed. There are no data available on the neurological consequences of long-term use of MDA or PCP in humans, but existing animal studies do not indicate cause for concern at moderate doses. 78, 134, 234

Chromosome and Birth Effects

A few years ago, considerable controversy and sensational publicity arose around the possibility that LSD might affect hereditary transmission through chromosomal alterations, produce changes in white blood cells resembling leukemia, or adversely affect the developing human fetus.". 147, 155 Related studies, involving test-tube preparations of human cells, live animal and insect experiments, and examinations of illicit drug users, are contradictory and provide no final answers to these important questions.25, 81, 151,136 The relationship between in vitro (test-tube) and in vivo (living organism) effects is rarely straightforward, and generalizations from one animal species to another are difficult. Furthermore, studying the users of 'street' drugs gives Little information regarding specific compounds, since such individuals typically use a variety of drugs, and neither the investigator nor the subject can be sure of the purity, quantity or identity of substances obtained from the illicit market. In controlled human studies, in which chromosomes were examined before and after clinically supervised administration of known doses of pure LSD, little evidence of significant change was noted.8. 72' 137' 355 The effects of prolonged frequent use of LSD have not been directly investigated in the laboratory, however, and the presence or absence of chromosomal alterations with heavy use of illicit materials can not be predicted on the basis of present information.

Research on chromosome changes is complicated by the fact that temporary or permanent chromosome breakage is not an uncommon response to a variety of non-drug experiences, and can be produced by nuclear radioactivity, x-rays, many pollutants, fever and a number of virus infections. Furthermore, there is evidence that a number of commonly used drugs, including caffeine and aspirin, may cause chromosome breaks in certain eells.158, 262, 292, 323 It should be noted that chromosome damage per se does not necessarily affect either the individual or his offspring, although the possibility must be considered. There is considerable controversy regarding the frequency of occurrence of various chromosomal abnormalities in the general population.27'

High doses of LSD administered at certain times early in pregnancy have been shown to produce deformities in the offspring of some animal species but not others.10, 17, 84, 102, 250, 311, 317 No unequivocal evidence of such teratogenic LSD effects in humans has been reported, although there have been a number of widely publicized instances of early abortion or abnormalities in babies born of mothers who had used LSD.40, 43, 52, 82, 147, 148, 300 Whether
such anomalies occur more frequently in LSD users than in similar or matched non-users is uncertain.2. 208, 291

Recent reviews of the literature suggest that LSD does not cause lasting chromosome breaks in vivo and that it does not produce cancer or birth deformities in humans.'', 78, 99, 192 However, many investigators still feel that the possibility of chromosome or fetal damage in humans forbids the use of LSD and related drugs, for either medical or non-medical purposes, by women who are either pregnant or expect to become so in the near future.

Physical Toxicity and Death

Human fatalities due directly to LSD overdose are unknown in the scientific literature. In terms of lethal physical toxicity LSD must be considered one of the safest drugs known. Mention of psilocybin or mescaline deaths in the literature is rare, as well. We have found no evidence of overdose deaths involving these drugs in Canada.123, 271Agi

Little data is available on the lethal toxicity of PCP in humans. There is no evidence in the scientific literature or from the Commission's studies of drug-related deaths that severe PCP overdose is a likely occurrence. We have not been able to document any such fatalities in Canada.217 No PCP poisonings have been recorded as such in the Federal Poison Control Program statistics.48 However, as noted earlier this may represent drug identification and classification errors rather than a lack of toxicity, since, in Canada, PCP is almost invariably sold as some other drug on the illicit market. While similar misidentification of drugs may exist in death records, such an error is less likely to occur since greater care is normally taken to chemically identify drugs in fatal cases. However, even in these latter instances, screening for drugs is usually not extensive or complete.217

The toxicity of MDA has been studied in animals, but little information is available regarding lethal levels in humans.57, 134, 240 Because of the close chemical and pharmacological similarities between MDA, mescaline and the amphetamines, and the rarity of overdose deaths with these latter compounds, it would seem reasonable to expect a similar lack of fatalities associated with MDA. Animal studies suggest that MDA and amphetamine have comparable lethal toxicity.12 Correspondingly, until recently, MDA overdose deaths were not mentioned in the literature. The Commission's survey of provincial coroners has provided information on 18 MDA-related deaths in Canada during the years 1969-1972.123 (Five of these cases have been described by Cimbura.31) Eight of the 18 cases involved other drugs as well, but in the remainder, MDA was the only drug found in the body. In several cases samples of the drug taken were available for analysis and were found to be relatively pure MDA, without significant adulteration or contamination. The majority of the fatalities involved oral use, although evidence of intravenous administration was noted in some instances. The actual mechanism of death was generally uncertain. Although the actual doses involved cannot be accurately determined, the coroners' reports noted a range from "one capsule" as a minimum, up to 60 capsules in one instance, and one-quarter ounce in another. It would appear that in most cases massive doses were involved. Sixteen of the individuals were males, and all were between 15 and 34 years of age.

Because of classification ambiguities, it is not possible to obtain information on MDA-specific fatalities from the death statistics published by Statistics Canada.5° As noted earlier, the Federal Poison Control Program has reported 151 cases of MDA toxic reaction poisonings in 1971, but in most instances it is not possible to determine to what extent these cases represent psychological adverse reactions or physical toxicity.221 However, five of the MDA-related poisonings were fatal; three of these cases involved opiate narcotics as well. Very recently there have been several reports of deaths attributed at least in part to PMA (paramethoxyamphetamine) in Canada and the United States.

MDA is unique in that it appears to be the only one of the common psychedelic-hallucinogen or stimulant drugs which seems to involve a significant risk of fatal overdose as these drugs are presently used in Canada. Further research is needed to determine what combination of behavioural and pharmacological factors are involved in this unexpected phenomenon.

TOLERANCE AND DEPENDENCE

Tolerance to the psychological and physiological effects of LSD develops rapidly on repeated use, although the form of psychological tolerance is unusual in several respects. Tolerance to most drugs can be overcome to a certain extent by simply increasing dosage. With LSD, often a period of several days must separate 'trips' if the full effects are to be obtained, regardless of dose.141,143 A second unusual quality of LSD tolerance is the rapidity with which it develops and dissipates. A reduction in intensity of the effects occurs after only a few consecutive administrations5 and tolerance is lost within a few days of last use. Furthermore, when LSD is used intermittently many users report a 'reverse tolerance', or increased sensitivity to the drug and may, after experience, require less of it to achieve the desired effects. These factors suggest that the pharmacological mechanisms underlying LSD tolerance are quite different from those seen with most other psychoactive drugs. Cross-tolerance exists between LSD and some related drugs, and an individual who has recently taken LSD will generally show a reduced response to mescaline and psilocybin, but not to PCP or cannabis.23, 144, 324

Physical dependence does not develop to LSD, even in cases in which the drug has been used more than two hundred times in a single year." Psychological dependence has been reported to occur in certain individuals who become preoccupied with the drug experience and feel emotionally depressed and unsatisfied without it. Normally, however, LSD use is intermittent and periods of weeks or months may separate 'trips' in even confirmed users. Chronic frequent use is very rare.

Because of the general sedative properties of PCP, some degree of tolerance and physical dependence might be expected with daily use, but little human data is available. There is evidence that tolerance develops to some of the effects of STP.133 Similar effects apparently occur with MDA. There is no data available regarding physical dependence on MDA or STP, but an amphetamine-like rebound response might be expected with these drugs after repeated use. The typical patterns of occasional or intermittent use of LSD-like drugs makes the development of physical dependence highly unlikely under most conditions.

HALLUCINOGENS AND OTHER DRUGS

Amphetamine is reported to intensify, prolong or otherwise alter the experience produced by LSD and related drugs. Chemical analysis of illicit drug samples suggests that such mixtures are not often used, however. LSD and PCP often appear in combination in illicit samples, yet little is known as to how these drugs interact in humans. They produce opposite effects on many physiological functions, and animal studies indicate that LSD and PCP are antagonistic in some respects.78 Further research into LSD-PCP interaction is needed.

The psychological effects of LSD, MDA and most related drugs are reduced significantly by chlorpromazine (Largactil®), a phenothiazine major tranquilizer, and to lesser degrees by barbiturates, minor tranquilizers and other sedatives. In rare instances phenothiazines may potentiate the LSD response. Niacin, niacinamide, succinate and glucose have also been reported to reduce some of the effects of LSD.64, 127, 153, 280 There are no confirmed antagonists of PCP, but there is some suggestion in the literature that certain psychological effects may be reduced by succinate, and that PCP sedation may be blocked by amphetamine.78, 237

When STP first appeared on the illicit market in California, toxic effects were reportedly potentiated by chlorpromazine given in treatment of adverse reactions. This gave rise to widespread warnings against the use of chlorpromazine in treating 'bad trips'.277 However, in subsequent laboratory studies involving chemically pure DOM, chlorpromazine clearly did not accentuate the effects of DOM, but lessened them to some degree.183, 281 However, the interaction of chlorpromazine and DOM over a wide dosage range has not been explored. It has been suggested that the unidentified drugs originally responsible for the alleged STP-chlorpromazine potentiation were actually atropine-like compounds rather than, or in addition to, DOM.

Antibodies to LSD and certain related drugs have been developed, in part for use in immunoassay techniques for the detection of drugs in body fluid and tissue 72, 312 Recently, such antibodies were shown to reduce the response to LSD in an animal study—thus demonstrating the possibility of immunization against hallucinogenic drug effects.313

Users of LSD typically also use a variety of other psychotropic drugs. Almost all LSD users have smoked cannabis, but only a minority of persons who have tried cannabis have also taken LSD. Heavy cannabis users are more likely to have tried LSD than are occasional users. A significant proportion of young users of speed or opiate narcotics also report previous use of LSD and related drugs. LSD is apparently not very popular among regular heroin or speed users, however.56, 108, 174, 175, 176, 207, 253, 274 (See also Appendix C Extent and Patterns of Drug Use.)