Do Hallucinogens Cause Residual Neuropsychological Toxicity?

Home , Dipropyltryptamine, TOM (psychedelic)

Drug and Alcohol Dependence 53 (1999) 247–256

Review Do hallucinogens cause residual neuropsychological toxicity?

John H. Halpern 1,a,*, Harrison G. Pope1 Jr. b

a Alcohol and Drug Abuse Research Center, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA b Biological Psychiatry Laboratory, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA

Received 20 March 1998; accepted 17 July 1998

Abstract

We collected and reviewed studies in which neuropsychological tests were administered to users of LSD or other hallucinogens. Interpretation of the studies is limited by various confounding variables, such as subjects’ premorbid cognitive and personality function and prior use of other substances. At present, the literature tentatively suggests that there are few, if any, long-term neuropsychological deﬁcits attributable to hallucinogen use. To better resolve this issue, however, it will be important to study larger samples of chronic, frequent hallucinogen users who have not often used other types of drugs. © 1999 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Neuropsychological tests; Hallucinogens; 5-HT; LSD; Long-term effects

1. Introduction 1997). Illicit use of hallucinogenic drugs has become widespread in the United States and elsewhere during Hallucinogenic drugs of plant origin, such as psilocy- the last 30 years, and represents one of the few types of bin (N,N-dimethyl-4-phosphoryloxytryptamine), N,N- illicit drug use presently increasing among Americans dimethyltryptamine (DMT), and mescaline (Hunt, 1997). The 1990s have seen a steady rise in (3,4,5-trimethoxyphenethylamine) have been used for hallucinogen use among 8th, 10th, and 12th graders, as thousands of years by various peoples around the world well as college students and young adults. For example, (Schultes and Hofmann, 1992; Ott, 1993). In the last 50 the proportion of high school seniors who had tried a years, these naturally occurring hallucinogens have hallucinogenic drug as least once in the prior 12 months been supplemented by a wide range of synthetic com- climbed from 4.4 to 8.4% between 1985 and 1995 pounds, beginning with the discovery of lysergic acid (Johnston et al., 1997). Preliminary results from the diethylamide (LSD) in 1943 (Stoll, 1947; Hofmann, 1996 National Household Survey on Drug Abuse sug- 1983), followed by N,N-dipropyltryptamine (DPT), 2,5- gested that 1.2 million Americans tried a hallucinogen dimethoxy-4-methylamphetamine (DOM), 3,4-methyl- for the ﬁrst time in the year 1995, which is twice the enedioxy-N-ethylamphetamine (MDE), 3,4-methylene- average annual number reported during the 1980s dioxy-N-methylamphetamine (MDMA), and countless (SAMHSA, Ofﬁce of Applied Studies, 1997). other structural analogs (Shulgin and Shulgin, 1991; Not surprisingly, a substantial literature has ad- dressed the possibility of residual neuropsychological effects from long-term hallucinogen use, with some * Corresponding author. Tel.: +1 617 8553703; fax: (617) 855- 2519; email: [email protected] reports reaching alarmist tones. For example, a 1971 1 Also at: Consolidated Department of Psychiatry, Harvard Medi- editorial in Journal of the American Medical Associa- cal School. tion asserted:

The psychedelic plague refers to the morbidity associ- tend much longer (Abraham, 1983; Abraham and ated with the major psychedelic drugs… it is becom- Aldridge, 1993) with one report of symptoms persisting ing increasingly more apparent that severe but often for 26 years (Abraham, 1998). DSM-IV does not com- insidiously developing personality changes occur in ment, however, on whether individuals with this or the chronic abuser… Perhaps only a few of those other hallucinogen-related disorders would be expected who experience more than 50 ‘trips’ are spared. to demonstrate residual cognitive impairment, much Which personality profiles are most vulnerable has less an organic brain syndrome, as suggested in the yet to be established. In any case, present clinical quotation above. evidence suggests that no longer can it be assumed Given the continuing controversy regarding the that these changes are found only in the residual effects of hallucinogens, we conducted a review schizophrenic-vulnerable population, for many pre- of available studies in which neuropsychological tests abusers possess adaptable personalities and their were administered to individuals who had used family histories include no instance of psychosis. The hallucinogens. form of the personality deterioration may range from a schizophreniform psychosis to an organic brain syndrome (Donlon, 1971). 2. Methods Other warnings appeared from investigators who hy- pothesized that brief psychotic reactions after the con- We searched the Medline database (1/1/64 to 1/19/ sumption of LSD may develop into chronic psychosis 98) for the key terms of hallucinogens (n=2189); in predisposed individuals (Glass, 1973; Vardy and LSD, lysergic acid diethylamide (n=3430); Mescaline Kay, 1983). By contrast, investigators have also sug- (n=767); Psilocybin, Psilocybine, Psilocin (n=324); gested that hallucinogens were unlikely to cause lasting DMT, N,N-dimethyltryptamine (n=313); and MDMA, impairment. For example, Cohen (1960) concluded that N-methyl-3,4-methylenedioxymethamphetamine, 3,4- LSD administration to humans under medical supervi- methylenedioxy-N-methylamphetamine (n=367). The sion was relatively benign, with psychotic reactions of search results were pooled and cross-referenced with more than 48 h occurring in only 1.8 per 1000 subjects Psychological Tests (n=20816), and Neuropsychologi- administered the drug. Strassman (1984), reviewing ad- cal Tests (n=11701). A total of 67 candidate papers verse reactions to hallucinogens, similarly concluded were found. These 67 papers included 19 in which that ‘it appears that the incidence of adverse reactions neuropsychological tests were actually administered to to psychedelic drugs is low when individuals (both hallucinogen users. Searching the references of these normal volunteers and patients) are carefully screened papers provided an additional 23 references, some prior and prepared, supervised, and followed up, and given to 1964, bringing the total number of papers under judicious doses of pharmaceutical quality drug’. As consideration to 42 investigations. We then applied five these conflicting reports suggest, the hallucinogens were exclusion criteria to this group of studies. First, since controversial psychopharmacologic agents from the be- we were interested in the residual, rather than the acute ginning, with claimed therapeutic potential on one effects of hallucinogen use, we excluded studies in hand and potential for disaster on the other (Barron et which testing was performed on subjects acutely intoxi- al., 1964). cated with these drugs (Landis and Clausen, 1954; Speculation about the residual effects of hallucino- Berlin et al., 1955; Silverstein and Klee, 1960; Gold- gens continues to the present day (McCann et al., berger, 1966; Duke and Keeler, 1968; Snyder et al., 1997). DSM-IV lists not only Hallucinogen Dependence 1968; Wagner et al., 1968; Fischer et al., 1970; Thatcher and Abuse, but also Hallucinogen Intoxication, Hallu- et al., 1970, 1971; Harrington et al., 1989; Hermle et al., cinogen Intoxication Delirium, Hallucinogen-Induced 1992). Second, we excluded studies examining neu- Psychotic Disorder, Hallucinogen-Induced Mood Dis- ropsychological performance in polydrug users (Riley order, Hallucinogen-Induced Anxiety Disorder, and and Jamieson, 1972; Cohen et al., 1974; Nishith et al., Hallucinogen-Related Disorder Not Otherwise Spe- 1994), since the contribution of hallucinogens in such cified (American Psychiatric Association, 1994). Yet cases could not be ascertained. Third, we excluded another DSM-IV category, unique to the hallucinogens, individual case reports (Glass, 1973) or collections of is Hallucinogen Persisting Perception Disorder (known small numbers of cases (Kleber, 1967; Duncan, 1970; also as Post-Hallucinogen Perceptual Disorder or Glass and Bowers, 1970; Hendin, 1973; McCann and ‘flashbacks’). Those with this latter disorder describe Ricaurte, 1991) and considered only those studies ex- brief or lingering recurrences of distorted perceptions amining at least five individuals. Fourth, we excluded reminiscent of hallucinogen intoxication itself. Usually studies that commented on the residual effects of hallu- hallucinogen persisting perception disorder sponta- cinogens but did not include formal neuropsychological neously resolves within weeks or months of cessation of testing (Unger, 1963; Klavetter and Mogar, 1967; Mc- use (Ungerleider and Pechnick, 1994), but it may ex- Glothlin et al., 1967; Fischer and Scheib, 1971; Mc- J.H. Halpern, H.G. Pope / Drug and Alcohol Dependence 53 (1999) 247–256 249

Glothlin and Arnold, 1971; Salzman et al., 1972; Broth- jects met the authors’ three inclusion criteria: (1) history ers and Gaines, 1973; Jones, 1973; Wackwitz et al., of 20 or more LSD ingestions; (2) residing in the Los 1974). Fifth, we excluded studies of dissociative agents Angeles area; and (3) lacking evidence of gross psycho- such as phencyclidine and ketamine (Cosgrove and pathology predating LSD use. Three additional subjects Newell, 1991). These exclusion criteria reduced the were excluded for heroin addiction and alcoholism, number of studies under consideration from 42 to 9 repeated psychiatric hospitalization, or severe emo- studies. tional disturbance with an inability to work. Of note, 12 (75%) of these had used other hallucinogens, 6 (38%) had used opiates, 12 (75%) had smoked marijuana, and 3. Results an unspecified number had engaged in ‘moderate’ use of oral sedatives and stimulants. The authors chose 16 The nine qualifying studies are summarized in Tables non-LSD-exposed controls matched for age, sex, and 1 and 2 and discussed in detail in this section. education. Thirteen of the 16 subjects in each group Blacker et al. (1968) compared 21 LSD users (whom had received psychotherapy from one particular thera- the authors referred to as ‘acidheads’) with unmatched pist. Four of 16 controls had consumed marijuana controls obtained from two sources: 63 male psychiatric more than 10 times; their other drug use, including inpatients from the United States Naval Hospital and current or past alcohol use, was not specified. The 25 ‘unselected’ normal volunteers. The investigators abstinence period was more than 12 months in 9 sub- found subtle electroencephalographic (EEG) changes in jects, but 2 were reportedly tested under the acute the LSD group in comparison to controls, with the effects of LSD. Neuropsychological tests generally former showing increased alpha, beta, delta, and theta showed no significant differences between groups, and activity and increased visual evoked response ampli- in particular failed to replicate Cohen and Edwards’ tudes at the dimmer intensities. They considered these (1969) finding of poor performance on visuo-perceptual findings ‘compatible with either drug effects and/or and spatial orientation tests. The only positive finding CNS dysfunction’, but acknowledged that their results in this area was that spatial orientation scores in the 16 were inconclusive due to lack of premorbid testing. users correlated negatively with their ranking on the Interpretation of results was further limited by not number of LSD ingestions (PB0.05). However, no reporting the total number of episodes of LSD use other visual tests demonstrated a significant relation- among the subjects and requiring an abstinence period ship between performance and doses consumed. Hal- of as little as 48 h between the last LSD ingestion and stead’s category test, a nonverbal test of abstraction, the time of testing. Also, the investigators did not did reveal diminished abstracting ability in the LSD systematically assess subjects’ current or past use of group (PB0.01), but this performance also did not other illicit drugs, alcohol, or prescription medications, correlate significantly with number of LSD ingestions. nor did they attempt to exclude subjects who might Guilford’s associational fluency test found the LSD have been intoxicated with these substances at the time group more proficient in verbal ability than controls, of testing. These limitations are shared by most of the and psychiatric interviewers judged the LSD users more subsequent studies reviewed here (see Table 2). often ‘eccentric’ in personality structure. Cohen and Edwards (1969) reported impaired visuo- Wright and Hogan (1972) failed to find any impair- spatial orientation among 30 LSD users in contrast to ment of organic brain functioning in subjects who had 30 controls matched for age, sex, years of education, been taking LSD with unspecified frequency for a mean and socio-economic background. The authors also of 12.2 months. Interpretation of these findings, how- found that performance on the Reitan Trail Making ever, is limited by the usual methodological consider- Test A and the Ravens Matrices correlated negatively ations: pre-LSD functioning was not assessed, past use with extent of LSD use. However, the drug-using group of other drugs was not documented, and past neuro- did not differ from the control group on IQ, concept logic or psychiatric history was not reported (although formation, speech perception, time perception, tactual neither group was in psychiatric treatment at the time performance, tactual recognition, motor ability, or spa- of testing). In addition, controls were selected from a tial orientation. Subjects were not excluded for history larger pool of ‘normal subjects’ experienced with neu- of psychiatric disorder, but were excluded if hospital- ropsychological tests from a previous study. ized, under current psychiatric care, or appeared ‘obvi- In an uncontrolled study, Acord (1972) reported ously mentally disabled’. Again, interpretation is impaired abstracting ability (as compared to population limited by the brief abstinence period and failure to norms) in chronic LSD users selected from an inpatient control for current or past use of other illicit drugs. and outpatient neuropsychiatric service. Using the McGlothlin et al. (1969) selected 300 prospective Wechsler Adult Intelligence Scale (WAIS), Halstead subjects from a random sample of 700 patients who had Battery, and the Trail Making Test, he reported that 32 received LSD in psychotherapy. Only 19 of these sub- of the 40 subjects scored within the ‘brain-damaged 250 J.H. Halpern, H.G. Pope / Drug and Alcohol Dependence 53 (1999) 247–256 tests of = g tests of kinesthetic ical tests ABDEGQ B ADEQ BDEFGQ ABDEFG BEFGQ Neuropsycholog- = f NR tion blind scoring e tests of visuospatial ability; G = Excluded for psychiatric history C: No ) Yes NR ABDEFQ + d 21 days. See text the raters were aware of subject status. 1 days No No, but some ] = × 50 days for MDMA. No No subjects were included despite significant past or current psychiatric history. 9 = Mean 38.9 days NR No No ABDEF NR No Abstinence period unknown. / month 66 / tests of short-term or delayed memory (includes both verbal and visuospatial tests); C h = tests of executive or attentional ‘frontal functions’; F 2.3 years Other = 9 1.7 doses MDMA c 9 drugs for 5.1 12–28 7 days No Yes mean age not reported; (NR), age range not reported. = 6.18 (NR) 5.46 (NR) Minimum 50 48 h No Yes b 7 (22–47) 1.9 9 9 9 other tests. = in years S: 20 (13–27)1) C: 32 (19–58) Mean 65 48 h S: Yes No G H 2) C: 25 (17–44) C: 22.67 (NR) a a SD if reported; NR 9 . See text a NR 2 groups of 28 tests of reaction time or psychomotor speed; E = a 7 Males2 Females 015 Males 15 Males S: ‘Age 34 matched’ 13 Males 1) 63 NR 8 Females 2) 25 NR 15 Females 15 Females C: 21.8 15 Males 15 Males12 Males 12 S: Males 21.7 S: 40 (28–51) 20–1100 Varied (1 day–1 year 4 Females 4 Females C: 40 (NR) Median 75 28 NR 5 Females 5 Females40 Males 015 Males C: 19.10 (NR) 15 Males S: 21.53 S: (NR) 20 (17–24) ‘at least 1 hallucinogen’ Subjects Controls Mean (range) age Controls; mean age = electrophysiological measures; and Q -dimethyltryptamine) from a plant source – see text for details. = N , N sex not specified. an attempt was made to exclude subjects with a past history of a major psychiatric disorder; No either the rater was blind to the subject’s hallucinogen use or the evaluation was done by machine; No intelligence tests or tests measuring or estimating general intellectual capacity; B subjects; C = = = = = 1992) King, 1974) C: NR (20–25) Median 17 1968) wards, 1969) Median 70 See text al., 1969) Barker, 1973) gan, 1972) Mean 29.3 1996) (NR) S Minimum time from the last personal use of a hallucinogen to baseline testing; NR, not reported DMT ( NR A Number of times that subjects had usedYes a hallucinogen in their lives. Yes (Krystal et al., (Grob et al., 100’s est. of DMT (Culver and S: NR (20–25) (Blacker et al., (Cohen and Ed- (McGlothlin et (Wright and Ho- 15 Males 15 Males S: 20.15 (17–24) 5–100 4 subj (Acord, 1972) (Acord and ‘at least 1 hallucinogen’ NR Yes, see text No Table 1 Studies of the residual neuropsychological effects of chronic LSD and other hallucinogen use: general methods a b c d e f g h Study No. of doses of LSD or other Blinded evalua- visuo-constructional ability; D function; H J.H. Halpern, H.G. Pope / Drug and Alcohol Dependence 53 (1999) 247–256 251 d Toxic Screen No indicates some attempt was made to exclude c = No Yes No / no screen performed. Attempted exclusion for = indicates that subjects and controls had used alcohol, marijuana, or other drugs = indicates that subjects and controls were actively using alcohol, marijuana, or other or controls is listed, when available. / = or controls is listed, when available. / NRNR Yes No No Yes No No No No No No Yes NR No No No No not reported. = No / b C: No C: No C: Yes C: Yes Current use of No Yes Yes / , controls. Percentages of past use by subjects and C , controls. Percentages of active use by subjects and C , subjects; No Yes / S C: NR C: NR C: 20% C: No C: ‘Most’ See text See text See text See text a , subjects; S unknown; / NR YesNR Yes 98% NR NR NR NR NR Alcohol MarijuanaS: NoC: Other NR illicit drugs Alcohol S: 100%NR C: NR Marijuana S: Other Yes illicit S: drugs C: 100% NR Alcohol S: Yes Marijuana NR Other illicit drugs NR NR NR No No Only ‘glue sniffers’ No NRYes S: 100% NR Yes NR NR NR No No No No Yes Yes Yes NR Yes C: NR C: NR C: NR C: NR C: NR S: Yes NR S: Yes S: No S: No S: No No No No unknown; / not reported = not reported = at the time of testing, subjects gave a urine or blood sample that was screened for psychotropic substances; No indicates that subjects and controls were not actively using alcohol, marijuana, or other drugs; Yes indicates that subjects and controls had not used alcohol, marijuana, or other drugs in the past; Yes indicates that the investigators did not exclude subjects with prior or current use of alcohol, marijuana, or other intoxicating drugs; Yes = = = = 1972) 1969) 1973) No Yes No No subjects with a history of current use of alcohol, marijuana, or other intoxicating drugs; NR drugs; NR (McGlothlin et al., 1969) (Wright and Hogan, NR(Acord, 1972) S: 95% S: Yes NR S: NR S: NR No S: No S: No No (Blacker et al., 1968)(Cohen and Edwards, NR NR No No No No (Acord and Barker, Table 2 Studies of the residual neuropsychological effects ofStudy chronic LSD and other hallucinogen use: drug screening criteria Prior use of a b c d (Culver and King, 1974) in the past; NR (Krystal et al., 1992) (Grob et al., 1996) 252 J.H. Halpern, H.G. Pope / Drug and Alcohol Dependence 53 (1999) 247–256 range’ on at least one test, 18 on two, and 4 on all three history and current or past use of other drugs repre- tests. However, the psychiatric diagnoses of the subjects sented potential confounding variables. were not specified, and subjects could qualify for the Grob et al. (1996) assessed 15 members of a legally study with as little as one exposure to LSD. sanctioned Brazilian religion, the Uniao do Vegetal In a subsequent controlled investigation, Acord and (UDV), which regularly uses a plant-based hallucino- Barker (1973) compared 15 LSD users with 15 controls, gen, ‘hoasca’/‘ayahuasca’, as a sacrament. This potion all recruited from among both patients and staff at a contains the powerful indole hallucinogen DMT, which military hospital. LSD users performed inferior to con- is orally activated by i-carbolines (also present in trols on several measures of the Reitan battery, includ- hoasca) through inhibition of intestinal monoamine ing the Trail Making Test B and the Category test, and oxidase. Fifteen controls with no history of hoasca use localization ability as measured on the Tactile Perfor- were matched for age, ethnicity, marital status, and mance Test. An attempt was made to exclude subjects level of education. The authors also attempted to match with ‘evidence of psychopathology’, except for ‘charac- for current alcohol consumption, but were not fully ter and behavior disorder with drug abuse as a symp- successful because the UDV strictly forbids its members tom’. Aside from the addition of a control group, from the use of all other psychoactive substances, in- however, this study suffers from methodologic limita- cluding alcohol, tobacco, marijuana, cocaine, and am- tions similar to those of the uncontrolled study above. phetamines. This limitation may explain why the Although the control group denied prior hallucinogen hoasca users performed better than controls on recall of consumption, other drug use was not systematically words on the fifth learning trial of the WHO-UCLA noted. Auditory Learning Verbal Memory Test. In contrast to Culver and King (1974) matched 3 groups of college prior reports of increased novelty-seeking (Kleckner, seniors for pre-drug use verbal and mathematical 1968) and aggression (Brickman, 1968; Edwards et al., Scholastic Aptitude Test (SAT) scores, and Minnesota 1969) among chronic LSD users, the members of the Multiphasic Personality Inventory (MMPI) results ob- UDV scored significantly lower than controls in the tained during freshman year. The first group reported novelty-seeking and harm-avoidance domains in the no history of marijuana or LSD use, the second group Tridimensional Personality Questionnaire. reported marijuana use but no hallucinogen use, and the third reported LSD use approximately once a month for at least 12 months, together with marijuana. 4. Discussion Subjects were excluded if they reported illicit drug use prior to college; in-college use of psilocybin, DMT, We reviewed nine studies assessing residual neuropsy- DOM, or heroin; use of cocaine or intravenous stimu- chological effects in chronic hallucinogen users. The lants more than 4 times; and use of ‘either pep pills or general impression to emerge from these studies is that barbiturates’ more than 20 times. A series of neuropsy- such effects, if present, are modest; the dire predictions chological tests was performed and repeated on 1-year of the 1971 editorial, quoted at the beginning of this follow-up. All results fell within the normal range, article, appear unjustified. although the LSD group’s performance on the Trail Admittedly, several of the studies have tentatively Making Tests A and B was significantly lower at one reported impairment on certain neuropsychological year than the other two groups. This difference re- measures in hallucinogen users as compared to con- mained significant in an analysis of covariance controls. These findings include changes in evoked poten- trolling for alcohol consumption. tials (Blacker et al., 1968), visuo-spatial impairment In an uncontrolled investigation, Krystal et al. (1992) (Cohen and Edwards, 1969), deficits on the Trail Mak- administered a series of neuropsychological tests to nine ing Tests (Acord, 1972; Acord and Barker, 1973; Culver self-identified MDMA users. Tests were administered at and King, 1974), and memory deficits (Krystal et al., least 3 h after IV infusion of 7 g of L-tryptophan, as the 1992). However, several other studies have failed to investigators were also evaluating neuroendocrine and replicate these results (McGlothlin et al., 1969; Wright behavioral alterations in those chronically exposed to and Hogan, 1972; Grob et al., 1996). MDMA (Price et al., 1989). Most tests showed no Importantly, all of these findings are subject to sub- impairment as compared to population norms, but, on stantial methodologic limitations, as illustrated in the the Wechsler Memory Scale (WMS), several subjects two tables presented above. First, most studies failed to displayed mild to moderate impairment in the Initial control for premorbid attributes of hallucinogen users Paragraph (44%), Delayed Paragraph (67%), and De- versus controls; indeed some studies included subjects layed Figural (33%) tests, but not in the Initial Figural known to have a history of psychiatric disorders prior Test. None of the WMS scores, however, correlated to any hallucinogen ingestion. Second, virtually all of significantly with cumulative lifetime doses of MDMA the studies failed to control for use of other illicit drugs in this small sample. Once again, prior psychiatric and alcohol, both in the past and at the time of J.H. Halpern, H.G. Pope / Drug and Alcohol Dependence 53 (1999) 247–256 253 evaluation. In fact, none of the nine studies included a et al., 1980; McCall, 1986; Jacobs, 1987; Sanders-Bush toxic screen to exclude subjects with evidence of illicit et al., 1988; Winter and Rabin, 1988; Glennon, 1990; drug use at or near the time of testing. Third, the Krebs and Geyer, 1994; Fiorella et al., 1995a,b; Marek studies varied widely in the abstinence period required and Aghajanian, 1996), whereas the atypical antipsy- between the most recent hallucinogen use and the time chotic medications are thought efficacious in part from of test administration. In some cases, this abstinence an opposite effect: potent antagonism at 5-HT2a/c (He period may have been very short, thus causing the and Richardson, 1995; Maurel-Remy et al., 1995; Glea- effects of acute hallucinogen intoxication to confound son and Shannon, 1997). Further, it has been noted evaluation of residual effects. that selective serotonin reuptake inhibitors (SSRIs) at- Most of these methodologic problems would be ex- tenuate or block intoxication (Bonson et al., 1996), and pected to increase the risk of a type I error; namely to may ameliorate hallucinogen persisting perception dis- show a residual effect of hallucinogens when none order (Young, 1997), suggesting that hallucinogens may existed. Despite such biases, these studies generally cause a reversible or irreversible neurotoxic impinge- found few residual effects. It therefore seems unlikely ment upon central serotonergic systems. Much research that hallucinogens produce major residual neuropsychi- is also being directed upon N-methyl-D-aspartate atric impairments, which have been missed in the stud- (NMDA) glutamate receptors (Coyle, 1996), since ies to date. This impression echoes the conclusions of NMDA antagonists (notably including PCP and ke- the earlier review by Strassman (1984): ‘The question of tamine) can induce psychotic-like intoxications in man organic brain damage as well as permanent changes in (Javitt and Zukin, 1991; Krystal et al., 1994) and also personality, attitudes, and creativity in patients and cause pathomorphological alterations in rat brain cere- normals who have repeatedly ingested psychedelic brocortical neurons (Olney et al., 1989; Corso et al., drugs is controversial, but tends to point to subtle or 1997). While traditional and atypical antipsychotic nonsignificant changes’. agents have proven neuroprotective to such damage in On the other hand, the possibility of a type II error preclinical models, LSD and DOM have counterintu- – failure to detect a true residual hallucinogen effect – itively proven similarly protective due to the very same cannot be excluded. One possible source of a type II 5-HT2a agonism as mentioned above (Farber et al., error is small sample size: the nine neuropsychological 1998). In short then, while there may be shared neu- studies assessed only 9–40 hallucinogen users each. roreceptor dysregulation between psychotic illness and With these numbers, it is possible that subtle toxic hallucinogen use, knowledge of the precise biochemical effects were missed. Such effects, even if modest, might effects of hallucinogens is clearly limited by our rudi- still be significant from a population perspective. An- mentary understanding of the pathogenesis of psychosis other possible source for a type II error is the lack of at the molecular level, despite evolving advances in our older subjects in most studies. Younger individuals understanding of signal transduction pathways. might exhibit little toxicity, whereas impairment might become more obvious with increasing age. Further, several of the studies investigated subjects who had 5. Conclusion used hallucinogens only a single occasion, and a major- ity of all subjects studied had used hallucinogens fewer Returning to the clinical question of the neuropsy- than 50 times. Thus, a neurotoxic effect after several chological toxicity of hallucinogen use, future studies hundred hallucinogen exposures cannot be excluded. should take care to address the various methodological Finally, the tests employed in available studies may problems reviewed above. A particular concern is the have failed to ‘tap’ specific areas of cognitive deficits. difficulty of securing a population of hallucinogen users Indeed, there are theoretical reasons to suspect that who are free of concomitant psychopathology and/or hallucinogens might produce neurotoxicity after long- other psychoactive drug use. To minimize this problem, term exposure. First, LSD and mescaline have been it will be important to match user and nonuser groups shown to produce vasospasm in isolated canine cerebral on as many of these potentially confounding variables arteries at drug concentrations equivalent to those re- as possible, and also to assess the correlation between quired to produce intoxication in humans (Altura and lifetime hallucinogen exposure and degree of neuropsy- Altura, 1980). Thus, these agents might produce re- chological impairment. Such assessments will require a peated hypoxic events. Second, hallucinogens bind to large sample of subjects with extensive hallucinogen some of the same neuroreceptors involved in the expres- exposure, as hallucinogens might have subtle neuro- sion of neurodegenerative psychotic disorders. In par- toxic effects not detectable with smaller samples or with ticular, the indolalkylamine (e.g. LSD, psilocybin) and individuals with lesser exposure. phenethylamine (e.g. mescaline) hallucinogens are po- Also, the existing literature essentially fails to illumi- tent partial agonists at 5-HT2a/c (serotonin 2a/c; 5-hy- nate which potentially confounding variables would droxytryptamine 2a/c) receptors (Winter, 1978; Sloviter form the basis for exclusion in an ‘ideal’ study and 254 J.H. Halpern, H.G. Pope / Drug and Alcohol Dependence 53 (1999) 247–256 which neuropsychological tests would be the most sen- Acord, L.D., 1972. Hallucinogenic drugs and brain damage. Mil. sitive. For this reason alone, any re-evaluation of the Med. 137, 18–19. Acord, L.D., Barker, D.D., 1973. Hallucinogenic drugs and cerebral neuropsychological toxicity of hallucinogens should in- deficit. J. Nerv. Ment. 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