| Hallucinogenic Drugs in Psychiatric Research and Treatment:
Perspectives and Prospects Rick J. Strassman, M.D. The Journal of Nervous and Mental Disease, Vol. 183, No. 3, pp. 127-138.
©1995 Williams & Wilkins
Clinical research with hallucinogens has resumed after a generation'shiatus. To place these new studies in context, this article reviewsthe history of hallucinogens' use and abuse, discusses their pharmacologicalproperties, and highlights previous human studies. Research withIysergic acid diethylamide and related hallucinogens with thousandsof patients and control subjects was associated with acceptablesafety when subjects were carefully screened, supervised, andfollowed up. Data were generated regarding hallucinogens' psychopharmacology,overlap with endogenous psychoses, and psychotherapeutic efficacy.Current American and European studies emphasize systematic psychopharmacology,in addition to psychotherapy protocols. Human hallucinogen researchwill help define unique mind-brain interfaces, and provide mechanistichypotheses and treatment options for psychiatric disorders. Itis critical that human hallucinogen research in the l990s makeuse of state of the art methodologies, or consensually definewhen modifications are required. Training and supervisory issuesalso must be explicitly addressed.
Hallucinogenic substances found in fungi, plants, and animalshave been used on all continents, and in a wide variety of cultures,both highly advanced and preliterate (Dobkin de Rios, 1984). Mescaline,from the peyote cactus, has been used in clinical research protocolsfrom the 1890s to the present (Mitchell, 1896). The thousand-timesmore potent effects of LSD-25 were discovered in 1943 by AlbertHofmann, 5 years after its synthesis (Stoll, 1947). The beginningof modern "biological psychiatry" can be said to havestarted as much with the appreciation of LSD's "psychotogenic"effects as the contemporaneous discovery of the one-thousandthas potent "antipsychotic" effects of chlorpromazine.
The study of hallucinogenic drugs in humans was, and remains,important for several reasons. First, they elicit a multifacetedclinical syndrome, affecting many of the functions that characterizethe human mind, including affect, cognition, volition, interoception,and perception. Characterizing hallucinogens' properties willenhance understanding of important mind-brain relationships, particularlyrelevant in this, the Decade of the Brain. Second, naturally occurringpsychotic syndromes share features with those elicited by thesedrugs. Understanding effects and mechanisms of action of hallucinogensmay provide novel insights and treatments into endogenous psychoses.Third, increasing use and abuse of hallucinogens over the lastseveral years, particularly LSD, by young adults may produce asimilar spate of adverse psychiatric sequelae seen with the firstwave of their illicit use in the 1960s. Treatment of these adverseeffects consume scarce public resources and safe, selective, andefficacious treatments of acute and chronic negative effects ofthese drugs are needed. Finally, the enhancement of the psychotherapeuticprocess, sometimes in treatment refractory patients, reportedby early studies, has relevance to current emphasis on time-limitedpsychotherapeutic interventions. Nomenclature Many terms have been used to describe the effects of these drugs,including psychedelic (mind manifesting), psychodysleptic (disturbingthe mind), phantasticant, psychotogen, oneirogen (producing dreams),entheogen (generating religious experience), phanerothyme (makingfeelings visible), psychotomimetic, and schizotoxin (Grinspoonand Bakalar, 1979; Stafford, 1992). Psychedelic represents thenonmedical, recreational, and illicit use of these drugs, whilehallucinogen refers to these compounds within a medical-legalcontext.
The "classical" hallucinogens belong to several chemicalfamilies: phenethylamines(e.g.,mescaline), indolealklyamines(e.g.,psilocybin and N,N-dimethyltryptamine [DMT]), andlysergamides(e.g.,LSD and morning glory seeds) (Nicholset al., 1991). 3,4-Methylene-dioxymethamphetamine (MDMA) ("X,""XTC") is a methoxylated amphetamine (phenethylamine),and produces effects that overlap those of classical compounds(Lister et al., 1992). Low doses of the dissociative anesthetics,phencyclidine and ketamine (Siegel, 1978), and antimuscarinicagents (Ketchum et al., 1973) also share subjective propertieswith the hallucinogens. However, hallucinogens do not produceanesthesia at high doses, as do the former compounds, nor is therea clouding of consciousness at "psychedelic" doses,as with the latter.
A clinically useful manner of representing hallucinogens refersto their temporal properties: onset, peak effect, and durationof action. An "ultra-short-acting" drug's onset is lessthan 1 minute, peak effects occur within 5 minutes, and durationis 30 minutes or less. Intravenous DMT is an example (Strassmanet al., 1994). A "short-acting" hallucinogen's onsetis between 5 and 15 minutes, peak effects are within 15 to 60minutes, and duration is 1 to 2 hours (e.g., intramuscularN,N-diethyltryptamine; Faillace et al., 1967). "Intermediate-acting"hallucinogens include the orally active tryptamine psilocybin(Rinkel et al., 1960). Onset is within 15 to 30 minutes, peakeffects are at 1 to 3 hours, with duration up to 6 hours. "Long-acting"hallucinogens include oral LSD and mescaline (Hoch et al., 1952),with onset at 30 to 90 minutes, peak effects at 3 to 5 hours,and duration of 8 to 12 hours. "Ultra-long-acting" compoundsinclude the poorly characterized African plant drug ibogaine (Fernandez,1982). Duration of action may last 18 to 24 hours. Prevalence of Use Hallucinogen use in the United States remained relatively constantfrom the late 1960s to the late 1980s (Pope et al., 1990). However,data from the National Institute on Drug Abuse (NIDA) show anincrease in any LSD use by high school seniors "within thelast 12 months" from 4.8% to 5.6% from 1988 to 1992. Whilethe magnitude of this rise is slight, it stands in contrast tothe abuse of other drugs. For example, the proportion of seniorswho had used any cocaine dropped from 7.9% to 3.1% during thesame period (Johnston et al., 1993). Thus, the proportion of respondentswho reported any use of LSD was almost twice as high as the proportionreporting any cocaine use by high school seniors in 1992. The1990 NIDA statistics reveal that lifetime prevalence rates forhallucinogens were about the same as those for cocaine, and 7to 8 times higher than for heroin. LSD ranked first in the categoriesof "most intense" and "longest" high amongrespondents. Between 13 and 17 million individuals in this countryhave used a hallucinogen at least once (NIDA, 1991). Legal Status Hallucinogens reside in Schedule I of the Controlled SubstancesAct of 1970, which is reserved for drugs with "high abusepotential," "lack of established safety even under medicalsupervision," and "no known use in medical treatment"(Anonymous, 1970). Compounds with "substantially similar"structure or function also are Schedule I drugs, as a result ofthe passage of the Controlled Substances Analog Bill of 1986 (Anonymous,1986).
The use of mescaline-containing peyote by the Native AmericanChurch has been debated for nearly a century (La Barre, 1989).Native American Church members may possess and ingest peyote inseveral states, and non-Native Americans may use it in Churchceremonies in some. In response to increasing judicial restrictionson peyote use, the Religious Freedom Restoration Act became lawin 1993 (Anonymous, 1993). Interpretation of this law with respectto hallucinogenic "sacraments" by traditional non-Western(Rivier and Lindgren, 1972) and other "neo-religious"groups will be of interest. Basic Neuropharmacology The nearly simultaneous discoveries of serotonin (5HT) and LSDundoubtedly have had an impact on the preeminent role of thisneurotransmitter in explicating hallucinogens' effects and mechanismsof action. Noradrenergic (Horita and Hamilton, 1969), dopaminergic(Ahn and Makman, 1979), and cholinergic (Cervoni et al., 1963)systems have also been investigated, but have received less attention.
Gaddum and Hameed (1954) and Woolley and Shaw (1954) first suggestedthat LSD antagonized the effects of 5-HT in lower animals. Soonthereafter, Freedman (1961) showed that LSD decreased particulatebinding of 5-HT in the axon, raising brain levels of 5-HT andlowering those of its metabolite 5-hydroxyindoleacetic acid. 5-HTmechanisms have been demonstrated for electrophysiological (Aghajanianet al., 1968), pharmacological (Conn and Sanders-Bush, 1986),and behavioral (Glennon et al., 1985) effects of hallucinogens.
The animal model of "hallucinogenesis" most used isdrug discrimination, wherein animals are trained to distinguishbetween a hallucinogen, usually LSD, and saline. Animal responsesto a test drug as if it were LSD suggest that the "interoceptive"or "discriminative" cue is similar to LSD's (Glennonet al., 1983). However, several nonhallucinogens are LSD-likein this model, such as quipazine (Cunningham and Appel, 1987)and lisuride (Nielson, 1985), while psilocybin is not (Koernerand Appel, 1983), which emphasizes the need for human studies.
Hallucinogens were important in stimulating the burgeoning fieldof 5-HT receptor subtypes (Peroutka and Snyder, 1979). Currentdata emphasize effects upon the 5-HTlA and 5-HT2A,C subtypes (Glennonet al., 1985; Spencer et al., 1987), alone or in combination (Arntand Hyttel, 1989).
Tolerance (Freedman et al., 1958) and cross-tolerance (Appel andFreedman, 1968) to behavioral effects of hallucinogens is seenrapidly, and is accompanied by downregulation of 5-HT2 sites (McKennaet al., 1989). Human PsychopharmacologyMeasurement of Hallucinogen Effects in Humans Initial human studies with hallucinogens relied upon careful clinicalobservation, using psychoanalytic (Savage, 1952) or behavioral(Cheek and Holstein, 1971) perspectives, in normal subjects (Snyderet al., 1967) and psychiatric patients (Hoch et al., 1952). Inaddition, hallucinogen effects on previously validated psychologicalscales, such as the MMPI (Belleville, 1956), assessed change scoreswithin individuals and allowed comparisons between hallucinogen-inducedsyndromes in normal subjects with other well-characterized psychopathologicalstates.
Three rating scales were developed specifically for LSD effectsin the 1960s. "Normative" data for all three scaleswere generated from effects in unexperienced hallucinogen userswho were not told what the effects of LSD might be, making thedata difficult to interpret, particularly when an attempt is madeto determine their reinforcing properties in those who use themrecreationally.
The Abramson et al. (1955) scale emphasized somatic, cognitive,and perceptual effects of LSD, while the Linton-Langs scale (Lintonand Langs, 1962) assessed effects predicated on a psychoanalytictheory of consciousness. The Addiction Research Center Inventory(Haertzen et al.,1963), the standard rating scale for assessingeffects of drugs of abuse, used LSD as one of several mind-alteringcompounds. Its LSD scale is known as the dysphoria scale, reflectingits emphasis on unpleasant effects (Haertzen and Hickey, 1987).
We have developed a new instrument, the Hallucinogen Rating Scale(HRS), that differs from these previous scales. It was draftedby interviewing experienced hallucinogen users, and modified duringpilot studies with DMT in an additional cohort of well-prepared,educated, well-functioning, experienced hallucinogen users (Strassmanet al., 1994).
The HRS also differs from other rating scales in its emphasison a "mental status examination" clustering of items.In the Abramson et al. scale, derivative factors, such as paranoidideation and generalized inhibitory effects, are used. The Linton-Langsscale also uses this manner of grouping items: feeling less inhibitedand suspiciousness are examples. In the Addiction Research CenterInventory, similarities or differences between a test drug and"reference" drugs are made, without determining thenature of these similarities or differences. In the HRS, itemsare grouped into six "clinical clusters": somaesthesia(somatic/interoceptive/visceral cues), affect, perception, cognition(thought content and processes), volition (willful ability tointeract with one's mental and physical self and the environment),and intensity (a global measure of robustness of response). Theseclinical clusters provided better resolution of subtle dose effectsfor DMT than multiple biological measurements in initial dose-responsestudies. Principal components factor analysis, choosing six factorsto correspond to the clinical clusters, also proved superior tobiological variables in differentiating among DMT doses, but generateda less heuristically useful grouping of individual items (Strassmanet al., 1994). Route of Administration Whether LSD and longer-acting compounds produce their effectsdirectly, or require secondary, "downstream" mechanisms,has been debated, because of the delay in onset of effects ofLSD even with intravenous administration (Aghajanian and Bing,1964). However, Hoch (1956) described nearly instantaneous onsetof LSD effects with intraspinal administration, and intravenousDMT effects also are immediate (Strassman et al., 1994). Thus,access of drug to relevant brain sites, lipid solubility, clearance,and other pharmacokinetic factors determine the time course ofdrug effects, rather than secondary processes. However, theremay be systems downstream from 5-HT receptor agonism that requireextremely short time domains for activation. Tolerance LSD and other classical compounds elicit behavioral tolerance(Isbell et al., 1956) and cross-tolerance (Abramson et al., 1960a)after several daily doses. The exception is DMT, for which nobehavioral tolerance has been demonstrated (Gillin et al., 1976),and which elicits a fully hallucinogenic response in LSD-tolerantsubjects (Rosenberg et al., 1964). Human Hallucinogen-Neurotransmitter Interactions Serotonin.Bromo-LSD, a potent 5-HT antagonist in loweranimals (Cerletti and Doepfner, 1958), although psychoactive inhumans at much higher doses than LSD (Isbell et al., 1959b), antagonizedLSD effects in both normal subjects (Ginzel and Mayer-Gross, 1956)and psychiatric patients (Turner et al., 1959). Cyproheptadine,a 5-HT2A c antagonist (Hoyer and Schoeffter, 1991), preventedthe subjective effects of DMT in two of three normal volunteers(Meltzer et al., 1982). 5-Hydroxytryptophan loading studies attemptedto surmount the 5-HT antagonism of LSD in humans, but did notdemonstrate clinically relevant effects (Pare and LaBrosse, 1963).Chronic monoamine oxidase inhibition reduced LSD's effects inhumans (Resnick et al., 1964), perhaps relating to downregulationof 5-HT sites. MAO inhibition also reduced DMT effects (Sai-Halasz,1963). This latter phenomenon may relate to inhibition of DMTmetabolism (Sitaram et al., 1987). Reserpine, if administeredat adequate dosage and duration, enhanced responses to LSD inhumans (Isbell and Logan, 1957; Resnick et al., 1965), supportinga functional "upregulation" of relevant mechanisms.
Both meta-chlorophenylpiperazine (Kahn and Wetzler, 1991) and6-chloro-2-(1-piperzinyl)pyrazine (MK-212) (Murphy et al., 1991)share pharmacological characteristics with the classical hallucinogens,and elicit "hallucinogenic" effects in patients withschizophrenia (Krystal et al., 1993) or alcoholism (Lee and Meltzer,1991), but not in normal subjects (Murphy et al., 1991). Higherdoses in normal subjects may produce more typical responses.
Dopamine.LSD has agonist effects at postsynaptic receptors(Burt et al., 1976), and DMT has dopamine-releasing properties(Haubrich and Wang, 1977). While chlorpromazine was suggestedto be a "specific antidote" to LSD effects (Isbell andLogan, 1957), it may enhance LSD's effects if given during theacute intoxication (Abramson et al., 1960b; Schwartz, 1967). Similarly,haloperidol pretreatment enhanced the neuroendocrine and subjectiveeffects of DMT in one subject (Meltzer et al., 1982). In addition,methamphetamine (a dopamine agonist) ameliorated acute LSD effects(Hoch, 1956). Thus, affinities of hallucinogens for dopamine receptors,relative to primarily dopaminergic or antidopaminergic compounds,may determine the end result of manipulating dopaminergic neurotransmissionon responses to hallucinogens. Other. Little data exist regardingmanipulating cholinergic (Isbell et al., 1959a) and adrenergic(Murphree, 1962) systems on hallucinogen effects in humans, andrequire further study. Hallucinogens and Schizophrenia The association between ingestion of hallucinogens and onset ofacute schizophrenic episodes is discussed below (seeAdverseEffects).One of the initial indications for LSD in clinicalresearch was for elicitation of a time-limited "psychotomimetic"syndrome. However, the degree of overlap has been vigorously debated(Hollister, 1962; Langs and Barr, 1968; Vardy and Kay, 1983; Young,1974). The criticism that visual effects were relatively uncommonin functional psychoses has been tempered by the high incidenceof these symptoms in later studies (Bracha et al., 1989). It appearsthat acutely ill, positive-symptom patients show more "psychedelic"symptoms than do chronic, undifferentiated, negative-symptom predominatingpatients, particularly in the prodromal state (Bowers and Freedman,1966).
Hallucinogens also were administered to psychotic patients andcomparisons were made between drug effects and preexisting symptoms(Cholden et al., 1955). These studies were limited by the highlyanecdotal nature of ratings of "subjective" effects.Some studies reported that hallucinogens produced different symptomsthan those patients were normally experiencing (Fink et al., 1966;Turner et al., 1959), while others reported an exacerbation ofpreexisting psychopathology (Hoch et al., 1952; MacDonald andGalvin, 1956). A relatively consistent finding was that "burnedout," predominantly negative symptom-laden patients showedblunted responses to hallucinogens (Boszormenyi and Szara, 1958;Hoch et al., 1952). This latter finding supports lower levelsof 5-HT2 sites in the cortex of schizophrenics (Mita et al., 1986).It also prompted a search for "endogenous schizotoxins,"in which case "tolerance" to naturally occurring psychotomimeticswould confer resistance to exogenously administered agents inpatients.
The short-chained tryptamines, DMT and 5-methoxyDMT, were leadingcandidates for endogenous hallucinogens (Corbett et al., 1978;Franzen and Gross, 1965). Requisite enzymes for DMT biosynthesiswere found in human blood (Wyatt et al., 1973), brain (Saavedraand Axelrod, 1972), and lung (Axelrod, 1962). Although correlationswere seen between acute symptomatology and DMT excretion in patients(Murray et al., 1979), interest waned because peripheral DMT levelswere not consistently different between normal and psychotic subjects(Gillin et al., 1976). However, peripheral levels do not accuratelyreflect either concentrations at discrete brain areas, nor differentialsensitivity to comparable levels between normal subjects and patientswith psychoses. Lack of tolerance to its psychological effects,given either twice daily for 5 days (Gillin et al., 1976) or every30 minutes four times, strengthens its importance as a putativeschizotoxin. Psychotherapy Research Relatively few studies used LSD as a "psychopharmacotherapeutic"agent in humans,i.e.,daily dosing regimes. Daily LSDelicited robust antidepressant responses in depressives in anuncontrolled study, while tolerance to its psychedelic effectsdeveloped rapidly (Savage, 1952). These data are consistent withsimilar
effects of chronic LSD and antidepressants on 5-HT receptor function(Buckholtz et al., 1990; Stolz et al., 1983). Beneficial responsesto daily dosing in some autistic children also were seen (Bender,1966; Freedman et al., 1962; Simmons et al., 1966).
The first suggestion that LSD may hasten psychotherapy was madein the early 1950s (Busch and Johnson, 1950), and series of casessoon followed (Eisner and Cohen, 1958). LSD was believed usefulin recovering early memories, enhancing associative processes,reducing repression, intensifying affective responses, and magnifyingaspects of the transference (Chandler and Hartman,1960; Hollisteret al., 1962; Snyder et al.,1968). These early protocols utilizedrelatively low doses (25 to 100 mcg) within the context of ongoingpsychoanalytic psychotherapy. This was termed the psycholyticapproach, and utilized multiple sessions over months or years.These studies were hampered by lack of adequate control groupsand impartial raters, small sample size, and primarily anecdotaldata. However, their emphasis on repeated sessions merits attentionwhen assessing results from "psychedelic" research protocols.This latter approach, described below, may have limited efficacyby depending inordinately upon one or two highly charged sessions,without the benefit of "working through" available inthe psycholytic model.
The psychedelic approach, favored by North American researchers,involved administration of a single, or at most a small numberof, high dose (300 to 1500 mcg) LSD session(s) after a relativelyshort course of psychotherapy (Pahnke et al., 1970). This psychotherapyencouraged the patient to undergo a "psychedelic experience,"which had many aspects of a religious epiphany. As many "spontaneouslyrecovered" drug abusers report similar spiritual-mysticalexperiences (Ludwig, 1985), this approach was turned to substanceabuse treatment (Hollister et al., 1969; Savage and McCabe, 1973).Uncontrolled, often anecdotal reports from psychedelic studiesalso demonstrated some promise in the treatment of sociopathy(Shagass and Bittle, 1967), prisoner recidivism (Leary and Metzner,1967-68), and the pain and despair associated with terminal illness(Grof et al., 1973; Kast and Collins, 1964).
Substance abuse treatment studies were numerous, and while initialreports were enthusiastic (Kurland et al., 1967; MacLean et al.,1961; Smith, 1958), studies using control groups and longer follow-updemonstrated less impressive results (Cheek et al., 1966; Hollisteret al., 1969; Johnson, 1969). However, a review of 31 studiesinvolving 1100 alcoholics concluded that meaningful generalizationscould not be reached because of the inconsistent designs and criteriafor improvement (Abuzzahab and Anderson, 1971).
In summary, many of the initial studies suggesting enhancementof psychotherapy with hallucinogens were hampered by lack of methodologicalrigor. However, placebo/control treatments are problematic. Forexample, when 50 1lg of LSD were used as "active placebo"against 450,ug of LSD in an alcoholism treatment study using thepsychedelic model, minimal differences in outcome among groupswere discerned (Kurland et al., 1971). That many of the low-dosegroup also underwent a "peak experience" emphasizesthe importance of assessing the interplay between pharmacology,psychotherapy, and subjective experience. Minimum requirementsfor future studies should include independent raters of effectsand outcome, identical (nondrug) treatment in the control group,and adequate follow-up (at least 1 year) (O'Brien and Jones, 1994).The choice of inactive and/or active placebo must be given carefulconsideration. Finally, a hybrid of the psychedelic and psycholyticmodels, in which more frequent high-dose sessions are used, mayprovide additional flexibility and allow more psychotherapeuticwork to take place than either model alone. Adverse Effects The profoundly altered mental status elicited by hallucinogensrequires astute clinical management, including thorough screeningand preparation of prospective patient or volunteer subjects,careful supervision of drug sessions, and consistent and responsivefollow-up which may require psychotherapeutic intervention.
Early clinical investigators provided reassuring safety data.A survey of American clinical research documented in normal volunteersa rate of attempted suicide of 0/1,000, completed suicide of 0/1,000,and "psychotic reactions over 48 hours" of.8/1,000.Corresponding figures in patients were 1.2/1,000,.4/1,000, and1.8/1,000 (Cohen, 1960). These data were derived from over 5,000subjects who had received LSD or mescaline more than 25,000 times,single individuals taking between 1 and 80 doses, using LSD dosesfrom 25 to 1,500 mcg. A British survey reported comparable results(Malleson, 1971).
Once hallucinogens escaped from the laboratory, however, emergencyrooms and clinics were quickly impacted by adverse effects inunprepared, unsupervised, and psychiatrically ill individualstaking hallucinogens, especially LSD (Frosch, 1969; Ungerleideret al., 1968). LSD was nearly always of uncertain quality anddose, and combinations of LSD and other drugs and alcohol wereusual (Frosch et al., 1965).
These adverse consequences may be classified temporally as acute,subacute, and chronic (Strassman, 1984). Acute Acute adverse effects include: a) brief panic reactions to effectsof the drug, which generally responded to verbal reassurance andprotection of the patient, and only in severe instances, to medication(Taylor et al., 1970); and b) psychotic reactions, disorganizedstates that lasted longer than 24 hours and required more intensivemanagement and often hospitalization. These psychotic reactionsusually were superimposed on preexisting psychotic disorders inpolydrug-abusing patients (Blumenfield and Glickman, 1967; Hekimianand Gershon, 1968; Hensala et al., 1967; Vardy and Kay, 1983).They typically responded to treatments appropriate to the non-drug-inducedsyndromes they resembled (Strassman, 1984).
Toxicology laboratories now can measure sub-nanogram/milliliterconcentrations of LSD in body fluids (Nelson and Foltz, 1992),aiding diagnosis of acute adverse reactions. Subacute Subacute effects requiring clinical intervention are flashbacks,which refer to unbidden re-experiencing of certain aspects ofhallucinogen-induced effects, often visual, but partaking of allpsychic functions (Wesson and Smith, 1976). They occur after anintervening period of normalcy after a drug experience (Horowitz,1969). Not all flashbacks are felt to be adverse, and many membersof the psychedelic subculture find brief "free trips"pleasurable (Wesson and Smith, 1976). The incidence is reportedto vary between 15% and 77% of individuals who have had at leastone LSD experience (Strassman, 1984).
In our DMT studies with experienced hallucinogen users, we haveseen an incidence of 5% to 10% in volunteers with at least onehigh-dose DMT session. These sessions, it should be noted, arealmost uniformly regarded as "higher than I have ever been,"and thus may be considered traumatic. Meditation, smoking marijuana,and falling to or waking from sleep are the most common precipitants.Several volunteers willfully attempt to re-experience aspectsof the DMT state by these means.
The etiology of flashbacks is not known, but organic, psychological,and social hypotheses have been proposed (Alarcon et al., 1982).Their presence in post-traumatic stress disorder and elicitationby lactate infusion (Rainey et al., 1987) suggest a complex interactionof anxiety and stress with memory processes (McGee, 1984). Flashbacksare usually self-limited, if psychoactive drugs, especially hallucinogensand marijuana, are avoided. Persistent or particularly disturbingsymptoms (Abraham, 1983) require a neurological evaluation. Chronic Chronic adverse effects may be divided into functional and organic.Functional syndromes rarely may be quite debilitating and treatmentresistant, resembling an ego-syntonic, negative symptom-ladenschizophrenic disorder (Glass and Bowers, 1970).
More difficult to diagnosis confidently as directly related toLSD use are changes in lifestyle and interpersonal behaviors associatedwith hallucinogen use (Blacker et al., 1968). The confluence ofdrugs and preexisting personality styles is suggested in McGlothlinand Arnold's (1971) 10-year follow-up of psychotherapy patientsand normal volunteers who participated in sanctioned LSD studies.This study suggested a catalytic effect of LSD use in individualspredisposed to unconventional aesthetic and philosophic ideas(McGlothlin and Arnold, 1971).
LSD-induced organic central deficits have been difficult to documentwith certainty, because of no premorbid data and an inabilityto control for other substances of abuse (Acord and Barker, 1973).Statistically, but not clinically, significant decrements werereported in several studies. Lower Halsteads' Category and Reitan'sTrail Making A test scores were reported in hallucinogen userscompared with control subjects; however, both of these tests werewithin normal ranges in drug users (Culver and King, 1974; McGlothlinet al., 1969). Nonspecific EEG changes also were described (Blackeret al., 1968).
Chronic visual disturbances, posthallucinogen perceptual disorder,akin to chronic flashbacks, may partake of functional and organicbases. The validity of this diagnosis is uncertain because oflack of premorbid data and inability to control for other drugsof abuse. Its responsiveness to benzodiazepines (Abraham, 1983)support an anxiety/functional rather than organic disorder (McGee,1984). Mutagenicity / Teratogenicity Initial reports of chromosomal (Cohen et al.,1967)andreproductive (Jacobson and Berlin,1972)disorders inLSD users were not replicated in later studies (Dishotsky et al.,1971;Muneer,1978).Until more controlled dataare forthcoming, however, woman who are pregnant or not usingreliable contraception are not suitable candidates for hallucinogenresearch protocols. Conclusions and Recommendations Hallucinogens are powerful drugs, with the potential to elicitor exacerbate psychiatric symptoms. Particularly aversive or overwhelmingacute effects may traumatize or sensitize the individual, settingup the potential for flashbacks akin to those seen in post-traumaticstress disorder. The use of experienced hallucinogen users mayreduce the traumatic nature of high-dose hallucinogen sessions,and is recommended for psychopharmacological research. Additionally,truly informed consent is possible only in experienced users.Studies comparing responses in normal subjects with those in psychiatricpatients (see below) should use the lowest doses that will generaterequisite data.
Psychotherapy protocols require a careful assessment of risk tobenefit ratios balancing morbidity or mortality of an untreatablepsychiatric condition with the likelihood of psychological sequelaeof hallucinogen exposure. The risk associated with psychotherapyresearch protocols may be lessened by using the lowest possibledose of drug. If high-dose administration is necessary, it maybe prudent to gradually build up to this dose over several sessions. Current Research In the United States, we have been administering DMT since late1990 (Strassman, 1991) in psychopharmacologic studies utilizingexperienced hallucinogen users (Strassman and Qualls, 1994; Strassmanet al., 1994). The University of Miami has begun phase I studiesof ibogaine in preparation for substance abuse treatment research.Similar phase I studies have begun at UCLA with MDMA, also inanticipation of therapeutic applications. Psychopharmacologicalstudies using subanesthetic, psychotomimetic doses of ketaminein normal volunteers and patients with schizophrenia are ongoingat Yale University (Krystal et al., 1994). A substance abuse treatmentamendment to the University of Maryland's inactive LSD protocolhas been approved, and may begin within a year.
In Europe, group and individual psychodynamic psychotherapy withLSD or MDMA has been taking place in Switzerland since 1985, butno research data have been generated. The University of Zurichis studying the effects of psilocybin and ketamine on positronemission tomography and neuropsychological responses in normalvolunteers (Vollenweider, 1994). In Germany, several sites arestudying mescaline and MDE (the N-ethyl derivative of MDMA) effectsin normal volunteers, studies in which multiple neurobiologicalvariables are characterized (Hermle et al., 1992, 1993). Areas for Future Research As described previously, a wide range of temporal characteristicsare available with the hallucinogens, and may be exploited forresearch with different goals. For example, psychotherapy protocolsmight be best served using short-acting drugs whose effects lastbetween 1 and 2 hours, while neuroendocrine challenge studieswould benefit from using ultra-short-acting drugs and keepinginteractions with the environment to a minimum. Protocols requiringmultiple within-individual assessments could use long-and ultra-long-actingdrugs. Measurement Variables Recent DMT studies demonstrate the superiority of subjective (HRS)responses to biological ones with respect to subtle dose effects(Strassman et al., 1994). Thus, despite better characterizationof mechanisms of action for neuroendocrine, cardiovascular, andother autonomic variables, sensitivity for effects of experimentalmanipulations is relatively low. This emphasizes the importanceof introspection and subjective data in characterizing the effectsof hallucinogens, especially using a within-subjects design. Psychopharmacology Human hallucinogen psychopharmacology requires further study,for both clinical and heuristic purposes. Research should assessthe role of non-5-HT neurotransmitters, particularly dopamine.Risperidone, with potent 5-HT2 and D2 antagonism, is more potentthan ritanserin, a pure 5-HT2A,( agent, in antagonizing animalresponses to LSD (Meert et al., 1989). The importance of combined5-HT/DA antagonism corresponds to efficacy in schizophrenia treatmentwith "atypical" antipsychotic medications (Meltzer,1989), and suggests that antagonists to hallucinogens' behavioraleffects in humans may be efficacious in schizophrenia.
Pretreatment blockade studies, based upon relevant animal andhuman data, will suggest interruption strategies for acute adversereactions in the emergency setting. Blockade strategies (Kostenand Kosten, 1991) also could be utilized to prevent subjectiveeffects in those prone to chronic abuse of hallucinogens in amanner similar to naltrexone.
Although most classical hallucinogens' qualitative psychopharmacologicalproperties are believed identical (Isbell, 1959), little dataexist for within-subject studies using multiple drugs. Many congenersof classical compounds have been administered safely to humans(Isbell et al., 1959b). Assessment of salient similarities anddifferences will suggest structure-activity relationships fordesign of drugs with desirable functional profiles for clinicalresearch purposes (Nichols, 1987).
Responses to hallucinogens in psychiatric populations with presumedabnormalities in neurotransmitter systems relevant to hallucinogenaction may be tested, if appropriate safeguards are in place.Such studies would generate unique human data relating disturbedsubjective experience in psychiatric patients to pharmacologicalmanipulations, generating both therapeutically and mechanisticallyvaluable data.
Studies exploiting recently developed hallucinogen-induced animalmodels of information-processing defects in schizophrenia (Braffand Geyer, 1990) could be applied to normal volunteers' responsesto these drugs, further comparing the two syndromes. In addition,the HRS could be applied to more carefully characterized schizophrenicpatients at various stages of the disorder, allowing novel comparisonsbetween functional and drug-induced psychoses.
Advances inin vivo brain-imaging techniques may bettercharacterize hallucinogen effects and mechanisms of action. Theseinclude topographic pharmacoelectroencephalography, positron emissiontomography (assessing metabolic effects of psychoactive doses,and distribution of low doses of labeled compounds), and magneticresonance imaging (spectroscopy and functional imaging). Psychotherapy Economic constraints create increasing pressure for cost-effectivemedical psychotherapy (Krupnick and Pincus, 1992). Sophisticatedpsychotherapy protocols with proven efficacy (Frank et al., 1990)provide a strong foundation upon which hallucinogen-assisted psychotherapyresearch may be re-examined. Courses of therapy utilizing adjunctive,high-dose, hallucinogen-assisted sessions should be consideredin a model combining the psychedelic and psycholytic models. Thiswould be a logical extension of earlier work that suggested robustshort-term improvement, but less impressive maintenance of therapeuticeffects, in high-dose models.
The growing numbers of terminally ill cancer and acquired immunedeficiency syndrome patients who require palliative, quality-of-lifetreatment suggest additional areas for future psychotherapy researchthat would build upon older, uncontrolled studies indicating beneficialresponses. The reported elements of increased pain control, improvedfamily relationships, and greater acceptance of illness and impendingdeath, if verified by controlled studies, would provide additionalclinical support for these patients. The use of "flooding"to treat post-traumatic stress disorder in both combat veterans(Grigsby, 1987) and others (Saigh, 1989) may also provide a uniqueinterfacing of hallucinogenic drug effects with an establishedtreatment modality for a particularly pernicious and common disorder.Hallucinogen-enhanced imagery and associations, and associatedaffective responses to these, could be used to enhance the efficacyof this treatment. Set and Setting Although complex and potentially controversial, set and settingissues require further study. Set refers to the personality, state,and expectations of the subject, and setting to the environmentin which the session takes place. Setting partakes of the physicalsurroundings,e.g.,inpatient, high-technology researchunit or comfortable outpatient consultation suite; nuances ofthe investigator/therapist presentation, including clothing, appearance,odor, and other physical characteristics; being belted to thebed (Smart et al., 1966) or able to move about freely; and eyesopen or blindfolded (Denber, 1958). In addition, it involves the"set" of the research team members, including the natureof countertransference and empathy (Day, 1957), type and amountof training in psychotherapy and working with regressed/psychoticindividuals, and the theoretical model and expectations of theresearch, psychotomimetic, psychedelic, or otherwise.
Finally, research team members' experience with hallucinogensmay affect the nature of the results of research/treatment protocols.Swiss and German health authorities require that the principalinvestigators first take study drugs at doses to be used in theirprotocols, both for safety issues and to provide more adequateinformed consent.3 In the United States, self-experimentationby research teams initially was encouraged (Cerletti and Rothlin,1955; Johnson, 1969; Szara, 1957). However, in response to highlypublicized cases of self-experimentation and extraresearch drugtaking with volunteers (Leary, 1968), this practice was discontinued.Future research must carefully account for these setting variablesin assessing outcome measures, and the European practice of "goingfirst" should be considered. Training Issues The small number of protocols using hallucinogens allows for veryclose contact between investigators and regulatory agencies overseeingthis work. However, renewed examination of these compounds maygenerate a large number of requests to use them in clinical studies.State of the art methodologies are no guarantee against disastersresulting from imprudent administration of hallucinogens to humans.
Transference and countertransference issues are rarely discussedin psychopharmacology research, and increasingly less so in psychotherapyresearch. However, the regressed, suggestible, and unusual behaviorof subjects under the influence of hallucinogens is easily observable.Interpersonal exchanges that would be readily overlooked in anormal state of awareness may assume extreme and confusing meaning.The clinical investigator not only may become the object of infantilewishes and fears, but may, in the subject's mind, actually look,smell, feel, and sound identical to highly emotionally chargedpeople in his or her life. In addition, the clinical researchermay have multiple, conflicting, and more-or-less conscious motivationsfor administering incapacitating drugs to humans. These may includenarcissistic, grandiose or sadistic, and voyeuristic impulses.Callous, offhand, or teasing remarks made for these and other,less malignant, but similarly unexamined, motivations can dramaticallyalter the course of a volunteer's hallucinogenic drug experience,from a psychedelic to psychotomimetic. Sexual relations betweenclinician and subject, during or after a hallucinogenic drug session,the most disastrous acting-out of both parties' drug-altered sensibilities,do occur.
Regulatory agencies determine professional qualifications andadequacy of facilities for conducting this research. However,I believe that specialized training, and perhaps certification,is necessary for clinical investigators performing human hallucinogenresearch. Such training/certification and ongoing periodic supervisionwould reduce the likelihood of subtle or flagrant misuse of thesecompounds by unknowing or unscrupulous clinical investigators.Specific proposals regarding the nature of this training and supervisionis beyond the scope of this article. This suggestion is meantto stimulate further debate and discussion at institutional andgovernmental levels. Conclusion The renewal of human hallucinogen research is encouraging. However,it must be tempered with an appreciation that the controversialnature of these drugs caused a suspension of nearly a generation'sworth of research in the field (Dahlberg et al., 1968). Ongoingstudies are taking a painstaking, systematic approach, and areavoiding claims that cannot be substantiated by data. Carefulattention to selection, screening, preparation, supervision, andfollow-up of subjects undergoing hallucinogenic drug sessionsis absolutely necessary. In addition, the training, characteristics,and research setting of clinical investigators desiring to workwith these compounds must be addressed directly.
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