THE JOURNAL OF

NERVOUS ANDMENTAL DISEASE

Adverse Reactions to PsychedelicDrugs

A Review of the Literature

RICK J. STRASSMAN, M.D.1

VOL. 172, NO. 10October 1984SERIAL NO. 1223

The useof naturallyoccurringandsyntheticallyderived compoundsfor their "psychedelic" effectshasbeenapartof humanculturefor thousandsof years.Thebasicpharmacologyof the thajor syntheticpsychedeliccompoundsprimarily lysergic aciddiethylamide[LSD]-25 is describedandreferenceis madeto their potentially beneficialpsychologicaleffects.

Adversereactions,defined as dysphoricand/or maladaptive/dysfunctionalresponsestothe use of these drugs, sometimesrequire careful clinical judgment in orderto diagnose.Thesereactionscan be effectively classifiedalonga temporalcontinuum,Acute, short-livedreactionsare often fairly benign, whereaschronic, unremitting coursescarry a poor prognosis. Delayed, intermittent phenomena"flashbacks" and LSD-precipitatedfunctionaldisordersthat usuallyrespndtctreatmentappropriatefor then-3n-psychedeiic-precipi;atedillnessesthey resemble,roundout this temporalmeansof classification,The questionoforganicbrain damageaswell as permanentchangesin personality,attitudes,andcreativityin patientsandnormalswho have repeatedlyingestedpsychedelicdrugs is controversial,but tendsto point to subtleor nonsignificantchanges.

Future areasfor study of the psychedelics’tic effects aresuggested.

pharmacological,psychological,and. therapeu

History

Theuse of naturallyoccurring, exogenouslyadministeredsubstancesfor inducing alteredstatesof consciousnessextendsback to ancienttimes. Cannabisproductsandcertain speciesof mushroomswereusedas long agoas the time of the Vedas,in India, nearly5000 B.C. In the New World, mushroomsandcertaincacti,barks, andvines were employedfor similar purposesby indigenouscultures147. Abuseapparentlywas fairly rare,perhapsbecausecarefulcultural, religious, and socialproscriptionsdetermineda uniformmannerin which thesesubstanceswereusedandtheexperiencesone was expectedto have as a result oftheir use 167.

The "modern era of speciflcallv mind-alteringdrugs is often said to have begim with Albert Hofmann’s accidentalingestionof LSD-25 in 1943 77.However, interest in mescaline/neyotewas brieflypursuedat the turn of the century 48 and in the19305 94, 98.

A great flurry of scientific activity with LSD andSimilarly actingdrugsoccurredin the 1950sand1960s,

‘Department of Psychiatry, University of California, Davis,Medical Center,2315 StocktonBoulevard,Sacramento,California958j7,

but was just as quickly abortedin the late 1960s asfears of adverseacute and chronic effects of widespreaduse andabusebeganto come to the attentionof media and legislators.

Therapeutic and "growth-enhancing" aspectsofthese substanceswere widely pursued early on,spurredby such "auto-experimenters’?9 as AldousHuxley 82, Timothy Leary 97, and Carlos Castsneda32, A discussionof theseaspectsof "psychedelic" drug use is beyondthe scopeof this paper,butinterestedreadersare referredto Grof 65-67, Caldwell 31, Tart 151, Hoffer and Osmond76, andothers64, 145, 146, as representativeselections.

Terminology

The confusion regarding the tenninology of thisclass of drugs, of which LSD-25 is consideredtheprototype. is reflective of the various orientationsrespective investigators have taken in approachingthem.

For those who have beenstruck by the primarilyperceptualeffects of thesedrugs, the terms hallucinogenicor illusogenicare used.The similarity betweenthe effects of LSD-like substancesand certain psychotic phenomenaa feature that causedthem to beemployedaspotentiallyproducinga "model’ of schiz

577

578 STRASSMAN

ophreniahasinducedothersto label them aspsychotoinimeticsor psychotogens39. Psychedelic,a termattributedto Osmond64, p. 8 anddefinedas"mind-manifesting,"although somewhatvague, also carriesa less restrictiveconnotation,and for that reason isthe preferred term in this paper. Other words thathavebeenusedto describethis classof drugsincludepsychodysleptics29, p. 4 mind distortive or minddisruptive, deliriants, and mind-exnandinRdrugs,

Definition

Psychedelicdrugs can be distinguishedfrom othercentrally active drugs that can also under certainconditions induce perceptualdistortions e.g., anticholinergics,paranoidand other delusionse.g.,amphetamineS,and other alterationsof cognition, behavior, and affect e.g.,opiates,bromides.They arecapableof, when pathologicaleffects are absent orminimal, "reliably inducing or compelling states ofalteredperception,thought, and feeling that are notor cannotbe experiencedotherwiseexceptin dreamsor at times of religious exaltation" 84, pp. 563-564.

Lysergic acid diethylamide-25 is the prototypicalpsychedeliccompound,andwasoften the activeingredient in most street"psychedelics,"during the periodin which mostof the referencestudieswereperformed.eventhoselabeled"mescaline"or "psiiocybin" Unlessotherwise mentioned, LSD-25 will be used interchangeablywith "psychedelic" in this paper.It is, asare psilocybin, psilocin, diethyltryptamine,anddimethyltryptamine, a member of the indolealkylamineclass ‘fdr:;s. Mescaline one of the most activeingredientsin peyotecactusis a phenylisopropylamme 84. PhencychclinePeP, "hog," "angel’s dust,"etc., an arylcyclohexylainine,has attainedgreatcurrency in the last 10 years, as a common street"psychedelic" in its own right, as well as a substitute/adulterantfor other psychedelics.Many currentsat-pies of thugssold as psychedelic,are often found tocontain variableamountsof PCP. However, PCPdidnotbecomeapopularlyabusedstreetpsychedelicuntilthe mid-1970s,a timeby which almost all of the majorreports of adversereactions to LSD had beenpublished.The effectsof PCPcan be differentiatedbothpharmacologicallyand clinically from true psychedelics 84. The interestedreaderis referredto Lisansky et al. 101 for a fuller discussion of theseimportantdistinctions.

On the basis of a subjectiveeffectsandneurophysiological actions, b cross-tolerancebetween compounds,andc responseto selectiveantagonists,Martin and Sloan105 have classifiedLSD, mescaline,psilocybin, and psilocin as "LSD-like" Differencesamongthe variousLSD-like drugsreferredto hereas

the psychedelicsare primarily a matter of rate oronset,peripheralside effects, durationof action, andintensity of experience.For example, LSD is longeracting8 to 12 hours andmorepotentaveragedoseof 100 to 500 pg thanmescalineaveragedose of 209to 500 nig arid averageduration of 6 to 8 hours andpsilocybin or psilocin average duration of 4 to .12hoursand a doserangeof it to 50 mg.

MechanismofAction

Pharmacology

Serotonergic5-HT systemsespeciallyin themidbrain raphenuclei, or neuronsprojecting from thosenuclei haveclassicallybeenimplicatedasthe primarysourceof psychedelics’effects 11, 17, 69, 102. Theyseem to preferentiallyinhibit serotonergiccell firingvia binding to cell-body or dendritic 5-HT receptorsand seem to spare postsynapticreceptors,althoughthis is controversial83. As serotoninis primarily aninhibitory neurotransmitter,inhibition of thesecellsby LSD would allow the next neuronin the chaintobe freedfrom inhibition 166.

Dopaminergicsystemsmay also be involved in thecentraleffects of psychedelics.There are preliminarydata41 indicting anagonisticandantagonisticeffectof LSD on postsynapticdopaminereceptors.

Carbon-14-labeledLSD given to animals has beenfound to be maximally concentratedin liver andkidney. Brain concentrationsare maximal in hippocampus, basal ganglia, thalamic nuclei, andcerebralcortex. Most of LSD’s etabc.litesare exactedin thefeces127.

Implanted cortical electrodes in humans haveshown LSD-associatedparoxysmalelectrical activityin hippocampalgyri, amygdaloidnuclei, and septumduring perceptualchanges which are reversedbychlorpromazine117.

PharmacologicalEffects

The effectsof an oral doseof LSD as low as 20 to25 gig canbeperceivedwithin a fewminutes,aJthougbwith psilocybin and mescaline,onsetof initial symptoms is somewhatlater 15 to 30 minutes.

Initial physical symptomsare sympathomimeticinnature. Theseinclude dilation of the pupils whichretain their reactivity, nausea,flushing, chilliness,increasedblood pressureand heartrate, tremor, hyperreflexia, piloerection, weakness,elevated bloodtemperature,anddizziness84, 102.

Psychologicaleffectssoonfollow, and,within 30t090 minutes,include feelingsof innertension,affectivelability, visual illusions and hallucinations followedin decreasingfrequencyof occurrenceby auditoryandother sense-modalities,blending of sensorymodah

ADVERSE REACTIONS TO PSYCUEDELICS 579

ties e.g., ‘seeingsound"-synesthesia,a slowing ofsubjective time, a sense of ego dissolution/detachment/fragmentation,recollection of long-forgottenmemories,and increasedsenseof meaningfulnessofwhat is being experienced.Religious and mysticalinsights occasionallyoccur. As the drug effect wearsoff, and if the xperiencehasbeenregardedas generally positive, there is a calm, yet energeticsenseofdetachment and control. In comparison with theaforementionedpositive-valuedeffects, adversereactions can occur at any stageof the acute experienceandmay endup being fairly prolonged.

Betweendosesof 1 and 16 ag/kg, the intensity ofeffect is proportionateto the dose 84. The half-lifeof LSD is about 8 hours in humans 8. Tolerancerapidly developsfor psychedelicdrugs,and at least 3to 4 days are necessaryfor recovery of preexistingsensitivityto a drug of this type.

A withdrawal syndromedoesnot occur with abuptcessationof LSD-iike drugs,and a syndromeof physical dependenceis not known. LSD use has beenreportedto be associatedwith the occurenceof randmal seizures52. "Overdoses"of LSD are notdirectlyfatal; however,one suspectedcaseof LSD as a causeof death, in a man whosebody was found in a warehouse 1 month after death,has beenpublished63.An LD50 for the human is not known. although anelephanthas been killed by a 300-mg intramuscularinjection 169. Death occurredin this instancebyasphyxiationsecondaryto laryngospasm.

There are several theoreticalframeworksavailablefor understandingthe role of LSD in producingpsychological effects. None of them are necessarilyproposedas absolute,and a perspectivethat takesintoaccountas manyviewpointsas possiblewill undoubtedly prove mostuseful.

From a neurobiological point of view, the exacteffects of LSD are controversial,but appearto implicateserotonergicfunction. In the mostgeneralsense,inhibited serotonergicfunction, especiallyin cortex,raphe,andlimbic system,csnbepresumedto decreasethe "filtering" of cognition,perception,andfeeling inwhich serotonergic systems are probably involved.Therefore,mentalandphysicaleventsare experiencedin a novei, less processe&manner.

Klee 89 has describedthe effect of LSD on egofunctioning i.e., thought, motility and perception.Body image is disorganized,time senseis profoundlyaltered, and perceptionsof others are distorted, resulting in the senseof "self"-perceptionbeing, by andlarge, lost. Therefore,distinctionsbetweenrealityandfantasy suffer. Thoughtprocessesbecomedreamlikeandconcentrationbecomesdifficult. Primaryprocessthinking comes to the fore, and previously neutralWords andideasare respondedto as thoughtheywere

traumatic. The distinction betweenautonomousandconflictual areasof the egobecomesblurred.From anego-defenseperspective,repressionand reactionformationappearmostsensitiveto the disruptiveeffectsof LSD; projection,denial,introjection,andregressionmay continue to function effectively. Motorically,someindividuals experienceimpairmentin theabilityto toleratetensionand delaydischarge.

Linton and Langs 99 validated and quantifiedmany similar findings describedby Klee. They concluded that "the drug producesan accentuationofthinking by meansof images,alterationsof self-experience,including feelings of detachedself-observation andestrangement,confusionof personalidentity,the experiencingof eventsin terms of implied meanings, loss of boundariesbetween the self and theenvironment,drive-dominatedthinking, alterationsinthe distribution of attention cathexis, somatization,and an increasein feelings of passivity, expressedasa subjectivelossof control" 99, p. 366.

Tart, in hissystemsapproachto statesof consciousness,describesa discrete stateof consciousnessas a"unique dynamicpatternor configurationof psycho.logical structures,an active system of psychologicalsubsystems"152, p. 5. This patternis stabilizedbyseveralprocesseshe has described.A changein stateof consciousnessoccurs through the effect of disrupting forces and subsequent action of patterningforces-andthen is stabilizedby the sameprocesses.Psychedelicdrugs are thought to provide disruptingandpatterningforces,the effectsof which operateincombination with other psychological factors mediated by the operative state of consciousness.Tartfeels that LSD causesa highly unstablepattern ofpsychologicalstructures,characterizedby transientformationsof patternsthat constitutediscretestatesof consciousness.

AdverseReactions

It is important to use caution in discussingtheconceptof adversereactionsto psychedelicdrugs.Atone extreme are those who believe that the drug-inducedstate itself is eitherprimarily a pathologicalone i.e.. a "model psychosis" or that the desire toinducasucha state is a fnction ofpreexistinnersc.naiity dysfunction. At the other extreme is the viewthat eventhe most disorganized,frightened,dysfunctional, and regressedreactionsto psychedelicdrugsare necessary/healthyreactionsseenin throwing off"straight" society’s "shackles" and in reaching a"higher" level of consciousness.The descriptionand/or reporting of adversereactions to psychedelicsis,therefore,subjectto somedegreeof investigators’perspectiveon the use of thesedrugs.

It is clearly an adversereactionwhenone presents

580 STRASSMAN

himself or herself to a mental health practitioner

with complaints referrableto symptomsinduced orexacerbatedby psychedelicdrugs. It is lessclearwhenchanges in behavior, values, or life-style that arebrought on, solidified, or symbolized by psychedelicdrug useare broughtto the attentionof care-giversbya concernedother-e.g., friends, co-workers,or relatives. These are caseswhere sensitive :i. udgment plays as ntuch a role in determiningpathologicaldiagnosesas do the salientpresentingfeaturesof thesyndrome.

A large numberof methodologicalissuesneedto beaddressedbefore beginning an analysis of availablereportsof adversereactions.I will attemptto addresscertain of the most salient featuresbefore discussingthesestudies.

I haveexcludedfrom analysis reportsthat includeless than 10 subjects.Many of theseare casereportsof a few individuals, Some are in-depth analysesofthesesubjects,often from a psychodynamicand geneticperspective.Although heuristicallyof value,theyare difficult to evaluatefrom the viewpoint of developing testablehypotheses.

Theremainingstudies,I believe,canbedivided intofour generalcategories:a Studieswith patientsseenin an acute treatment

facility emergencyroom or inpatientunit becauseof symptomsthoughtto be related to LSD.

b Studies where questionnaireswere mailed to clinicians and/or researchers,polling their experienceswith subjects in therapeutic,experimental,anduncontrolledsettings.

c Follow-up studies of subjectswho took LSD inexperimental, therapeutic, or uncontrolled settings.

d Studieswhere subjectswere given LSD in a controlled environmentandthen responsesevaluatedimmediatelythereafter.

Table 1 is organizedaround this categorization ofrelevantstudies.

One of the most confoundingaspectsof almost allstudiesof either acute or chronic effects of LSD istheir lack of pre.LSD data. The role of LSD in producing "LSD psychoses,"brain damage,long-lastingpersonalitychange,and flashbacksis difficult, if notimpossibleto discern without pre-LSDvaluesfor thedependentvariables.

Table 1 lists the featuresI believe to be importantto addressin studiesof adversereactionsto psychedelics. They would be includedin what might be calledthe "ideal" studyon adversereactionsto psychedelics.

Samplesize: Should include ratio of male to femalesubjects.

Case-findingmethods:This will obviously haveaneffect on the populationstudies.Forexample,subjects

volunteeringto be studiedwill often have differentcharactertraits, and possibly pathology,from thoserefusingto do so.

Age range and averageage should be specified,areports often emphasizethe increasedsusceptibiljjof youngersubjectsto adversereactionse.g.,77.

The definition of an adversereaction needsto bespecified. as moreor less liberal definitionswill haverelatedeffects on the frequencyof their occurrence.Itwould be ideal to test inter-raterreliability andvalidity of the definitions, as well.

Sourceof the drug is self-evident,as adulterantsof"psychedelics"can be quite psychotoxic.

The numberofdrug exposuresand,if available,thedosagetaken can indicate total cumulativeexposureto psychedelics,a factor that appearsto be quiteimportantin severalregardse.g.,frequencyof adversereactions,long term psychologicaleffects,flashbacks,etc..

The time elapsedbetweenthe last trip andthe dateof being interviewed or tested is important, both intermsof retrospectivealterationof the subject’smemory of the experience100, as well as the presenceorabsenceof acute drug effects.

Study methodscan vary widely and range fromsimpledirect clinical observations,to detailedneurochemical studies. Other methods have included in-depth clinical interviews, questionnaires,paper andpencilpsychologicaltesting,andinterviewingsubjects’therapistsandfamilies.

The setthg i.e., i3OC andpeoplepresentneedstobe specified.Early reportsof adversereactionsoccurring in controlledsupervisedsettingsweremarkedbya very low frequencyof occurrencek34, and whetheror not the setting was unsupervisedcould have apowerful effect on the frequencyandnatureof adversereactions.

Premorbidpopulationcharacteristicsincludea lEgalhistory as an indicatorof sociopathy,drug abuse,andobject relations in general;b previouspsychiatrichistory, either in the subject or in the family of origin.This is particularly germaneto addressingthe questions of preingestionpsychopathologyandwhetherornot a genetic/biological"diathesis"exists in selectedindividuals to develop adversereactionse.g., 61; cotherdrug use is obviouslyrelevant,particularly if oneis to assign an etiological role to LSD is causiflfaberrantbehavior,braindamage,or personaldistress’

Motloationfor psychedelicdrug use hasbeenshowflby many groupsto be relatedto outcomeof the drugexperienceand relatesboth to premorbidcharacteristics of the subject,as well as to the setting in whichhe/shewould mostlikely be taking the drug e.g.,Sb.

The presenceof placebo, whether preferablyactive one e.g., stimulant drug or an inactive Ofl

ADVERSE REACTIONS TO PSYCHEDELICS 581

e.g.,saline in controlled experimentswould add tothe validity of a psrticular study. The presenceofappropriately matchedcontrols would also provide

helpful comparisondata.The presenceor absenceof pre-LSDdata asprevi

ously discussed,helps differentiatethe etiological vs.associativerelationshipbetweenLSD useandrelevantfindings.

Presenceor absenceof follow-up and its durationneedto be specified, especiallyin terms of studying

long term effects of these drugs. The re-emergence,disappearance,or prolongationof symptomswill determine, to a large extent, the degree of disabilityincurredby the use of the psychedelics.

The incidenceof adversereactionsobviously is determinedby the definition of thesereactions,andthepoulationbeing studied. It is clear that, amonginpadentsadmittedbecauseof LSD reactions,100percentof these individuals havehad an "adversereaction."Likewise, the incidenceof transientpainful, anxious,anddepressedexperiencesat some time during mostLSD experiencesappearsto be quite common. Moststudieshave definedadversereactionsoperationally,i.e., thosereactionsthat havecome to the attentionofindividuals in the mental healthfield.

Keepingthesepoints in mind, onecanbegin sortingthrough the voluminous and variegatedliterature onadverse reactions to psychedelic drugs 33, 25-37,137. Table 1 is meant to aid in analyzing variousreports,particularly in terms of the absenceor presence of theseparametersbeingspecified.

Classification

The temporal relationship betweenthe ingestionofa psychedelicdrug and subsequentdysphoricor maladaptive symptoms is probably the most helpfulmeansof beginning a classification of adversereactions, i.e., on a continuum from acute to chronic.Betweenthesetwo endsof the spectrumwould be thephenomenaof delayedreactionse.g.,apanicreactionorpsychosisoccurringafteranasymptomaticinterval70, intermittentreactionssuchas "flashbacks",andthe "LSD psychoses"including the psychedelic-precivitatedmajor functionaldisorders.

The most common adversereaction is a temporaryless than 24 hoursepisodeof panic-the bad trip159-462. Symptoms include frightening illusions/hallucinationsusuallyvisual and/or auditory; overwhelming anxiety to the point of panic aggressionwith possibleviolent acting-outbehavior;depressionwith suicidal ideations,gestures,or attempts;confusion; and fearfulnessto the point of paranoiddeluSions.

Reactionsthat areprolongeddaysto monthsand/or require hospitalization, are often referred to as

"LSD psychoses,"and include a heterogenouspopulation and groupof symptoms13, 18, 42, 44, 57, 128,129, 131, 141, 161-163. Although there are no hardand fast rules,some trendshavebeennotedin retrospectiveanalysesof thesepatients.There is a tendency for peoplewith poorerpremorbidadjustment,ahistory of psychiatric illness and/or treatment, agreaternumberof exposuresto psychedelicdrugsandcorrelatively, a greateraveragetotal cumulative dosage takenover time, drug-takingin an unsupervisedsetting,a historyof polydrug abuse,andself-therapeutic and/orpeer-pressure-submissionmotive 122 fordrug use, to suffer thesecomplications.

In spite of the impressivedegreeof prior problemsnotedin many of thesepatients,thereare occasionalreportsof severeandprolongedreactionsoccurringinbasically well adjustedindividuals 70. in the samevein, thereare many instancesof fairly poorly adaptedindividuals who suffer no ill effects from repeatedpsychedelicdruguse.In fact, it hasbeenhypothesizedthat some schizophrenicsdo not suffer adversereactions becauseof their familiarity with such acutealt.ered states,sr1d their ability to let the run thaircourse59. Anotherpossibility is that theseindividuals may be"protected"by possible"down-regulation"of the receptorsfor LSD, by the over- productionofsome endogenouscompound.Individual prediction ofadversereactions,therefore,is quite diffleult. However, some well designedprospective studies haveshownthatparticular individuals are especiallyproneto adverseacutereactionsseebelow.

Symptomatically,thesepatientspresentwith a widevarietyof symptoms,belying the greatvariety of theirpremorbid features120. Formal thought disorder,hallucinations,illusions, violence,paranoidandotherdelusions,depression,regression,emotional lability,bizarrebehavior, insomnia, hypomania,depersonalization,dissociativestates43, confusion,andapathycan be seen.

Bowerset al. analyzedsome neurohumoralfeaturesof LSD-inducedvs. non-LSD-inducedpsychoses,andfound that the CSF of the former groupgaveevidenceof decreasedcentral5-hyd.roxyindoleaceticacida metabolite of serotonin formation, a finding that persistedduring phenothiazinetreatment.Homovanifficacid a dopamnnemetaboiite in theOSE did not showa differencein levelsbetweenthesetwo groups24.

Infrequentlyreported,butreceiving greatpublicity,were the articleson homicidesthat occurredin associationwith L8D use.Knudsen93 describeda youngwoman with a long history of polydrug and alcoholabuse, sexual masochism,sociopathy,and a majordepression treated with electroconvulsive therapyECT, who murderedhersexualpartner 3 days afterthe fifth of a seriesof LSD psychotherapysessions.

TABLE 1Studiesof AdverseReaetinn.sto LSD

St d N Age Case-Einding Drug Dose Other Settin controls Pre’U

‘ mi’ Avg. Method Source No. ezp. Drugs - g Placebo Data

AcuteLSDReactions

Frosch56, 51 12 18-32 Hospitalizedfor "LSD N.M. 200-400pg Polydrug,alcohol abuse Uric. None None7,5 23 reaction" 1-10 in 11 None

Tietz 157 49 os. 1-Jospitalizedfor "LSD N.M. 100-2500pg Polydrug,alcohol abuse Une. Yes None37,12 <25 reaction’ n.e. in "most" None

Ungerleider 70 16-38 P.R. visit with 1.50 N.M. na. Polydrugabusein 46% Unc. "CuC usersof None161, 162 53,17 21 mentionedin diag- 1-200 1.50

notia NoneRobbins128, 22 15-43 Hospitalizedfor "LSD N.M. os. Polydrugabuse"typi. Unc. None None

129 11,11 21 reaction" 1-100+ cal" None

Biumenfleid 22, 25 n.e. PR. visit for "L5D a.s. ?o,ycrug,sjc000i aouse Uoc. None NonekO2i react,orC 1-12± inmost None

Froeco 55 23 16-33 Hospitalizedfor "1.50 N.M. 400-600pg Polydrugabusein most Unc. Yes None14,9 22 reaction’ 56%with 1-5 None

Baker 3 67 n.e. Hospitalizedfor drug N.M. n.s. Potydrugabusein 26 Unc. None None34,33 no. abuse na. None

Dewhurst 44 19 18-27 Hospitalizedfor "LSD N.M. na. Otherdrug abusein 14 3 Med. None None13,6 24 reaction’ 3-once 16 Unc. None

11-chronicForrest54 60 ns. Hospitalizedfor "LSD N.M. n.e. Previousdrug usein None None

43,14 20 reaction" as. 72% NoneQuestionnaire Studies

cohen34 5000 u.s. 44/62 questionnaires M. 25-1500 pg n.e. vrisble n.e. u.s.n.e. os. returned 1-80 n.e.

Ungerleider 2000 15-30 1580/2700question. os. n.e. n.e. n.s. n.s. n.e.163 On>0 n.e. nairesreturned n.e. na.

Mallesoes103 4470 n.e. 73/74 questionnaires M. 25-1500pg n.e. Variable n.e. n.e.nt. n.e. returned 49,000 n.e.

Folkw.upStudies

Ditman 45 74 n.e. volunteers.or,. M. 100 pg 50% alcoholic Med. None Nonen.s. na. 1 None

Savage136 93/ n,s.Pt.volunteers M. 200-600pg" n.e. Med. Nona/Nooe Noneos. 22-67 M. 1 n.e. Med. None/None None

74 3748,26

Kleber 87, 85 21 18-24 Volunteer, n.a. Marijuana in 9 Unc. None Nonet21,0 n.s.j 1-20 None

Bhattacharya .581 nt. Pta. M. n.e. n.e. Med. n.e. n.e.19 n.e. n.e. 2742 n.e.

Shagass139 20 16-36 Inpt. volunteers M. 2.5 pg/kg n.e. Med. Yea Psychiatricdx’s13,7 24 iv. Amphetamine

1Ditman 46 116 15-47 volunteers,pta. M., 75-1500 pg Other drug abusein Unc. None None

98,18 n.e. treatedfor LSD N.M. 1-100+ 80% Nonereactions

Barron15 20 16-31 Volunteers N.M. 100-150pg Poydei.igabusein all Unc, None None14,6 22 8-250 None

McGlothin 247 n.e. volunteers,pts. M., N.M. 25-700pg Someueed multiple Variable Yes n.e.113 164,83 34 1-20 drugs None

Nad.iteh120, 483 n.e. Volunteers N.M. n.e. Marijuanain 92% Unc. None None121, 123 453,0 21 1-100+ None

lnuaediata ObservationStudies

Pauk 125 14 19-37 Inpt. volunteers M. 15-500pg n.e. Med. None Peychiatricdx’s8,6 23 3-5 None

Anaataeopouloe 97 n.e. Relativesof echizo- M. 1-15 pg/kg n.e. Med. Yea Nonsymptometie10 n.e. n.e. phrenice p.o. None

1Fink 50 65 20-53 lope,volunteers M. 60-250pg concurrentpsychotrop- Med. None Psychoticdx’s

n.e. 36 1-15 ice SalineLange96 50 21-42 Volunteers M. 100 pg n.e. Med. None Extensive

50,0 ne 1 Tap water

Abbreviations:m, male; f, female; Avg., average;No. exp.,numberof exposures;PsychHz, pastpersonalpsychiatric history; Pam lix, family peycltetothistory; adv. rxn., adversereaction;N.M., nonmedical;Unc,, uncontrolled;n.e., notspecified; az symptom; P.R.,emergencyroom; halluc’s, helbcinatiOoapt..patient;Med., inedicedsetting; M., medical;na.,not applicable;Inpt., inpatient; Lv., intravenously;dx, diagnosis.

Somepatienteadmittedmore thanonce."Plus 300 to 400 m of mescaline,

TimeMethod Population Legal Psych Hz Motivation D:fenitUnoi Incidence Follow- Comments

Acute LSD Reactions

1-90 days clinical obeer- White, un- na. 5 psychotic Pleasure Panic,ax recqr- 0.4% of admie- n.e. 3 psychoticswith Hz of psychoeisvation married n.e. reoce, pey eione

chosie

i-90 daye clinical obser- Low encioecc- ns. None n.e. Panic,ex recur- n.e. 1-5 moe 67% with extendedpeychoeievation; test- ooeniceta- n.e. rence, pey- for 17ing tue choeie

j-42 days Clinical obeer- 33% unem- 14% 37%;45% n.e. Seenin P.R. 11.5. 0.9. 25% hoepitalized 68% needed>1vation; ployed no date moof treatmentchart review n.e.

1 day to 12 clinical obeer- White, mar- n.e. 3 psychotic ‘Kicke," Panic,ax recur- n.e. n.e. 3/8 with psychosispreviouslyillmoe vation ned n.e. self-help rence,pey

choeia1 day for clinical obser- 26% unem- 40% 72% Self.help, Suicidal,anxiety, 0.3% of admie- n.e. PsychHz almostalwayspreceded

14 vation; ployed n.e. curiosity confueione, eions LED usechartreview helluc’e

n.e. Clinical obeer- Upperend n.e. n.e. Pleasure Panic,cx recur- n.e. n.e. Youngerpte.over.repreeentedvation middle n.e. rence,pey

class chosien.e. Clinical obeer- n.e. n.e. n.e. n.e. Psychosis,suici- n.e. n.e. LSD relationto ez’e unclearin 36

vationt n.e. del, aggressive‘Soon Clinical Lbeer. Above avg. n.e. S n.e. Psychosis n.e. n.e. No residualproblemsat discharge

after" for vetiod IQe; atu- n.e.8 F dents

n.e. Clinical bbeer- 40% unem- 69% 83% n.e. Needinghoepi- n.e. n.e. 16 neededpsychiatric helpvatino ployed n.e. taliration

Questionnaire Studies

n.e. Clinical Liner- n.e. n.e. commonin Volunteers, Psychosis,euici- SeeComments n.e. Psychoeie:0.5-1.8/1000;suicidevation edv. rxn, patieota del, agitation attempts:0-1.2/1000

co-a.n.e. clinical obser- n.e. n.e. Many in n.e. Arbitrary SeeComments n.e. 27% of respondentshad seen"ad

vation edv. rxn. versereactions’n.e.

n.e. Clinicai obeer- n.e. n.e. n.e. n.e Suicidal pay- SeaComments n.e. Psychosis:9/1000 ½ previcuab’vetion n.e. chosie ill; suicide: 0.7/1000

FoIlcw-up Studies

na. Question- 50% profee- n.e. 50% aico- Volunteers Anxiety, depres- 15% 2 yra Symptomslasted1-21 daysnames eicnal holic sion, head

n.e. ncheen.e. Interviews; n.e. n.e. 100% n.e. Therapy "Felt harmed," 1/1.67 Variable 80% improvedna. question- n.e. n.e. 100% n.e. Therapy suicide,psy- 1/167 2-6 moe

oairee chosisna. Interviews Students;top n.e. 11 Curiosity, Panic,cx recur- 24% Variable "Stable’ groupwith no adv. rxns.

half of n.e. eelfhelp, rence, flesh-class press- backs

suren.e. n.e. n.e. n.e. 100% n.e. n.e. None n.e. AU with traueientemotionaldie

na. turbancena. Interviewe n.e. Moat 100% Therapy n.e. None 1 yr Psychopathsoften improved

n.e.

n.e. Interviews; n.e. n.e. n.e. Volunteers Needingtreat- None n.e. Polydrugabusersdid mostpoorlytesting n.e. ment

n.e. Interviews; 16 working or n.e. None Curiosity, Panicover 9ev- 15/20 n.e. Marginaladaptationpredatedtesting in school n.e. insight, erelhours 11/20 with LSD use

aecape fiaehhncksn.e. Tjiterviewe: n.e. n.e. 123 Therapy, Psychosie,euici- 1 psychosis;7 10 yrs 6/7 suicideswere 2 yrs after last

testing n.e inst dxl suicides ‘trtp’

na. Question- 65% students os n.e SeW.help. Fearof psychosie n.e. n.e. Set, frequency,relatedto adv.nairee n.e. pressure, rzns.

pleasureImmediate ObeervetiooStudies

immediate Clinical obser- n.e. n.e. 100% Voiunteere Psychosis 50% n.e. Object of etudywas to inducevation n.e. psychosis

Immediate Clinical obeer- n.e. n.e. None Volunteers Parenola,depree- 37/97 6 weeks Adv. rxne. in normalsnot spedvstion Schizo- eion Sad

phrenicImmediate Clinical obeer- n.e. n.e. 100% Volunteers Increasedex’e, 2% 3 moe "Classic"echizophrerrioedid rela

vetioo n.e. confueion tively wellImmediate Clinical obeer- Actors n.e. No overt Volunteers Paranoiaduring 27% Several Primitive characterdisordersdid

vation; teat- psychosis study daye poorlying n.e.

584 STRASSMAN

Barter andReite 16 describedthe caseof a youngchronic paranoidschizophrenicmale who killed hismother-in-law.Hehadtakensmall quantitiesof LSDin the past,his last experiencehavingbeen a monthbeforethe murder. In the interim, he hadbeendrinking large quantitiesof alcohol and abusingbarbiturates.The sameauthorsdescribedanotheryoung manwith no previousdrugabuseor psychiatrichistorywhomurdereda "comparative strangerduring an argument" 16. n. 33: the details of both :tis ;eiationsnipto the strangerand the nature of the argumentarenot included in the report.He hadalso beendrinkingthat night andrememberednothingof the incident.

Klepfisz andRacy 92 describeda young manwitha 3-yearhistory of polydrug abuse,includingamphetamines and cocaine, who killed a girlfriend 2 daysafter an LSD experienceS

ReichandHepps126 describeda young manwithparanoid and borderline character pathology whokilled a strangerafter 8 days of sleep deprivation,round-the-worldtravel, and psychosis,following anLSD experience.He had a history of depressionandpolydrug abuse.

These cases,except perhaps for the Reich andHeppsexample,do not clearly implicate LSD in themurdersdescribed.The role of other drugs andalcohol, as well as chronic psychosis,seemat leastequallyrelevant, in the Reich and Hepps case, a temporalrelationshipbetweenLSD use andpsychosiswas apparent, but as will be discussed later, the specificnatureof LSD as having precipitatedthe psychosis,as opposedto otherdrugs,jet travel, or the cumulativeeffscts or transient,unsatistactoryrelationships in apreviously marginally adaptedindividual, is difficultto determine.

Reportsof suicidehavebeenoccasionallydescribedin the literature 86, and are most often included inlarge caseanalyses.Dataregardingthe role of LSD intheseindividuals’ self-destructivebehavioris difficultto glean from these reports, but McGlothlin et at.115, for example, describeda weak temporal relationshipbetweenLSD Use andsuicidal actions.Whatis missingin thesereports,but mostgermaneto them,is information regardingpremorbidsymptomatologyand suicide attempts,other drug alcohol abuse,andthe natureof the situationin which LSD wastaken.

Self-inflicted ocularinjuries, including seif-enucleation 130, 155 or retinal burns from staring at thesun 58, havebeen reportedinfrequently. Theseinjuries were describedin individuals for whom little orno premorbid and/or psychiatric follow-up data areavailable,and what was describeddemonstratedpooradjustmentin the years beforethe self-inflicted injuries.

Major "functional" psychosesvs. "LSD psychoses.

A diagnosticissuedealt with explicitly in only a fewpapers is that of LSD-precipitatedmajor functionajillnesses,e.g., affective disordersor schizophrenia.jotherwords,many of theseso-calledLSD psychose3could be other illnessesthat were triggered by thestress of a traumatic psychedelic drug experience.Some of the same methodological issuesdescrTheearlieraffect thesestudies,but they are, on the average, bettercontrolie-± with more family andpastpsychiatrichistory available for compariscn.

Hensalaet at. 74 comparedLSD-usingand nonLSD-using psychiatric inpatients. They found thatthis group of patientswas generallyof a youngerageandcontainedmore characterologicallydisorderedindividuals than the non-LSD-üsing group. Patientswith specific diagnoseswith or withoutLSD historieswerenot compared.Basedon their observations,theyconcludedthat LSD was basicallyjust anotherdrugof abusein a population of frequently hospitalizedindividuals in the SanFranciscoarea,andthat it wasunlikely thatpsychedelicuse couldbe deemedetiological in the developmentof their psychiatricdisorders.

Roy 133, Breakeyat al. 28, and Yardy andKay165 haveattemptedto relate LSD use to the onsetanddevelopmentof a schizophrenia-likesyndrome.Afew commentsregarding this conceptualframeworkseemin order,beforetheir findings are discussed.Themajor factor hereis that of choosingschizophrenia,orin the Vardy and Kay study, schizophreniformdisorders,as the comparisongroup.There is an implicationhere that LSD psychosesare comparable,phenornenologicaily, to schizophrenia-likedisorders,and thatLSD can "cause" the developmentof suchdisorders.The multiplicity of symptoms and syndromesdescribed in the "adverse reaction" literature shouldmakeit clear that LSD can causea numberof reactions that can last for any amount of time-fromminutesto, possibly,years.1 believethat what is beingstudiedhere is the questionof the potential role ofLSD in acceleratingor precipitating the onsetof anillness thatwas "programmed"to developultimatelyin a particularindividual-in amannercomparabletothe major physical or emotional Stress that oftenprecipitatesa bona fide myocardial infarction in anindividual with advancedcoronary atherosclerosIs-The stressdid not causethe heartdisease;it was onlythe stimulus that acceleratedthe inexorableprocessto manifestillness.

In looking at the relevant studies, Breakeyat ci-28 found that schizophrenicswho "useddrugs" hada earlier onsetof symptomsandhospitalizationthannon-drug-usingschizophrenics,andhadpossiblybetter premorbidpersonalitiesthan non-drug-usingpatients although Vardy andKay havechallengedthtsanalysisof Breakey’sdata [165].

ADVERSE REACTIONS TO psycHEnELIcs 585

Bowers 23 compared12 first-admissionpatientswith psychosesrelated to LSD use, requiring hospitalizationandphenothiazines,to 26 patientshospitalized andtreatedwith phenothiazineswith no historyof druguse.Six of thesecontrols hadbeenpreviouslyhospitalized. Drug-induced psychotic patients werefoundto havebetterpremorbidhistoriesandprognostic indicatorsthan the nondruggroups. Therewasnodifference in rates of family history of psychiatricillness, However,severalissuesflaw this study.Oneisthe polydrug-abusingnature of the "LSD-induced"psychoticpatients,comparedto the controls.The roleof LSD, therefore,in causingor precipitating thesesymptomaticdisorders,is opento dispute. The otheris the lack of an adequatecomparisoncontrol group,i.e., the controls were specified only as "psychotic,"and did notnecessarilymatchthe LSD group in eithersymptoms or diagnostic classification. A follow-upstudy of the LSD patientsoccurredbetween2 and6years later 25. One half did well and one half didpoorly, althoughthe lack of control group for a follow-up in a similarly symptomaticcontrol group makesinterpretationof the datadifficult.

Roy ,i33y, in a somewhatdifferentdesign,comparedchronic schizophrenicpatients diagnosedaccordingto DSM-III criteria who had used LSD within theweek precedinghospitalization,and found no differences in age of symptom onset or hospitalizationcomparedto patientswithout a history of illicit druguse.

Vardy and Kay, in an elegantstudy with a 3- to 5-yearfollow-up period, demonstratedthatpatientshospitalized for a schizophrenicpicture that developedwithin 2 weeksof LSD use patients with otherdiagnoseswereexplicitly excludedfrom comparisonswithnon-drug-usingschizophrenicswere "fundamentallysimilar to schizophrenicsin geneology,phenomenology, and course of illness" 165, p. 877. Premorbidadjustment,ageof onset of symptomsand hospitalization, family historyof psychosisor suicide,andmostcognitive features were also equal betweengroups.Family histories of alcohol abuse were markedlygreaterin the LSD group.

I believe that thesedata, taken as a whole, limitedas they are in terms of comparingsubgroups i.e.,LSD-using vs. non-LSD-using of "schizophrenialike" disorders.point toward, at the most, a possibleprecipitatory role in the developmentof thesedisorders, in a nonspecific and not etiologically relatedmanner.

Most reportshavestressedthe similarities betweenLSD-inducedpsychoticstatesandschizophrenia,andthereforecompare"functional" schizophreniato LSDinducedstatesthat resembleschizophrenia.However,

tive iliness and LSD-inducedpsychoses.Lake et at.95 describeda caseof mania precipitatedby LSD;Muller 119 andDewhurstandHatrick 44 describedthe efficacy of ECT in LSD psychoses;caseshavealsobeen treatedwith lithium 80. Bowers 26, in hisdiscussionof the role of serotonin in psychosis,emphasizesthefactthat "good prognosis"schizophrenicsand LSD-inducedpsychoseshave similar CSF levelsof the serotonin metabolite 5 -hydroxyindole-aceticacid. The fact that many of the so-called"good prognosis" schizophrenicsare eitheroften rediagnosedasaffectively ill, and/or will often have family historiesof affective illness, lends support to the contentionthat the relationship betweenrelatively long-lastingpsychedelicdrug-inducedpsychosesandaffectivedisordersdeservesfurther study 85.

Prospective studies of acute adverse reactions, Aunique group of studiesdeservesmention: those ofKlee and Weintraub 90, Pauk and Shagass125,Anastasopoulosand Photiades10, Fink at at, 50,and Langs andBarr 96. Theseare representativeofthe small numberof studiesthat havelooked at individuals before administrationof LSD, in order moreconfidently to state relationships between adversedrug reactionsand preexistingcharacteristics.Threestudiesof somewhatsimilar design are thoseof Kleeand Weintraub, Pauk and Shagass,and Langs andBarr. Here, individuals were pretestedwith variousinstrumentsbefore being given LSD. Klee andWeintraub found that individuals with a fear of ciosenessof same-sexothersand a strongtendencyto use projection as a major defensemechanismwere regularlythose who developeda paranoidreaction during theLSD state,lasting, at themost,24 hours.

Pauk and Shagassfound that individuals who respondedto low dosesof LSD with disorganizationoftheir Bender-Gestalttestsweremost likely to develop"psychotic" statesafter higher dose LSD ingestion.They thought that this testwas helpful in indicating"ego-function" impairmentby LSD.

LangsandBarrappliedmultiple psychologicaltests,interviews, and questionnairesto a group of "normals." Thosewho hadshort-lived lessthan 24 hoursparanoidreactionswere found to be "more anxious,manipulative,hostile with conflicts aboutaggression,depressedand self-punitive: to feel physically impaired, prone to a thought-disorderand confusedintheir identities; and likely to use projection as a defense" 96, p. 168. Thesethree studiesall point towardthe possibledevelopmentof more effectivepersonality screeningtools for individuals being consideredfor LSD experiments.

Anastasopoulosand PhotiadesadministeredLSDto previously "asymptomatic" relatives of schizophrenics, although more sophisticatedstudies werethereare datato supporta relationshipbetweenaffec

586 STRASSMAN

not performed.A very high percentageof theseindividuals hadadversereactionslastingup to 6 weeks.Siblings of schizophrenicsshowedadversereactionsto LSD only in cases where one or both parentsshowed decompensation.The significance of thesefindings is clear, and may relate to the often foundrelatively high rate of familial mental illness in theso-calledLSD psychoses.

Fink et at, gave LSD to 65 psychoticsubiectsandnoted a 2 per cent incidence of nroionged adversereactions,which were describedas basically exacerbations of preexisting psychopathologywith accompanyingsignsof a confusionaldelirium. Chlorpromazine, later introducedas a prophylacticagentat theend of subsequentLSD studies, was successful inpreventingny further prolonged adversereactionsfrom occurring-Thesedataare particularlyinterestingfrom the perspectiveof the high incidenceof premorbid psychopathologyof many of the "LSD casualties"reportedin the literature on unsuperviseduse of thedrug.

A Noteon the Etiologyof AdverseReactions

What are the etiologiesof the abovedescribedadverse reactionsto psychedelicdrugs? I believe thatthis questionshould be addressedfrom several perspectives,with multiple levels of interaction.The heterogeneityof responsesto LSD makegeneralizationsaboutresponsivenessto thedrug impossible.Theoretical frameworks explaining their effects have beenproposedin terms of biological, psychological, andsystemsaunroaches.The interulav of these factors,combinedwrth the effect of’ the drug and particularsetting, result in one particular individual’s "LSDexperience."

Constitutionalpredispositionshavebeendescribed,wherein family histories of major functional illnessesare often associatedwith poor outcome in uncontrolled settings. A past personalhistory of previouspsychiatrictreatmentand/orthe presenceof particular characterologicalpathologyhave also beenshownto be associatedwith adversereactions.

My feeling is that, in a particularly predisposedindividual be it genetic, motivational, or characterological, the flood of images,drives, feelings, andperceptions,occurring in a setting where the personhas not been eitheradequatelypreparedand/or supported, abreakdownin the normal meansof processing internally and externallyderived information occurs, with associatedreactions,dependingon one’sability to toleratesuchexperiences.I will notaddressthe issue of mystical experiencesobtainedduring thebreakdownof normal mentalprocessesoccurringduring LSD intoxication,exceptto saythat they do occure.g.,106] and appearto be most likely subject to the

sameformal rules of operationand developmentasadversereactions [i.e., constitutional, genetic, char.acterological,preparation,motivation, etc.].

Now, the duration of such an experiencemay lastfrom minutesto hours to weeksor longer. The duration appearsto be dependenton several variables,including, most likely, a familial or personalpredis.positionto themajor functionalpsychoses158.TouJcumuiative ernosuremay also have direct bearingespeciallyas describedby Abraham3 andGlass andBowers60.

Chronic effects. The chronic adverse reactions topsychedelicdrugs describedin the literature are alsocomposedof a fairly heterogenouspopulation andgroup of symptoms 37, 51, 87. Studies of chroniceffects of. LSD canbe divided into two categories:1thoseinvolving long-lastingpsychologicalandpersonality effectsof LSD usein patientsand nonpatientsincludingexperimentalsubjects;and2 thoseinvolving measuresof organicityin individuals with repeateduse.

The study of Blacker at at. 20 focused on 21chronic LSD-using volunteer nonpatients, a groupthey referredto as "acidheads."Predrugmeasuresofpersonality or other variables were not available.Theseindividuals were describedas "havingprofoundnon-aggressiveattitudes,magic-mysticalbeliefs, relatively intact interpersonalrelationships,andcognitiveabilities that are more similar to individuals usuallytermed eccentric than to individuals diagnosedasschizophrenic"20, p. 349. However whether thesebeliefspredatedthe LSD usecould notbe determined.

IvlcGlothhn et at. 115 studiedchangesin personality, attitude,values,aestheticinterest,andperformance resulting from LSD administrationin normalswho had participated in a series of three well controlled LSD sessions.Follow-up on this group wasat2 weeksand6 months.Galvanicskinresponsedroppedin three individuals at 6-month follow-up, idjcatingan elevatedability to managestressfulsituations.Inspite of subjective feelings that subjectshad becomemore creative,aestheticallyappreciative,andlessdefensive, objective data did not particularly supporttheseperceptions.

Axelrod and Kessel 12 administered the Rorschachto three groupsof 10 individuals describedashaving taken LSD more than 30 times in a 3-yearperiod, oneto five timesin that sameperiod,or never.Significantly more"ego disturbance"wasfound in the

LSD-using groups comparedto nonusers.However,this study suffers from lack of premorbicltesting,andcontrol issuesregardinguse of otherdrugs.

Salzmanat at. 135 comparedindividuals who had

discontinuedtakingpsychedelicdrugs6 monthsbeforebeing studiedwith thosestill taking psychedelics-In-

ADVERSE REACTIONS TO PS’CHEDELICS 587

dividualswere studiedby a varietyof paperandpencilpsychological tests. Except for elevated risk-takingbehavioramongcontinuers,thetwo populationscouldot be differentiated.

McGlothlin andArnold 113 performeda 10-yearfollow-up on 247 individuals who hadreceivedLSD in

an experimentalN = 123 or psychotherapeuticsetting N = 124 with carefulmedical supervision.Thegroups were controlled by comparingpatients whotook LSD on their therapists’initiative, with patientsof the sametherapistswho did notuseLSD in therapy.The samplewas further distinguishedby a groupwhocontinuedusingpsychedelicsafter the experimentsortherapywere over. Patientswho had LSD in a therapeutic settinginitiatedby their therapists,showednogreaterchangeson individual variablesthan the non-drug-experiencedcontrol group over a comparabletime period. The LSD continuersdid showappreciabledifferencesin a numberof areasrelatingto measuresof personality, values, beliefs, and attitudes. Thenonmedicalcontinuersof LSD also usedmore drugsand alcohol in general than the two other groups.Thsy also engagedin andv-crc interestedin nonpharmacologicalways of altering consciousness.The authors thoughtthat perhapsa particular type of individual was drawn to LSD, which then acted in acatalyticmannerto reinforcethe individuals’ interestin altered.statesof consciousness.Interestingly,LSDuse, by the "continuing" sample,declinedwith time.

Thequestionof organicdeficits in usersof LSD hasbeenaddressedby severalinvestigators.Blacker at at.20 usedcognitive,perceptual,andEEG testsin theirpopulationof "acidheads."The incidenceof abnormalbaselineKEGs was thought to be no greater thanmight havebeenexpectedin a non-drug-usinggroupof young adults. Computer analysesof EEG datashowed increasedenergy in four specific frequencybandsin the LSD group over the left occipital areaascompared to LSD nonusers. The significance wasunknown.Visual evokedpotential studiesshowedincreasedsensitivity in a few instancesin the LSDgroup.Auditory evokedpotential responsesweresimilar to normals,and cognitive studiesrevealedsomeslower responsetimes as comparedto normals. Theauthors could not conciude that LSD producedanyform of CNS damage. As in the description of thecharacterologicalanalysispartof this studypreviouslydescribed,these findings are limited by a lack ofpremorbidstudiesand control for other drug use.

Accord 5 studied40 white males,with an averageage of 20 and a mean educationallevel of 12 years.Intelligence testswere thoughtto bean average.Neuropsychologicaltesting was performedusing the Indiana NeuropsychologicalBattery. Thirty-two subjects performedin the "brain-damagedrange" on at

least onetest,18 on at leasttwo, andfive on all three.No gross cerebral pathology was noted. This study,however, is flawed by lack of controls, premorbidtesting, andconsiderationof otherdrug use.

In a laterpublication,AccordandBarker 7 studiedin the samemanner, 15 patients with a history ofpsychedelicuse.In this study an age-matchedpopulation of non-psychedelic-usingpatientswasobtained..Psychedelic-usingpatients scored lower than non-drug-using patients. In one of the three tests, theresultsof psychedelicUsersfell belowcutoff scoresfornon-brain-damaged individuals. However, thesenormswereestablishedfor individualsnearlytwice asold as the subjectsof the study. This study is alsoflawed by lack of predrug use measuresand poorcontrol for otherdrugs.

Culver and King 40 performed a retrospectivestudy of 42 college seniors,divided into three equalgroupsof 1 controls,2 marijuana/hashishusers,and3 LED users all of whom also usedcannabisproducts. Other drug use was carefully controlled for,exceptalcohol. Groupswere matchedby verbal andmath ScholasticAchievementTest SAT scoresfreshmanMMPI profiles. Gradepointaveragesamonggroups showedno differences.A neuropsychologicaltestbatterywas administered,including the HaisteadBattery, WechslerAdult Intelligence Scale, Reitan’sTrail-Making Test, and several others.The Only abnormality found in the LSD group was a poorer performanceon the Trail-MakingTests althoughscoreswere well within the normal range. The degree ofLED usedid not correlatewith subjects’performance.Alcohol use was greater in both LED and cannabisusers, but the abnormalresults of the Trail-MakingTestpersistedafterastatisticaladjustmentfor alcoholconsumptionwas made.The authorswereunclearasto the significanceof the relatively low Trail-MakingTest performanceandthought that lack of pre-druguse testing could not rule out the existenceof thisfinding as a "premorbid" characteristic.

Cohenand Edwards38 compared30 LED-usingnonpatient volunteers equal numbers of men andwomen to 30 age-. sex-, education-,IQ-, and socioeconomic status-matchedcontrols. Members of theLSD group had taken illicit LED in uncontrolledsettingsat least 50 times, and had used very largequantitiesof other illicit drugs as well. Glue-snifferswere excluded,and individuals were askedto refrainfrom taking drugs for 48 hours before testing. Thedrug-takinggroup was found to performsignificantlyworseon Trail-Making Test A andthe visual spatialorientation testof the Haistead-ReitanBattery.Bothgroupsperformedequally well on all other subtests,andon the RavenProgressiveMatrices. Therewas nopre-druguse data, nor could the effect of LED per se

588 STRAS S MAN

be specified,particularly with the quantitiesof otherdrugsabused.

McGlothin et al. 114 studiedi43 individuals withan averageage of 40. All were white, two thirds weremale,andall butonehada collegeeducation.TenhadreceivedLED as psychotherapysubjects ar1d six asexperimentalsubjects.Averagenumber of doseswas20, and 13 hadusedLED outsideof a medicalsetting.Combined number of exDosures in medical andnonneicalsettingswas 5. Most hadnot takenLEDfor i yearbeforetesting.A control group,matchedforage, sex, education, psychotherapy,occupation,anduse of marijuana,wasalso studied.A large numberoftests were administered,including the Trail-MakingA Test and the Spatial-OrientationTest, these twotestshavingdemonstratedperformanceabnormalitiesby LED uses in Cohen and Edwards’ study. Thisgroup found only one subtestto be performed in astatistically significant poorer mannerby the LEDgroup, and this test Haistead’sCategoryTest wasstill performedwithin the normal range.No correlation wasshownbetweendegreeof LED useandscoreson this subtest.In spiteof this being a generallymuch-better-designedprotocol,it still lacksthe crucial factorof pre-druguse testing.

Wright and Hogan 170 studied a group of 20frequentLED users five women and 15 men with ameanageof 20 anda meandurationof LSD use of 12months.The averagenumberof LED experienceswas30. Approximately1 monthwasthe averagetimefromlast using LSD. Twenty age-, sex-, education-,andintelligence-matchednon-druguserswereusedas controls. The Halstead-ReitanNeuropsychologicalTestBatteryandthe Halstead-WepmanAphasiaTestwereadministeredto both groups. No significant differencesbetweengroupscould be found.Hereagain,predrugusetesting,andcontrol for otherdrugandalcoholusewere notperformed.

An unusualchronic adversereaction was recentlydescribedby Abraham 1. Forty-six patientswith ahistory of LED use average number of experienceswas 88 with an averagedurationof 2 yearssince lastuse,were studiedin an experimentof color discrimination. A control group of 31 patients,with unspecified criteria for matching,werealso studied.The LEDuserswere further divided into thosewith flashbacksseebelow 25 percentandthosewithout flashbacks.No differencewasfoundbetweenthe two LSD groups,but the controls scoredsignificantly better than theLED groups.Oncemore, however,thesefindingsmustbe interpretedwith someskepticism,asotherdruguseand pre-drugusetestingwere not included.

There are surprisingly few case studies of thechronic, undifferentiated, ego-syntonic psychoticstate,graduallyresultingfrom hundredsof psychedelic

drugexperiencesduringdifficult maturationalperiodsin thepatients’lives 59, 60. Theseindividuals closelyresemblechronicundifferentiatedschizophrenicsandare quite disabledandtreatmentresistant.They anoften referredto as "burnt out." Very little is knownabout predisposingfeatures.family history, motivations for use.etc., for these individuals.

In summary,it appearsthat nonpsychoticindividuals who have taken LED a large number of timesappearto nave particular personality characteristicsthat may or may not havepredatedtheir use of LED116. They may be describedin terms of being some.what odd, noncompetitive,andeccentric,but are notgrossly impaired. The critical questionthat remainsis whethertheseparticularcharacteristicsbelongto agroupof individuals who seekout, and are reaffirmedin their beliefs by, altered states of consciousness,includingpsychedelic-drug-inducedones,or if the experiencesthemselvesare etiological. Evidenceappearsto point toward the former explanation.

The questionof long term organic impairmenthasbeemcomplicatedby poorly controlled studies,However, the most carefully performedstudiesto date donot lend evidenceto support the contentionthat frequent LED use is associatedwith permanentbraindamage.

Flashbacks. These are intermittent phenomenawhich may last for some time after psychedelicdruguse up to years andare one of the most intriguingforms of "chronic" psychedelicdrug-inducedalteredstatesof consciousness.They maybe definedas transient. spontaneousrecurrencesof thepsychedelicdrugeffect appearingafter a period of normalcyfollowing apsychedelicdrug experience168. Schick and Smith140 havedivided theseinto a "perceptual,"b "somatic," andc "emotional," dependingupon the predominantaspectsof the experience.

The reportedincidenceof flashbacksvariesfrom 15to 77 per cent 21, 79, 113, 140, 148, 163 in thosesubjectswho havehad at leastone psychedelicexperience. Subjectswill often not report thesephenomena, however,either becauseof their acceptanceofflashbacksas part andparcel of the psychedelicdrugsubculture’sexpectations,and/or becauseof the generalpositive connotationtheseexperienceshave, i.e.,they are sometimesreferredto as a "free trip." As wasdescribedin the preface to AdverseReactions,usingthe term "adverse" when discussingflashbacks canalso be fraughtwith interpretive difficulties.

The etiology of flashbacksis a topic of debateat thepresenttime. Various theories have been proposedand may not necessarilybe mutually exclusive, dependingon the subjectpopulation.

Although predisposingfactors in the developmentof flashbackshavenot beenas well documentedas for

ADVERSE REACTIONS TO PSYCI-IEDELICS 589

the more severe psychopathological reactions de

scribedabove,it doesappearthat a greaternumberofpsychedelicdrug experiencesin subjectsmay increase

the likelihood of flashback developmente.g., 124.

There is some sensethat perhapsthosewith adverseacute or chronic reactions may be more likely todevelopand/orreport suchphenomena79.

Matefy and co-workers108, 109, 111, 112 have

shown that "flashbackers"show no significant psy

chopathological differences as measured by theMMPI, or attentionalprocessesas measuredby the

EmbeddedFigures Test, as comparedto "non-flash-

backing" drug users. Flashbackershave also beenshown to score higher on a hypnotic suggestibilityscalethan nonflashbapkingdrug users.This researchgroup flavors a "role-playing" model of flashbacks,wherebythe phenomenonis describedas a reactionlearnedduring a stateof high arousalresulting fromdrug use. Therefore, under other nonspecific higharousalstates,a "psychedeliceffect" is againexperiencedby meansof consciousor unconsciousassociation.

Other groups 72, 73, 124 believe that flashbacksare a result of situationally inducedexacerbationsofpervasivepersonality characteristics.These characteristics would lead toward the experiencingof flashbacks in circumstancesthat tend to induce alteredstatesof awareness,e.g., decreasedsensoryinput, fatigue, fever 142, extreme relaxation 110, stress,marijuanause 49, 149, andemergenceinto a darkenvironment4.

Psychodynamicformulations 81, 134 considerflashbacksto be comparableto conversionreactions/traumaticneuroseswhere defensivefunctions of theego are incapableof completely repressingmemories/conflicts that were stimulated/exacerbatedby the intensepsychedelicdrug-inducedeffects. Symptomaticexpressionsflashbacksare the result.

Rosenthal 132, in one of the earliest reports offlashbackphenomena,proposeda physiological,neurochemicalbasis of flashbacks,which hasbeen elaboratedupon by Abraham 4, who hypothesizesthatLSD’s effect on visual pathwaysroutedthrough thelateral geniculatenucleuscould result in "visual seiSExes."

LSD as a Model of Schizophrenia

One of the major differential diagnostic questionsconfronting the clinician in the case of psychedelic-relatedpsychosesis that of schizophrenia.In the earlyyears of psychedelicdrug research,there was hopethat a psychedelicdrug-inducedaltered stateof consciousnesscouldprovidea "modelpsychosis,"wherebytheoreticalandclinical tools could be brought to bearon an easily inducible, reproducible,and reversible

stateresemblingschizophrenia27. Severalexcellentreviews of this subjecthaveappeared,beginningwithHolliter’s in 1962 78. Subsequentstudies71, 91,96, 104, 171 using a variety of approacheshave allconfirmedthat thereare significant major differencesbetweenthesetwo syndromes,especiallyin comparingpsychedelicdrug-inducedstateswith the chronicformof schizophrenia.There appearsto be a greatersimilarity betweenLED-inducedstatesand acuteschizophrenia,but careful observationcan still usually distinguisb thesetwo states.

Affectively, LSD statesshow lessflattening of moodthan schizophrenia. Visual perceptual alteration.shallucinations, illusions generally predominateinLED states comparedto schizophrenia,where auditory perceptual changes hold sway. LSD-inducedstatestend to show less well fixed delusionalsymptoms than schizophrenia,most likely due to the acknowledgmentof the drug-inducednature of theirexperience.

Historically, theknowledgethatapatienthastakena psychedelicdrug is of obviousvalue in clinical diagrosis. Also, the absenceor uresenceof a familyhistory of schizophreniais helpful, as is premorbidhistory, in arriving at a quick working differentialdiagnosis,viz., the etiology of a particular psychoticepisode.

Treatment andCourse

Treatmentof acutepanic reactions should be directed toward allaying the patient’s overwhelminganxiety. A quiet, comfortable room with a minimumof distractionsshould be available, and the patientshouldnotbe left alone. Most of theseindividualscanbe "talked down" by calmly discussingtheir fears andfantasies,orientingthe patientas necessary,reinforcing the conceptthat the experienceis drug inducedandtimelimited, andthatno permanentbraindamagehasbeensuffered.

For moresevereagitation,minor tranquilizerssuchasdiazepamshouldbe used,in oral or parenteralformchlordiazepoxideis preferablefor intramuscularuse,asits absorotionby this route is moreconsistentthanfor diazepam.Usual dosesrangefrom 15 to 30 mg fordiazepam50 to 100mgfor chiorthazeporiderepeatedevery hour or two as necessaryto calm or sedatethepatient154, 164. -

Major tranquilizersshouldbe reservedfor only themostdisturbedandagitatedpatients.Chlorpromazinewas initially believedto be a specific LSD antagonist5, butparadoxicalreactions138 andthe problemsof hypotensiveand anticholinergiccriseswhen usedwith 2,5-dimethoxy-4-methylamphetaniine"STP"and PC? 101, 143, 144 would point toward using

590 - ST}LASSMAN

haloperidol 5 to 10 mg intramuscularly,or 10 to 20mg by mouth, a high potency antipsychoticwithminimal anticholinergiceffects, every hour, asnecessary. Antiparkinsoniandrugs e.g, benztropineor tnherphenidyl should be available for use in the caseof acuteextrapyramidalside effects from halopenidol.

Restraint and/or gastric lavage are generallyavoided in a frightened, hallucinating patient, althoughwherethereis a concernthat the patientmayhurt himself or herself,or others,or whereother morepotertiaiy life-threatenrngdrusshavebeeningested,theseproceduresmight be necessary.

Hospitali2ationis usuallynot necessary,but shouldbe available. Once the acute reaction has subsidedusuallywithin 12 to 24 hours, the patient shouldbesent home with someoneresponsiblefor monitoringhim or her for the next 12 to 24 hours. A follow-upappointmentshouldbe arrangedin order to evaluatethe need for further therapy 68. The prognosisisgenerallygood for uncomplicatedpanicreactions,andmany drug userswill curtail the use of thesedrugssubsequentlyon their own.

The treatmentof the "LSD psychoses,"as the previous discussionof thesestateswould imply, will varywith the salient symptomatology14. Tricychc anti-depressants,monoamineoxidase MAO inhibitors,major tranquilizers,lithium carbonate80, ECT 44,53, 119, vitamin B5 75, andthe serotoninprecursor,L-5-hydroxytryptophan2 have all beenused, withvarying ratesof success.A period of drug.free observation for at least severaldays if possible,using onlyminor tranquilizersas necessary,and then treatingthe resultingclinical picture a it comesmore clearlyinto focus, would seem the most prudent meansofclinical management.

Treatmentof flashbacksshouldbe temperedby thefactthat they are usually self-limited anddiminish induration, intensity, and frequency with time. Theindividual often respondsto assuranceandeducationabout the phenomena,but if extremelypanicky, thetreatnientshouldbe similar to that of the acutepanicreactions.Minor tranquilizers may be used acutely,and on a judicious, time-limited, "as needed"basis.Behaviormodification 107, ECT 44, diphenylhydantoin 156, psychotherapy184, and other pharmacotherapeutic strategies, including haloperidolwhich may transiently increase visual flashbacks[1l8J andbenzodiazepines4 haveall beenused,alsowith varying ratesof success.

Patientsshouldbe advisedthat their flashbackswillmost likely increaseif psychedelic drugs are usedagain,as may also be the casewith stimulantsand/ormarijuana. Persistently troublesome or increasingflashbacks indicate the need for a more thoroughpsychiatricand/orneurologicwork-up. The prognosis

for flashbacks,if the patientrefrains from furtheruseof mind-alteringdrugs, is generallygood.

SummaryandConclusions

The mid-l950s to mid-1960sshowed a greatburstof enthusiasmfor the therapeutic,growth-enhancingand heuristic valueof LSD-25 and other psychede0drugs. However, the increasingly reportedand occasionaily lethal adverse reactic-ns to these drugs inunsupervisedsettingsmadesubsequentobtainingandusingpsychedelicsin human subjectsquite difficult.Their blackmarketuse,on the otherhand,continuedto flourish,, andit is unfortunatethat theonly currentdataon the use of psychedelicsare being generatedbystreet-drug-using"LSD casualties"outsideof majorpsychiatricresearchcenters.

Adversereactionsto this classof psychoactivedrugscan be conceptualizedas occurringalong a temporalcontinuumwith acutepanic reactionsthat often resolve spontaneouslywithin a day, andchronic undifferentiatedpsychotic,treatment-resistantcases,atthetwo ends of the spectrum. In between exist "LEDpsychoses,"lasting longer than 1 to 2 days after theingestion of a psychedelic compound, and "flashbacks," transientrecurrencesof some aspectsof theoriginal LSD experienceafter an intervening periodof normality.

The researchon adversereactionsto psychedelicdrugs is fraught with methodological difficulties.Many of thesehavebeenaddressedin this paper,andsuggestionsfor datato be includedin an "ideal" studyhavebeengiven.

With the available data, it appearsthat the incidenceof adversereactionsto psychedelicdrugsis low,when individuals both normal volunteers and patients are carefully screenedand prepared,supervised, and followed up, and given judicious doses ofpharmaceuticalquality drug. The few prospectivestudiesnoting adversereactionshave fairly consistently described characteristicspredicting poor responseto these drugs. The majority of studies ofadversereactions,retrospectivein nature, have describeda constellationof premorbidcharacteristicsinindividuals seeking treatment for these reactionswhere thugsof unknown purity were taken in unsupervisedsettings.

The relationshipbetweendrug-inducedmental illnessand mental illness accompaniedby psychedelicdrug use has been discussed.The majority of studieshave focused primarily on "schizophrenia-like" i-IFnessesand seem to indicate a fairly similar clinicalpicture and coursefor both schizophrenicswho haveor have not usedpsychedelicdrugs. A possiblerela

ADVERSE REACTIONS TO PSYCHEDELICS 591

tionship betweenaffective disorders and LSD psy

choseshas beenraised..The "long term effects" of LED use have been

studiedin a variety of settingsand populations.Objective datain normalvolunteersdo not appearto tap

the subjective senseof subjects’ changed internalworlds, although individuals who appearto use LSDregularly as a tool for consciousnessalteration havebeen found to show a characteristicpersonality and

coping style. Long term psychiatric sequelaein patientshavebeenstudiedin surprisinglyfew largecaseload reports, with a very tentativeconclusionbeing

that chronic, heavy LSD use appearsto produce anunusually ego-syntonic disorder, in fringe-elementtype individuals,which is quite resistantto treatment.

Comprehensiveand well controlledstudiesof neuropsychologicalfunction havegenerally failed to discern significant differencesbetweengroups of LEDusersandcontrols.

Studiesof flashbackshavealso focusedon the description of subject characteristicswho experiencetheseusually short-lived, delayed, intermittent phenomena, and have generally found an incidence ofabout 50 per cent. Populations experiencing theseevents havebeen found to be of varying degreesofpsychopathologyandassociateddrug use,thusengendering quite different causal explanationsfor theiroccurrence.

Etiologies of adversereactionsto psychedelicdrugshavebeenproposed,from psychodynamic,behavioral,andbiological perspectives.The systemsapproachtounderstandingthese disorders has also been introduced.

Suggestionsfor Further Research

The human neurobiology of psychedelicdrugs isstill poorly understood.Severalof the recently described biological markers for the major functionaldisorders,e.g.,plateletMAO activity in schizophrenia,and abnormalcortisol suppressionin responseto exogenoussteroidsin depression,might possiblybeusedto analyze more carefully the effect of psychedelicdrugson relevantbiological parameters.Newly refinedmeansof computer-assistedpowerbandandspectralanaiysesof EBOs and evokedpotentials, and theeffects of psychedelicson these, may also provideadditional insights into the mechanismof action andeffect of these thugs. A particularly exciting development in neurobiologicalresearchis that of positronemissiontomographyPET scanning,wherebyradioactively labeledpharmaceuticalagentscan be shownto bond to specific brain sites in vivo. Labeling psychedelic compounds in this mannercould possiblyhelp elucidate localization of their effects, as could

studyingthe effect of LED on regionalmetabolismofothercompoundse.g.,dopamineor serotonin.

From a clinical perspective,it appearsthat certainindividuals should probably be excluded from psychedelic drug researchparticipation in the future-theseare thosewith eitherovert, or a history of, severemental illness, unlessthey were institutionalizedatthe time of drug exposureand could be followed in acarefully supervisedsetting for at least 1 to 2 *eeksafterthe drug experience,or after any acutesequelaeresolved. Individuals with poor object relations e.g.,unemployment,uninvolved with a significant other,or showing"downward drift" or thosewith primarydefensive mechanismsincluding projection, denial,and tendency toward psychotic thought disorders,should also be included in drug studiesonly with theutmost caution and close follow-up. Individuals whoare currently well functioning but havea family history of mentalillness, especiallyschizophrenia,shouldbe enlistedwith extra caution, andperhapsscreenedwith some of.the more currentbiological markerstotest for presenceof "trait" abnormalities.

There are several psychologicalareasthat call forexpandedinvestigation. One is a further elucidationof thephenomenologyof the psychedelicstate,particularly with regardto someother, recentlywell studiedalteredstatesof consciousness,e.g., the so-calledneardeathexperience,andstatesof religious exaltation.inmy own observationsof studentsof meditativedisciplines in various settings,I haveoften struck upon athemethat runs through the motivation of many ofthesestudents;that is, psychedelicdrugsled them todiscoverthe existenceof these"sublime" states,butweretoo unpredictableandtoxic for regularuse.Preparation for the developmentof the gradualunfoldingof various statesof consciousnesswas a much appreciated elementof these individuals’ involvement inmeditative disciplines. Grof 65 has attemptedtodrawtogetherthesedisparatephenomenain a cohesive framework. Much more work is needed,and atopographicalmapof consciousnesscould begin to bedrawnup. Buddhistpsychologicalworks haverecentlybeenpublished 30 and have been shown to haveheuristic valuein describingvarious levels of alteredstatesof consciousness62, 150. Their relevancetothe studiesof psychedelicstatesremainsuninvestigated,althoughHofmann,the discovererof LSD, hassuggestedthatpsychedelics’usebe returnedto thatofa "sacred"drug,useful in supplementingmeditationalpracticesfor the attainmentof religious insights 77.

Another clinical usefor psychedelicsis in terms oftherapeuticvalues.Who canbenefitfrom psychedelic-assistedpsychotherapy?How best to utilize theseagents?What agents are most useful with whatgroups? For example, some early work seemedto

592 STRASSMAN

indicate a particularly positive therapeuticresponseto LED in sociopaths47, 136, a traditionally verytreatment-resistantgroup. Intriguing are the reportsof helpingthe dying with the aid of psychedelicdrugs66, 67.

The developmentof agentswith specific characteristics, in termsof durationof action,side effects,withspecific perceptual, cognitive, or emotional effectscouldbepursued,usingcarefullypreparedandtrainedindividtais i5:3 in order to match more carefullydruewith specific therapeuticrequirements.

With thesevererestrictionsplacedon researchwithpsychedelicsin the 1960s, investigative work withpsychedelicdrugshasgroundto ahalt. It appearsthat,with proper restrictions and safeguards,it might betime to carefully begin this work again. The questionof reinstituting psychedelic research in humans isbound to arouse powerful argumentsboth for andagainst.My feeling is that a decadeof inactivity inthis areaof researchhas given usthe necessarytimeto reflect on what has beenlearned and what needsfurther investigation. The relative roles of set andsetting,motivations for druguse,personalandfamilyhistory of mental illness, defensivestyle, and level ofobject relatedness,should all be used in carefulselection, screening,and preparationof subjectsfor psychedelic research.It appearsthat, if thesefactors arecarefully controlled, the incidenceof acuteand morelong term problemsassociatedwith their use can bekept to a minimum. The benefitsthat canbe obtainedin terms of an increasedknowledge of psychedelicdrug-inducedalteredmentalstates,andtheir potentialtherapeuticroles,seemsto justify theserisks.

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