Drug and Alcohol Dependence 69 (2003) 109 Á/119 www.elsevier.



Hallucinogen persisting perception disorder: what do we know after 50 years?
John H. Halpern *, Harrison G. Pope, Jr
Harvard Medical School, Biological Psychiatry Laboratory, Alcohol and Drug Abuse Research Center, McLean Hospital, 115 Mill Street, Belmont, MA 02478-9106, USA Received 10 May 2002; received in revised form 29 July 2002; accepted 19 August 2002

Abstract ‘Flashbacks’ following use of hallucinogenic drugs have been reported for decades; they are recognized in DSM-IV as ‘Hallucinogen Persisting Perception Disorder (Flashbacks)’, or HPPD. We located and analyzed 20 quantitative studies between 1955 and 2001 examining this phenomenon. However, many of these studies were performed before operational criteria for HPPD were published in DSM-III-R, so they are difficult to interpret in the light of current diagnostic criteria. Overall, current knowledge of HPPD remains very limited. In particular (1) the term ‘flashbacks’ is defined in so many ways that it is essentially valueless; (2) most studies provide too little information to judge how many cases could meet DSM-IV criteria for HPPD; and consequently (3) information about risk factors for HPPD, possible etiologic mechanisms, and potential treatment modalities must be interpreted with great caution. At present, HPPD appears to be a genuine but uncommon disorder, sometimes persisting for months or years after hallucinogen use and causing substantial morbidity. It is reported most commonly after illicit LSD use, but less commonly with LSD administered in research or treatment settings, or with use of other types of hallucinogens. There are case reports, but no randomized controlled trials, of successful treatment with neuroleptics, anticonvulsants, benzodiazepines, and clonidine. Although it may be difficult to collect large samples of HPPD cases, further studies are critically needed to augment the meager data presently available regarding the prevalence, etiology, and treatment of HPPD. # 2002 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Flashbacks; Hallucinogen persisting perception disorder; Hallucinogens; LSD; Toxicity; Adverse reactions

1. Introduction Reports of ‘flashbacks’ following the use of hallucinogenic drugs date back for decades in both the scientific and popular literature. Indeed, after ingesting mescaline more than 100 years ago, Ellis (1898) reported prolonged sensitization to ‘‘the more delicate phenomena of light and shade and color’’. It was not until 1986, with the American Psychiatric Association’s (American Psychiatric Association, 1986) publication of the revised third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R), that standardized op-

erational diagnostic criteria for ‘flashbacks’ were offered, under the diagnosis of ‘posthallucinogen perception disorder’. These criteria were slightly modified for DSM-IV (American Psychiatric Association, 1994) under the diagnosis of ‘Hallucinogen Persisting Perception Disorder (Flashbacks)’ (HPPD), and are as follows: A) The reexperiencing, following cessation of use of a hallucinogen, of one or more of the perceptual symptoms that were experienced while intoxicated with the hallucinogen (e.g., geometric hallucinations, false perceptions of movement in the peripheral visual fields, flashes of color, intensified colors, trails of images of moving objects, positive afterimages, halos around objects, macropsia and micropsia).

* Corresponding author. Tel.: '/1-617-855-3703; fax: '/1-617-8553585 E-mail address: john_halpern@hms.harvard.edu (J.H. Halpern).

03765-8716/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 6 - 8 7 1 6 ( 0 2 ) 0 0 3 0 6 - X

Halpern. 1973. Methods 2. 1977.. Lowry.1.. DSM-IV cites visual epilepsies. McGuire et al. Young. 2. 1963. 1993). show no current drug toxicity.. Weil. if an individual has pre-existing perceptual symptoms that persist and/or evolve after hallucinogen intoxication. Harley-Mason et al. In the paragraphs below. or anxiety disorders. 2. Thus.. Welpton. 1976. Pope. 1997. 1994. On the one hand.. 1970. For all studies meeting our criteria.’’ (p. Abraham et al. Frosch et al.. . symptoms lasting only days after hallucinogen ingestion are presumably insufficient to represent HPPD. the phenomenology of the flashback experience. 1968. C) The symptoms are not due to a general medical condition (e. Sadoff. 233). 1969.. 1971.. information about comorbid psychiatric and medical disorders. 1973). Despite these somewhat contradictory statements. 2001. 1997. Favazza and Domino. 1967. 1969. 1984. Finally. Keeler et al. 313). an individual must display several attributes. Survey methods We surveyed the literature (using MEDLINE 1966Á/ present. Thurlow and Girvin. or other important areas of functioning. Smith. McGee.g. Third. for example. one must exclude other hallucinogen-induced disorders recognized by DSM-IV. First. Schizophrenia) or hypnopompic hallucinations. Simply seeing bright spots in front of one’s eyes upon entering a dark room. DSM-IV specifies that ‘‘the person must. Saidel and Babineau. 1991. probably should not qualify for the diagnosis of HPPD. and (2) the individuals were assessed in some quantitative manner for the presence of perceptual phenomena reminiscent of hallucinogen intoxication. 1967. we were more ‘generous’ than DSM-IV. 1965. 1954. Fischer. 1997. we assess the extent to which these cases meet modern criteria for HPPD. prudence dictates withholding the diagnosis of HPPD in cases where current or prior use of a drug may be causing or contributing to aberrant perceptual experiences.2. 1967. Alarcon et al. Keeler... 1976. 11 were excluded because they were review articles or commentaries not reporting original or quantitative data on specific subjects (Abraham and Aldridge. mood. 1994. 25 were excluded for containing fewer than eight cases (Abraham and Mamen.. Other conditions to be ruled out before diagnosing HPPD should be posttraumatic stress disorder (PTSD) and depersonalization and derealization associated with severe anxiety and depression. but the same text specifies that the abnormal perceptions may be ‘‘triggered’’ by ‘‘various drugs’’ (p. migraine. and hypnopompic hallucinations as specific disorders to rule out.110 J. We also excluded 12 studies describing various visual phenomena and electroencephalographic changes associated with hallucinogen use. 1972. and ten were excluded for describing flashbacks associated with other drug use and/or providing insufficient evidence that subjects had ingested hallucinogens (Annis and Smart. Markel et al. We conclude with a summary of the present state of knowledge about the epidemiology. Less clear in DSM-IV is whether to exclude acute intoxication with other drugs that might cause visual disturbances. 1967. . Tennant and Groesbeck. hallucinogen use must precede the syndrome. such as hallucinogen-induced psychotic. Anderson and O’Malley. Sandison et al. occupational. but which did not explicitly present subjects experiencing perceptual abnormalities occurring after acute . Creighton et al. in that we included cases even where the perceptual experiences did not induce distress or impairment. 1998. Lerner et al. delirium.H. Smart and Bateman. Matefy. 1970. 2001. 1972. suggests that perceptual phenomena should be sufficiently striking to be outside the range of normal experience. Moreover. 1993. Of these. . as discussed above. Wentworth-Rohr. Worarz. Schwarz. Juve. Morehead. schizophrenia. 1972. 233). Kleber. dementia. Screening results We screened a total of 85 publications that tentatively met our criteria. 1971. and any information about treatments administered. the word ‘reexperiencing’ in criterion A.. 1996. visual epilepsies) and are not better accounted for by another mental disorder (e. together with the requirement for ‘distress or impairment’ in criterion B. delirium. anatomical lesions and infections of the brain. 1968. 1970). alternative etiologies for unusual perceptual experiences must be considered before diagnosing HPPD. dementia. Jr / Drug and Alcohol Dependence 69 (2003) 109 Á/119 B) The symptoms in Criterion A cause clinically significant distress or impairment in social. 1968. To strictly meet these criteria. H. We applied the above standards to studies of individuals with hallucinogen-induced flashbacks. . however. 1968. Cohen and Ditman. we attempted to summarize information about the hallucinogens used by the subjects. In one respect. Aldurra and Crayton. Second. Cohen. Zeidenberg. 1973.. We then assessed whether the study subjects appeared to meet current DSM-IV criteria for HPPD. 1996.G. as indicated in criterion C. Ungerleider et al. 1966. a diagnosis of HPPD is not justified. etiology. 1973. 1966. DSM-IV suggests in its text that HPPD persists ‘‘long after the use of hallucinogens has stopped’’ (p. and the references from these collected MEDLINE-sourced papers) for all studies of ‘flashbacks’ or persistent drug-induced perception disorders meeting the following criteria: (1) at least eight cases were presented of individuals who had ingested hallucinogens. and treatment of HPPD.g. Denson. 1982. Shick and Smith. Wesson and Smith. 1958.

The most common symptoms noted were brief episodes of depersonalization. necessary for the rigorous diagnosis of HPPD.G. Despite this definition. 3. Horowitz (1969) described three types of flashbacks: spontaneous return of perceptual distortions (e. or research protocols (N 0/123). 1954. 1953. defined as ‘‘the return of the effects of an hallucinogenic drug after the immediate effects of the drug have worn off’’. 1965. At the time of interview. changes in body image. in 11 (55%) of 20 community hallucinogen users recruited by advertisement. Forty-four questionnaires were returned. transient. isolated events. The investigators concluded that ‘‘the majority of the descriptions cited were relatively minor.g. In response to the question. but one had never used hallucinogens. H. 1996. (1970) reported ‘‘recurrences of ‘trip phenomena’. McGlothlin and Arnold (1971) performed 10-year follow-up interviews on 247 subjects who had received LSD in conjunction with psychotherapy (N 0/124). 1988. educational. This represents perhaps the first case series approaching the current diagnosis of HPPD. depression or paranoid thought. such as marijuana and secobarbital. Ostfeld. spatial and temporal distortions. However. and 80% active amphetamine users. Frosch et al. The investigators asked about subjective short and long-term effects of LSD use. 1960. Gastaut et al. .. Investigators were asked to report ‘‘any major complications’’ encountered. outlined above. which is structured to emphasize the various criteria. A total of 20 qualifying studies remained to be analyzed. 1961. and episodes of anxiety. which were reported across 29 separate publications.. Specific symptoms of flashbacks are not described. (1965) and Robbins et al. but only five (2%) subjects described ‘‘major perceptual changes’’ suggestive of HPPD. Cooper (1955) described eight psychiatric patients (with unspecified diagnoses). history of other drug use. eight (26%) reported flashbacks. Holiday et al.. Wikler. Abraham and Wolf. Four subjects were described as having ‘‘fleeting afterimages’’ following mescaline administration. Krill et al. In the text below. Cohen (1960) sent a questionnaire to 62 investigators who had administered LSD or mescaline to patients or to normal volunteers.In very few instances does there appear to be . occupational. peculiar. Apter and Pfeiffer. and occasional auditory and visual illusions or hallucinations. 36 (15%) LSD users answered affirmatively. and history of alcohol abuse is not reported. Blumenfield (1971) examined 431 US Air Force recruits who acknowledged illicit substance use. ‘‘regression to childish behavior’’. Fischer et al. and six were diagnosed with other psychiatric disorders. Although the questionnaires did not specifically inquire about symptoms of HPPD. 94 reported flashbacks. at least 8 patients had been psychotic prior to any LSD use. Barron et al. Kawasaki and Purvin. Importantly. summarizing experience with 5000 subjects.’’ lasting up to 3 months.H. finding 11 (32%) with ‘‘spontaneous return of perceptual distortions or feelings of depersonalization similar to those experienced under the influence of LSD’’. 1970). together with 50 control subjects who had never received LSD. disorientation. ten of the 94 recruits were said to have flashbacks from non-hallucinogens (five from marijuana use alone and five from either amphetamine or barbiturate ingestion).. who reported persistent inappropriate mood swings. seeing halos around people. and recurrent unbidden images (examples of which are not furnished by the investigators). Among 31 subjects interviewed in the Haight-Ashbury drug-using community of San Francisco. 100% of subjects were active marijuana users. Pope. . nor whether symptoms re-emerged in subsequent months. increased susceptibility to spontaneous imagery (seeing a green iguana under the investigator’s chair). when flashbacks occurred. These symptoms generally resolved within 1 day. It is unclear whether any patients experienced the specific perceptual phenomena required for a diagnosis of HPPD. but one patient complained of continuous symptoms for 3 weeks. and medical history. Landis and Clausen. Woody. It is not clear to what degree the subgroup experiencing flashbacks and the subgroup with psychosis overlapped. Apparently all eight subjects were continuing to use various drugs at the time of evaluation. ‘‘subsequent to your LSD use. 1957. 1980. we present further details of these investigations. tactile phenomena (itching skin). including two with ambulatory schizophreniform psychosis. all of which were claimed as first experienced during hallucinogen intoxication. have you experienced any uncontrolled LSD-like experiences without using drugs’’. the author notes that the findings might have been influenced by malingering to avoid military service during the Vietnam War. Halpern. treated with an unspecified number of weekly doses of LSD. Some subjects also described recurrent visual hallucinations of ‘‘devils’ faces’’. seeing the sidewalk undulating). no such cases were mentioned among subjects administered LSD. 1969. 1954. Results The highlights of the 20 qualifying studies are summarized in Table 1. and the spontaneous appearance of color hazes or curtains. Jr / Drug and Alcohol Dependence 69 (2003) 109 Á/119 111 hallucinogen intoxication had subsided (Abraham. the absence of any spontaneous responses suggestive of HPPD is striking. (1967) reviewed 34 LSD-related psychiatric admissions to Bellevue Hospital in New York from 1965 to 1966. some were apparently intoxicated with other drugs. alcohol use is not reported. and family. Of these.J..

1980 Yager et al. 1976 Matefy and Krall.112 Table 1 Research of hallucinogen-induced ‘‘flashbacks’’ Citations Sample Hallucinogen ingested/dose/ Other drugs no. N 0 narcotics. 32 hospitalized 3 personality disorders NS J. 1976 Holsten.. FB0 flashbacks. 1999 Lerner et al. 1983 Abraham. 1971 McGlothlin and Arnold. C/O 0 ‘complaining of’. MJ0 cannabis. O0 opiates. H. 1965. 1996. 2000 8 patients 5000 patients or volunteers identified in survey of 44 investigators 34 psychiatric inpatients 31 ‘‘representative members of the drug-using community’’ 20 community LSD users LSD/50 Á/500 mg/NS NS LSD/25 Á/1500 mg/1 Á/80.. S 0 sedative/hypnotics. all were psychiatric inpatients NS NS Unclear (see text) Most subjects were psychiatric patients NS NS All subjects with alcoholism NS No No No Yes NS Yes NS (see text) P/R 15 44 27 8 P(V) P/R NS R All subjects with polysubstance use No disorder. 1967 Horowitz. 1988 Hemsley and Ward. 1970 Blumenfield. 1971 Moskowitz. 1984. %0 percentage of subjects reporting active drug use. 11 with active psychosis 2/8 ambulatory schizophreniform psychosis. 1974 Heaton and Victor. 1976. T0 tobacco.S. no LSD in 6 cases LSD/ B 300 Á/1200' ‘‘street Am/MJ/N/NS mg’’/8 Á/250 431 US Air Force basic trainees 422 tried NS/NS/1' Am & B (14%)/N who admitted to drug use (16%)/MJ/NS 247 subjects given LSD in research LSD/25 Á/700 mg/0 Á/20'. 1974. mescaline/ NS/NS LSD/NS/NS LSD/NS/16 (range: 1 Á/871) LSD/NS/1 Á/100' LSD/NS/NS NS NS Al/Am/O/MJ MJ (92%)/NS NS Al/B/C/I/MJ/O AL/C/MJ/N/S NS NS Al/NS S/NS Some with prior ‘‘mental health No treatment’’ No prior psychiatric hospitalization NS Unclear. 1971 Stanton and Bardoni. NS Mescaline/200 Á/1200 mg/NS LSD/200 Á/400 mg/1 Á/100' Al/Am/B/MJ/NS 8 4 (see text) 11 8 11 94 5 (see text) 8 95 22 16 53 64 34 146 R(V) NS P/R(V) P/R P/R R R P/R NS P/R(V) NS P/R NS P/R(V) R NS NS NS Yes NS Yes (see text) No NS Yes (see text) Yes NS Yes (see text) NS Yes Yes Yes NS NS NS Yes Psychiatric illness noted? Medical illness? NS NS Psychiatric patients Primarily psychiatric patients All psychiatric inpatients.H. P 0 symptoms persisted beyond one month. 1977 Matefy et al. 1969 Barron et al. NS Al0 alcohol. 1978.. 1972. (V)0 variable: symptoms persisted beyond one month for only some subjects or symptoms only partially described as the re-experiencing of hallucinogen intoxication. Halpern. Naditch and Fenwick.. 1985 Abraham and Duffy.G. Am 0 amphetamine. Matefy. 2001 Batzer et al. 1976 Naditch. NS0 not stated. I0 inhalants. R 0 symptoms described as the re-experiencing of hallucinogen intoxication. Army soldiers ‘‘unfit for military service’’ 123 psychiatric patients and some staff 29 hospitalized polydrug abusers 44 HPPD outpatients. Abraham and Wolf. 1983. 4/8 other diagnoses ‘‘No psychotic or organic illness’’ Malingering and ‘‘underlying psychosis’’ 50% of subjects in psychotherapy. Sx 0 symptoms. 1955 Cohen.. 1979. . times used ingested Cases with FB Nature of FB Evidence for alternative explanation Other drugs? Cooper. Stanton et al. Robbins et al. Pope. 88 matched healthy controls 110 alcohol dependent inpatients from a 6-week treatment program 8 psychiatric outpatients c/o HPPD LSD/NS/NS LSD/NS/ median 150 LSD/ NS/1 Á/1000' in 65 cases LSD/NS/NS in 235 cases LSD/NS/NS in 63 cases LSD/NS/NS in 179 cases LSD/100 mg/NS. C 0 cocaine... Jr / Drug and Alcohol Dependence 69 (2003) 109 Á/119 NS NS NS NS NS NS NS LSD/NS/3 Á/15'/NS in 25 Am/B/MJ/NS cases. Al/Am/C/MJ/O/ or psychotherapy ‘‘strong’’/NS/NS S/T 8 military prisoners LSD/NS/2' NS 2001 US Army personnel NS Am/B/MJ/O/NS 44 college students 32 community hallucinogen users 91 inpatients with drug abuse 483 male ‘‘drug users’’ 87 college students 280 U. B0 barbiturates.. 1960 Frosch et al.

J. and 179 specifically admitted to using hallucinogens. and ‘‘union with the world’’ (14). 235 admitted to experimenting with LSD. Of the 207 heavy users of any drug. Among the 235 LSD users. he found that one third of LSD users in this prison experienced ‘‘spontaneous recurrences (flashbacks) of LSD reactions’’. ranging from ‘‘simple visual experiences‘‘ (N 0/109). Also. Thus. 1972. Halpern. paranoia (26%). of whom 34 (54%) acknowledged ‘flashbacks’ in response to an initial interview question regarding ‘‘.’’ Moskowitz (1971) reported using haloperidol successfully to treat flashbacks in eight military prisoners. 35 subjects still experienced flashbacks. Jr / Drug and Alcohol Dependence 69 (2003) 109 Á/119 113 substantial evidence of a causal relationship between the LSD experiences and the incidents described. However. . and an additional 81 soldiers reporting flashbacks were taking unspecified psychotropic medications. 50 (77%) reported flashbacks. disorientation or confusion (15). but it is unclear how many subjects may have had psychiatric or medical disorders other than drug abuse prompting initial hospitalization. 16 reporting flashbacks and 16 denying flashbacks. Stanton and Bardoni. which apparently was as frequent as once per day. and another to prior ‘nondrug’ events. . 22 (65%) subjects had flashbacks triggered by marijuana or alcohol */raising the question of how often flashbacks were experienced as part of the intoxication with another drug.G. the authors speculate that 57% of flashbackers showed features of hysterical conversion. asking subjects whether they ‘‘had ever experienced flashbacks or spontaneous recurrences of the LSD experience non-volitionally’’. 1978) and Matefy (1980) recruited 87 subjects. flashbacks were reported by 28% (either 65 or 66 subjects. The questionnaire assessed current drug use. episodes of depression (19%). Anonymous questionnaires were then distributed. and at least 26 others had apparently never used a hallucinogen. 1969. and anxiety/tension (17%) were claimed as typical flashback effects. Of 65 subjects with a history of hallucinogen use. Overall. Interestingly. Only 20 (59%) of the 34 subjects described ‘‘perceptual illusions’’ as a feature of their flashbacks. The case descriptions suggest that several subjects also possessed chronic psychotic symptoms. Notably. 1972. . The nature of flashback symptoms and time from last use of hallucinogens are also not specified. only percentages are provided). Holsten (1976) interviewed 91 young drug abusers consecutively admitted to a Norwegian hopspital.5 Á/4-year follow-up. 22 (50%) reported subsequent episodes of flashbacks. 1976).H. 63 were ‘‘psychedelic drug users’’. Two subjects described flashbacks after marijuana use exclusively and one after sniffing organic solvents. tension. which raises the possibility that some of the cases may have been due to an underlying primary psychotic disorder. The perceptual symptoms detailed in this paper appear very similar to those of HPPD. The authors describe flashbacks as ‘‘the transient recurrence of psychedelic drug symptoms after the pharmacologic effects of such drugs have worn off and a period of relative normalcy has occurred’’. by advertisement. H. (1983) consecutively interviewed 280 Army soldiers prior to administrative discharge for being unsuitable or unfit for further military service in 1971. Pope. 1975) and Minnesota Multiphasic Personality Inventory (MMPI) profiles (Heaton and Victor. Matefy et al. all of the six subjects deemed to have ‘‘severe’’ flashbacks displayed symptoms of ‘‘severe psychopathology’’ other than active psychosis. Although 95 soldiers reported flashbacks. and another as a hermit who spent 6 months living in a cave. Thirty-six percent of these ‘‘flashbackers’’ found their experiences ‘‘disruptive of their normal behavior’’ and 16% stated that they sought clinical treatment for flashbacks. On 1. for studies of expectancy (Heaton. eight soldiers reported flashbacks without a history of hallucinogen use. one had used no drugs at all. 1976) administered an anonymous questionnaire to 2001 male soldiers entering or exiting the Vietnam War in November. 146 (71%) reported flashbacks. primarily college students. ‘‘Virtually all‘‘ soldiers admitted to using alcohol and marijuana. anxiety. Also. For example. Also. the other common features reported were depersonalization (18 subjects). 207 admitted to the heavy use of at least one drug other than alcohol. Many of these cases appear to meet criteria for HPPD. Stanton et al. These experiences recur at some time after the last ingestion of the psychedelic drug and after a period of relative normalcy’’. Yager et al. a majority of the subjects do not appear to meet the specific perceptual criteria required for HPPD. (1978. however. and thoughts which were previously experienced during the drug trip. Matefy and Krall (1974) recruited through campus newspaper advertisements 44 college students with a history of hallucinogen use.recurrences of sensations. but specific details are not furnished. one subject attributed flashbacks to prior hashish use. and it appears some may have had underlying psychotic disorders independent of their LSD exposure. the investigators mention one subject as isolative and preferring to sleep in area parks. Naditch (1974) and Naditch and Fenwick (1977) interviewed 483 male drug users through an unspecified system of chain referrals. the paper does not describe the specific symptoms reported by the subjects.. and ‘‘retrips‘‘ (N 0/76) */all suggestive of HPPD*/to more complex non-perceptual phenomena apparently quite different from HPPD. ‘trails’ (N 0/98). or panic (15). feelings. Stanton and Bardoni (Stanton. Heaton and Victor recruited 32 hallucinogen users.

LSD users were defined as ‘any person having used LSD’. level of education.1 different forms of visual disturbances following LSD use. they specifically had to show absence of hallucinations prior to their first LSD use. In another communication (Abraham. Batzer et al. LSD was more strongly associated with visual disturbances than any other category of drug use. and duration of flashbacks are not reported. and documented 16 types of visual disturbances. trailing phenomena. H. perceptions in the peripheral field. imagistic pseudohallucinations. Thirty-five subjects reported past LSD use. although patients with neurological or metabolic disorders were excluded.9% of LSD users and 20% of controls were reported to have a history of psychosis and 14. Halpern. positive afterimages. (2000) recruited eight polysubstance users who ‘‘fulfilled DSM-IV diagnostic criteria for HPPD’’ to study the potential benefits of treatment with clonidine. 1986). hospital-based walk-in emergency psychiatric service. and micropsia. Jr / Drug and Alcohol Dependence 69 (2003) 109 Á/119 Abraham (1983) interviewed 53 LSD users. .6% controls) and using marijuana more than once a day (27. Notably. they demonstrated alpha acceleration and shortened flash visual evoked response latency as compared to 88 carefully screened control subjects. confirmed by random urine screens. of flashbacks was associated with extent of LSD use and number of ‘‘bad trips’’.0001). sex. a prior diagnosis of a seizure disorder. He then assessed these visual disturbances in a fresh sample of 70 LSD users and 40 controls. household size. Patients were reported to improve in Clinical Global Inventory scores over 2 months of treatment. . The two greatest triggers for flashbacks were entering a dark environment (16%) and intention (14%). However. seeking consultation. compatible with previous literature reports of ‘flashbacks’. However. The LSD users exhibited depressed CFF and reduced sensitivity to light during DA (both significant at P B/0.114 J. but many subjects reported flashbacks when intoxicated with another drug. marital status. All were required to meet DSM-III-R criteria for HPPD. 22. lasting weeks or longer after last LSD exposure. Statistically significant differences between LSD users and controls did exist with history of narcotic addiction (21.5% LSD users vs. 2. 16 (21%) of the 75 patients denying LSD use also reported at least one visual phenomenon. Pope. he offered further details about eight other study participants experiencing flashbacks: four had ‘‘concomitant anxiety or panic disorders’. apparently using most of the same subjects. each of these symptoms was found in at least one of the control subjects who had never used hallucinogens.) time from last LSD use was 1. Abraham (1984) noted that one of the LSD users complaining of flashbacks in the study was later diagnosed with temporal lobe epilepsy and responded to treatment with carbamazepine. or alcohol. intensified colors. They had used LSD a median of 16 times. Subjects were also excluded if they displayed evidence of current psychosis. or referred by clinicians. 2001). obtained by advertisement at a busy.9% vs. matched for age. Lerner et al.3%). 20 (83%) of the LSD users were psychiatric patients.according to conventional tests and according to brain electrical activity mapping (BEAM) studies’’.D. The symptoms. Visual disturbances occurring significantly more often in LSD users than controls included geometric pseudohallucinations. regarding extent of LSD use and experiences with 9 specific visual phenomena commonly described in HPPD. In a subsequent communication. race. All complained of HPPD for at least 3 months and were also drug-free for at least 3 months. amphetamines. flashes of color. and of these.9 (0. regardless of whether the subjects attributed any clinical problems to prior LSD use. Mean (S. admitted into a 6-week alcoholism treatment program. 8. The subjects in this study were probably more rigorously diagnosed than those in any of the other studies reviewed here. In a later study (Abraham and Duffy. Although the LSD users had used many other types of drugs. halos around objects. Hemsley and Ward (1985) administered questions about LSD intoxication and flashbacks to 29 poly-drug abusers admitted to an inpatient drug dependence unit. Although subjects with neurological disorders or acute drug intoxication were excluded. but not the persistence. and seven ‘had temporoparietal abnormalities. (1999) administered a questionnaire to 110 patients. Abraham and Wolf (1988) also administered visual function tests of dark adaptation (DA) and critical flicker frequency (CFF) to 24 LSD users and 20 controls from the above sample. macropsia. The frequency. but no details regarding their specific symptoms are provided. again recruited from the emergency service or from clinic staff.G. and history of psychosis. On electroencephalogram. frequency. Active drug use was not reported. such as marijuana. or use of any psychoactive drug within 10 days prior to evaluation. 27 (77%) reported at least one of the visual phenomena mentioned in the questionnaire.3) years. ‘three had major affective disorders’. .H. Fifteen subjects reported experiencing ‘‘flashbacks or other drug effects after the drug should have worn off’’. the same investigators found differences in EEG spectral coherence between 38 individuals with flashbacks and 33 controls. Abraham and Duffy (1996) reported electroencephalographic findings in a new sample of 44 individuals with HPPD who were self-referred. a medical history that could account for visual hallucinations.2% of LSD users and an unspecified number of controls were current psychiatric inpatients. The subjects exhibited a mean of 8. and a mean duration of symptoms of about 9 years.

This lower incidence has been attributed to the fact that ‘‘individuals (both normal volunteers and patients) are carefully screened and prepared. Several investigators have published theoretical articles surmising that ‘flashbacks’ reflect lasting memories from the unusually distinct and powerfully emotional experiences induced under hallucinogen intoxication (Shick and Smith. The studies use a wide variety of methodology. 1974. First. Third. Second. and given judicious doses of pharmaceutical quality drug’’ (Strassman. 1976. report virtually no such phenomena in series of hundreds or thousands of cases. although it should be noted that these papers are subject to the same limitations as the studies of cases summarized above. depersonalization. since some of its diagnostic criteria resemble the criteria for HPPD. the studies vary widely in their estimated prevalence of such abnormalities in hallucinogen users. Additionally.G. Some studies describe specific recurrent perceptual phenomena. or even other anxiety disorders such as posttraumatic stress disorder (PTSD). 1977. and persisting for weeks or months after last hallucinogen exposure.2. most studies were performed prior to the publication of operational diagnostic criteria for HPPD. neurological conditions. ‘aeropsia’ (a sense of bright whiteness in the air between [individuals] and observed objects). it seems inescapable that at least some individuals who have used LSD.3. similar to those enumerated in DSM-IV criterion A for HPPD. supervised.1. Despite all of these reservations. 1984). Apparent differences may also be attributable to selection bias in some studies. Three principal explanations emerge from the literature. For example. First. we have also reviewed a number of additional papers that address the issue of HPPD in general. the perceptual phenomena described by some individuals with ‘flashbacks’ might simply represent a heightened awareness of normal visual phenomena (Horowitz. Most of this literature is at least 20 years old. General findings Several general impressions emerge from our review. current psychotic or affective disorders. and thus understandably lack many details required for a formal diagnosis of HPPD. In general. but most studies also include other psychiatric symptoms. 1984). 1976) among individuals who have taken LSD. hypochondriasis. it is often unclear whether symptoms occurred exclusively following hallucinogen intoxication. 4. For example. one psychiatrist reported that he was able to personally induce symptoms similar to those of his own patient with HPPD by suspending his ‘‘habitual state of consciousness’’ (Genova. Wesson and Smith. the variety of definitions for the term ‘flashbacks’ almost certainly contributes to the heterogeneity of published results. In particular. Some. it appears that individuals administered LSD in therapeutic or research settings are far less likely to develop HPPD than individuals using LSD illicitly. Discussion 4. various line-shape illusions such as level bookshelves slanting. some ‘flashbacks’ might represent merely instances of normal memory accompanied by emotional distress so upsetting to a subset of individuals that their clinicians are informed about them. Jr / Drug and Alcohol Dependence 69 (2003) 109 Á/119 115 4. experience persistent perceptual abnormalities reminiscent of acute intoxication. 1976). the information provided in most studies is too limited to allow the reader to determine how many subjects truly displayed HPPD. when we restrict consideration to reports of specific perceptual abnormalities similar to those specified in DSM-IV for HPPD. Studies reviewed We located and reviewed 20 studies presenting quantitative information on individuals with ‘flashbacks’ following hallucinogen use and then examined whether these cases met current criteria for the DSM-IV diagnosis of HPPD. H. 1970. Halpern. Second. such as panic attacks. 1969. These symptoms included ‘‘visual ‘trails’ of moving objects. 2000). in that symptomatic individuals were more likely to come to the investigators’ attention. Fischer. Etiology The data remain unclear as to what might cause these phenomena. Others have postulated that ‘flashbacks’ are manifestations of learned. conclusions must be limited.J.H. McGee. Wesson and Smith. whereas others report rates as high as 33% (Moskowitz. under the heading of ‘flashbacks’. the term ‘flashback’ has been defined in so many ways that it has become virtually useless. or experiences of ‘unity’ and transcendence. dissociation. Finally. Consequently. in particular. hysterical phenomena (Na- . and followed up. information on current medical or psychiatric conditions or use of other illicit substances and alcohol is not typically reported. psychosis. 1980). not better attributable to another medical or psychiatric condition. mood changes. In addition to these studies of actual cases. 1971) and 77% (Holsten. 4. Pope. Matefy. PTSD poses a special quandary. It is also difficult to rule out other medical or psychiatric conditions that might cause ‘flashbacks’. with only a few papers published in the last several years. sometimes not extending much beyond the level of simple anecdotal case series. and ‘dancing bright spots’ originating between the letters and words on a printed page’’. such as Cohen (1960) and McGlothlin and Arnold (1971). imaginative role-playing (Matefy and Krall. as shown in Table 1. malingering. including current intoxication with another drug.

both of which have been reported to trigger or worsen HPPD.9% of the 70 LSD users he studied had a history of psychosis. 1960. will be critical to resolve these questions. for example. although millions of doses of hallucinogens have been consumed by millions of individuals since the 1960s. In approximately 500 Native American Church members screened for our study. even crudely.. Halpern.. Indeed.. the literature on this point remains largely anecdotal. and whose symptoms are not potentially attributable to other substance use or to medical or psychiatric . Conversely. Worarz. Abraham (1983) noted that 22. 1976). for example. and more severe cases involving frank neurological or psychiatric abnormalities. To extend this hypothesis to the molecular level. 2002). 2002). 1999). McGlothlin and Arnold. hypothesizes that HPPD is a ‘‘disinhibition of visual processing related to a loss of serotonin receptors on inhibitory interneurons’’. studies examining subjects given LSD in research settings (where subjects were screened to exclude those with serious psychiatric or medical pathology) have reported few instances of flashbacks (Cohen. (SAMHSA.5. 1983. as the central cannabinoid receptor gene.. behavior modification (Matefy. 1993). Although we have questioned whether such episodes are ‘true’ HPPD in the sense of being purely related to hallucinogen use. as mentioned earlier. and four other cases were reported to worsen with serotonin-selective reuptake inhibitors (Markel et al. with the possible exception of three reports of various types of ‘flashbacks’ following use of MDMA (Creighton et al. we are left with a core of ‘strict’ HPPD cases. (1996). where a neurological or psychiatric diathesis in some individuals leads to persistent visual phenomena long after hallucinogen exposure. The mechanism of these cases remains uncertain. If flashbacks are attributable to ‘kindling’ or some similar phenomenon. 1973). it seems likely that some instances of HPPD may require other intoxicants as co-factors. and LSD does alter the genetic expression of the neuroreceptors involved in the pathophysiology of psychosis (Nichols and Sanders-Bush. 2000. 1997).H. Jr / Drug and Alcohol Dependence 69 (2003) 109 Á/119 ditch and Fenwick. CNR1.. we have found no reports of HPPD with hallucinogenic ‘designer drugs’ or with hallucinogen-analog ‘club drugs’. the data do not permit us to estimate. psychostimulants (Strassman. 1983). 1971. Morehead. Schwarz. 1996). Weil (1970). Office of Applied Studies.G. 1968). Such studies should attempt to screen large numbers of hallucinogen users for ‘flashbacks’. No randomized controlled trial has as yet assessed the efficacy of any pharmacological agent in patients with HPPD. 1991. 1971).4. who had taken peyote on at least 100 occasions over years or decades. 1984). McGuire et al. 1983). H. McGlothlin and Arnold. describes eight patients who complained of ‘‘recurrence of hallucinogenic symptomatology (‘flashbacks’)’’ only while intoxicated with cannabis. It remains puzzling. cases of ‘flashbacks’ reported in the various studies may well represent combinations of the three possible types described above. For example. The prevalence might be very low. Abraham et al. Unfortunately. for example. 2001). After excluding these types of cases. Stanton and Bardoni. 1969. HPPD still can cause substantial morbidity for some individuals */leading to the question of potential treatments.116 J. meeting modern methodological standards. why there is no apparent correlation between the number of episodes of hallucinogen exposure and the presence of flashbacks (Horowitz. Pope. Moreover. Samples of subjects meeting rigorous DSM-IV criteria for HPPD. 4. Another possibility is that biological co-factors may combine with the residual effects of hallucinogens to produce HPPD phenomena. and then follow up individuals reporting these phenomena. Treatment Despite its apparent rarity.. who regularly ingest this mescaline-containing cactus as a religious sacrament. 1972. Of course. hallucinogen exposure may combine with other psychoactive substance exposure to disregulate genes linked to processing of visual and other cues. with milder cases perhaps often representing simple heightened awareness of normal visual phenomena. psychotherapy (Abraham et al. four patients receiving the atypical antipsychotic risperidone (Abraham and Mamen. 1994). the prevalence of ‘strict’ HPPD. several reports have noted that the use of other drugs such as cannabis may trigger flashbacks in some individuals. few large reported series of HPPD cases have appeared. one might expect that individuals with massive hallucinogen exposure would show higher rates of HPPD than individuals with only a few exposures */but this does not appear to be the case. Further studies. worsening of HPPD has been reported in at least 12 subjects receiving phenothiazines (Abraham. Prevalence Unfortunately. 2001). however. Among other possible co-factors are alcohol (Batzer et al. was recently found to be associated with susceptibility for hebephrenic schizophrenia in a Japanese cohort (Ujike et al. none has described symptoms suggestive of HPPD. 1977). some cases have been reported to improve with the use of sunglasses (Abraham.. Finally. 1996. 1994. Abraham. or various pharmacological agents (Table 2). 4. We ourselves have had similar experiences in a study screening for residual neuropsychological effects from peyote among Navajo in the Native American Church (Halpern et al. Cannabis may do likewise. or ‘‘situationally induced exacerbation[s] of more pervasive personality characteristics’’ (Heaton and Victor.

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