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Hallucinogenic Drugs in Psychiatric Research and Treatment:
Perspectives and Prospects
Rick J. Strassman, M.D.
The Journal of Nervous and Mental Disease, Vol. 183, No. 3, pp. 127-138.
©1995 Williams & Wilkins
Clinical research with hallucinogens has resumed after a generation's
hiatus. To place these new studies in context, this article reviews
the history of hallucinogens' use and abuse, discusses their pharmacological
properties, and highlights previous human studies. Research with
Iysergic acid diethylamide and related hallucinogens with thousands
of patients and control subjects was associated with acceptable
safety when subjects were carefully screened, supervised, and
followed up. Data were generated regarding hallucinogens' psychopharmacology,
overlap with endogenous psychoses, and psychotherapeutic efficacy.
Current American and European studies emphasize systematic psychopharmacology,
in addition to psychotherapy protocols. Human hallucinogen research
will help define unique mind-brain interfaces, and provide mechanistic
hypotheses and treatment options for psychiatric disorders. It
is critical that human hallucinogen research in the l990s make
use of state of the art methodologies, or consensually define
when modifications are required. Training and supervisory issues
also must be explicitly addressed.
Hallucinogenic substances found in fungi, plants, and animals
have been used on all continents, and in a wide variety of cultures,
both highly advanced and preliterate (Dobkin de Rios, 1984). Mescaline,
from the peyote cactus, has been used in clinical research protocols
from the 1890s to the present (Mitchell, 1896). The thousand-times
more potent effects of LSD-25 were discovered in 1943 by Albert
Hofmann, 5 years after its synthesis (Stoll, 1947). The beginning
of modern "biological psychiatry" can be said to have
started as much with the appreciation of LSD's "psychotogenic"
effects as the contemporaneous discovery of the one-thousandth
as potent "antipsychotic" effects of chlorpromazine.
The study of hallucinogenic drugs in humans was, and remains,
important for several reasons. First, they elicit a multifaceted
clinical syndrome, affecting many of the functions that characterize
the human mind, including affect, cognition, volition, interoception,
and perception. Characterizing hallucinogens' properties will
enhance understanding of important mind-brain relationships, particularly
relevant in this, the Decade of the Brain. Second, naturally occurring
psychotic syndromes share features with those elicited by these
drugs. Understanding effects and mechanisms of action of hallucinogens
may provide novel insights and treatments into endogenous psychoses.
Third, increasing use and abuse of hallucinogens over the last
several years, particularly LSD, by young adults may produce a
similar spate of adverse psychiatric sequelae seen with the first
wave of their illicit use in the 1960s. Treatment of these adverse
effects consume scarce public resources and safe, selective, and
efficacious treatments of acute and chronic negative effects of
these drugs are needed. Finally, the enhancement of the psychotherapeutic
process, sometimes in treatment refractory patients, reported
by early studies, has relevance to current emphasis on time-limited
psychotherapeutic interventions.
Nomenclature
Many terms have been used to describe the effects of these drugs,
including psychedelic (mind manifesting), psychodysleptic (disturbing
the mind), phantasticant, psychotogen, oneirogen (producing dreams),
entheogen (generating religious experience), phanerothyme (making
feelings visible), psychotomimetic, and schizotoxin (Grinspoon
and Bakalar, 1979; Stafford, 1992). Psychedelic represents the
nonmedical, recreational, and illicit use of these drugs, while
hallucinogen refers to these compounds within a medical-legal
context.
The "classical" hallucinogens belong to several chemical
families: phenethylamines (e.g., mescaline), indolealklyamines
(e.g., psilocybin and N,N-dimethyltryptamine [DMT]), and
lysergamides (e.g., LSD and morning glory seeds) (Nichols
et al., 1991). 3,4-Methylene-dioxymethamphetamine (MDMA) ("X,"
"XTC") is a methoxylated amphetamine (phenethylamine),
and produces effects that overlap those of classical compounds
(Lister et al., 1992). Low doses of the dissociative anesthetics,
phencyclidine and ketamine (Siegel, 1978), and antimuscarinic
agents (Ketchum et al., 1973) also share subjective properties
with the hallucinogens. However, hallucinogens do not produce
anesthesia at high doses, as do the former compounds, nor is there
a clouding of consciousness at "psychedelic" doses,
as with the latter.
A clinically useful manner of representing hallucinogens refers
to their temporal properties: onset, peak effect, and duration
of action. An "ultra-short-acting" drug's onset is less
than 1 minute, peak effects occur within 5 minutes, and duration
is 30 minutes or less. Intravenous DMT is an example (Strassman
et al., 1994). A "short-acting" hallucinogen's onset
is between 5 and 15 minutes, peak effects are within 15 to 60
minutes, and duration is 1 to 2 hours (e.g., intramuscular
N,N-diethyltryptamine; Faillace et al., 1967). "Intermediate-acting"
hallucinogens include the orally active tryptamine psilocybin
(Rinkel et al., 1960). Onset is within 15 to 30 minutes, peak
effects are at 1 to 3 hours, with duration up to 6 hours. "Long-acting"
hallucinogens include oral LSD and mescaline (Hoch et al., 1952),
with onset at 30 to 90 minutes, peak effects at 3 to 5 hours,
and duration of 8 to 12 hours. "Ultra-long-acting" compounds
include the poorly characterized African plant drug ibogaine (Fernandez,
1982). Duration of action may last 18 to 24 hours.
Prevalence of Use
Hallucinogen use in the United States remained relatively constant
from the late 1960s to the late 1980s (Pope et al., 1990). However,
data from the National Institute on Drug Abuse (NIDA) show an
increase in any LSD use by high school seniors "within the
last 12 months" from 4.8% to 5.6% from 1988 to 1992. While
the magnitude of this rise is slight, it stands in contrast to
the abuse of other drugs. For example, the proportion of seniors
who had used any cocaine dropped from 7.9% to 3.1% during the
same period (Johnston et al., 1993). Thus, the proportion of respondents
who reported any use of LSD was almost twice as high as the proportion
reporting any cocaine use by high school seniors in 1992. The
1990 NIDA statistics reveal that lifetime prevalence rates for
hallucinogens were about the same as those for cocaine, and 7
to 8 times higher than for heroin. LSD ranked first in the categories
of "most intense" and "longest" high among
respondents. Between 13 and 17 million individuals in this country
have used a hallucinogen at least once (NIDA, 1991).
Legal Status
Hallucinogens reside in Schedule I of the Controlled Substances
Act of 1970, which is reserved for drugs with "high abuse
potential," "lack of established safety even under medical
supervision," and "no known use in medical treatment"
(Anonymous, 1970). Compounds with "substantially similar"
structure or function also are Schedule I drugs, as a result of
the passage of the Controlled Substances Analog Bill of 1986 (Anonymous,
1986).
The use of mescaline-containing peyote by the Native American
Church has been debated for nearly a century (La Barre, 1989).
Native American Church members may possess and ingest peyote in
several states, and non-Native Americans may use it in Church
ceremonies in some. In response to increasing judicial restrictions
on peyote use, the Religious Freedom Restoration Act became law
in 1993 (Anonymous, 1993). Interpretation of this law with respect
to hallucinogenic "sacraments" by traditional non-Western
(Rivier and Lindgren, 1972) and other "neo-religious"
groups will be of interest.
Basic Neuropharmacology
The nearly simultaneous discoveries of serotonin (5HT) and LSD
undoubtedly have had an impact on the preeminent role of this
neurotransmitter in explicating hallucinogens' effects and mechanisms
of action. Noradrenergic (Horita and Hamilton, 1969), dopaminergic
(Ahn and Makman, 1979), and cholinergic (Cervoni et al., 1963)
systems have also been investigated, but have received less attention.
Gaddum and Hameed (1954) and Woolley and Shaw (1954) first suggested
that LSD antagonized the effects of 5-HT in lower animals. Soon
thereafter, Freedman (1961) showed that LSD decreased particulate
binding of 5-HT in the axon, raising brain levels of 5-HT and
lowering those of its metabolite 5-hydroxyindoleacetic acid. 5-HT
mechanisms have been demonstrated for electrophysiological (Aghajanian
et al., 1968), pharmacological (Conn and Sanders-Bush, 1986),
and behavioral (Glennon et al., 1985) effects of hallucinogens.
The animal model of "hallucinogenesis" most used is
drug discrimination, wherein animals are trained to distinguish
between a hallucinogen, usually LSD, and saline. Animal responses
to a test drug as if it were LSD suggest that the "interoceptive"
or "discriminative" cue is similar to LSD's (Glennon
et al., 1983). However, several nonhallucinogens are LSD-like
in this model, such as quipazine (Cunningham and Appel, 1987)
and lisuride (Nielson, 1985), while psilocybin is not (Koerner
and Appel, 1983), which emphasizes the need for human studies.
Hallucinogens were important in stimulating the burgeoning field
of 5-HT receptor subtypes (Peroutka and Snyder, 1979). Current
data emphasize effects upon the 5-HTlA and 5-HT2A,C subtypes (Glennon
et al., 1985; Spencer et al., 1987), alone or in combination (Arnt
and Hyttel, 1989).
Tolerance (Freedman et al., 1958) and cross-tolerance (Appel and
Freedman, 1968) to behavioral effects of hallucinogens is seen
rapidly, and is accompanied by downregulation of 5-HT2 sites (McKenna
et al., 1989).
Human Psychopharmacology
Measurement of Hallucinogen Effects in Humans
Initial human studies with hallucinogens relied upon careful clinical
observation, using psychoanalytic (Savage, 1952) or behavioral
(Cheek and Holstein, 1971) perspectives, in normal subjects (Snyder
et al., 1967) and psychiatric patients (Hoch et al., 1952). In
addition, hallucinogen effects on previously validated psychological
scales, such as the MMPI (Belleville, 1956), assessed change scores
within individuals and allowed comparisons between hallucinogen-induced
syndromes in normal subjects with other well-characterized psychopathological
states.
Three rating scales were developed specifically for LSD effects
in the 1960s. "Normative" data for all three scales
were generated from effects in unexperienced hallucinogen users
who were not told what the effects of LSD might be, making the
data difficult to interpret, particularly when an attempt is made
to determine their reinforcing properties in those who use them
recreationally.
The Abramson et al. (1955) scale emphasized somatic, cognitive,
and perceptual effects of LSD, while the Linton-Langs scale (Linton
and Langs, 1962) assessed effects predicated on a psychoanalytic
theory of consciousness. The Addiction Research Center Inventory
(Haertzen et al.,1963), the standard rating scale for assessing
effects of drugs of abuse, used LSD as one of several mind-altering
compounds. Its LSD scale is known as the dysphoria scale, reflecting
its emphasis on unpleasant effects (Haertzen and Hickey, 1987).
We have developed a new instrument, the Hallucinogen Rating Scale
(HRS), that differs from these previous scales. It was drafted
by interviewing experienced hallucinogen users, and modified during
pilot studies with DMT in an additional cohort of well-prepared,
educated, well-functioning, experienced hallucinogen users (Strassman
et al., 1994).
The HRS also differs from other rating scales in its emphasis
on a "mental status examination" clustering of items.
In the Abramson et al. scale, derivative factors, such as paranoid
ideation and generalized inhibitory effects, are used. The Linton-Langs
scale also uses this manner of grouping items: feeling less inhibited
and suspiciousness are examples. In the Addiction Research Center
Inventory, similarities or differences between a test drug and
"reference" drugs are made, without determining the
nature of these similarities or differences. In the HRS, items
are grouped into six "clinical clusters": somaesthesia
(somatic/interoceptive/visceral cues), affect, perception, cognition
(thought content and processes), volition (willful ability to
interact with one's mental and physical self and the environment),
and intensity (a global measure of robustness of response). These
clinical clusters provided better resolution of subtle dose effects
for DMT than multiple biological measurements in initial dose-response
studies. Principal components factor analysis, choosing six factors
to correspond to the clinical clusters, also proved superior to
biological variables in differentiating among DMT doses, but generated
a less heuristically useful grouping of individual items (Strassman
et al., 1994).
Route of Administration
Whether LSD and longer-acting compounds produce their effects
directly, or require secondary, "downstream" mechanisms,
has been debated, because of the delay in onset of effects of
LSD even with intravenous administration (Aghajanian and Bing,
1964). However, Hoch (1956) described nearly instantaneous onset
of LSD effects with intraspinal administration, and intravenous
DMT effects also are immediate (Strassman et al., 1994). Thus,
access of drug to relevant brain sites, lipid solubility, clearance,
and other pharmacokinetic factors determine the time course of
drug effects, rather than secondary processes. However, there
may be systems downstream from 5-HT receptor agonism that require
extremely short time domains for activation.
Tolerance
LSD and other classical compounds elicit behavioral tolerance
(Isbell et al., 1956) and cross-tolerance (Abramson et al., 1960a)
after several daily doses. The exception is DMT, for which no
behavioral tolerance has been demonstrated (Gillin et al., 1976),
and which elicits a fully hallucinogenic response in LSD-tolerant
subjects (Rosenberg et al., 1964).
Human Hallucinogen-Neurotransmitter Interactions
Serotonin. Bromo-LSD, a potent 5-HT antagonist in lower
animals (Cerletti and Doepfner, 1958), although psychoactive in
humans at much higher doses than LSD (Isbell et al., 1959b), antagonized
LSD effects in both normal subjects (Ginzel and Mayer-Gross, 1956)
and psychiatric patients (Turner et al., 1959). Cyproheptadine,
a 5-HT2A c antagonist (Hoyer and Schoeffter, 1991), prevented
the subjective effects of DMT in two of three normal volunteers
(Meltzer et al., 1982). 5-Hydroxytryptophan loading studies attempted
to surmount the 5-HT antagonism of LSD in humans, but did not
demonstrate clinically relevant effects (Pare and LaBrosse, 1963).
Chronic monoamine oxidase inhibition reduced LSD's effects in
humans (Resnick et al., 1964), perhaps relating to downregulation
of 5-HT sites. MAO inhibition also reduced DMT effects (Sai-Halasz,
1963). This latter phenomenon may relate to inhibition of DMT
metabolism (Sitaram et al., 1987). Reserpine, if administered
at adequate dosage and duration, enhanced responses to LSD in
humans (Isbell and Logan, 1957; Resnick et al., 1965), supporting
a functional "upregulation" of relevant mechanisms.
Both meta-chlorophenylpiperazine (Kahn and Wetzler, 1991) and
6-chloro-2-(1-piperzinyl)pyrazine (MK-212) (Murphy et al., 1991)
share pharmacological characteristics with the classical hallucinogens,
and elicit "hallucinogenic" effects in patients with
schizophrenia (Krystal et al., 1993) or alcoholism (Lee and Meltzer,
1991), but not in normal subjects (Murphy et al., 1991). Higher
doses in normal subjects may produce more typical responses.
Dopamine. LSD has agonist effects at postsynaptic receptors
(Burt et al., 1976), and DMT has dopamine-releasing properties
(Haubrich and Wang, 1977). While chlorpromazine was suggested
to be a "specific antidote" to LSD effects (Isbell and
Logan, 1957), it may enhance LSD's effects if given during the
acute intoxication (Abramson et al., 1960b; Schwartz, 1967). Similarly,
haloperidol pretreatment enhanced the neuroendocrine and subjective
effects of DMT in one subject (Meltzer et al., 1982). In addition,
methamphetamine (a dopamine agonist) ameliorated acute LSD effects
(Hoch, 1956). Thus, affinities of hallucinogens for dopamine receptors,
relative to primarily dopaminergic or antidopaminergic compounds,
may determine the end result of manipulating dopaminergic neurotransmission
on responses to hallucinogens. Other. Little data exist regarding
manipulating cholinergic (Isbell et al., 1959a) and adrenergic
(Murphree, 1962) systems on hallucinogen effects in humans, and
require further study.
Hallucinogens and Schizophrenia
The association between ingestion of hallucinogens and onset of
acute schizophrenic episodes is discussed below (see Adverse
Effects). One of the initial indications for LSD in clinical
research was for elicitation of a time-limited "psychotomimetic"
syndrome. However, the degree of overlap has been vigorously debated
(Hollister, 1962; Langs and Barr, 1968; Vardy and Kay, 1983; Young,
1974). The criticism that visual effects were relatively uncommon
in functional psychoses has been tempered by the high incidence
of these symptoms in later studies (Bracha et al., 1989). It appears
that acutely ill, positive-symptom patients show more "psychedelic"
symptoms than do chronic, undifferentiated, negative-symptom predominating
patients, particularly in the prodromal state (Bowers and Freedman,
1966).
Hallucinogens also were administered to psychotic patients and
comparisons were made between drug effects and preexisting symptoms
(Cholden et al., 1955). These studies were limited by the highly
anecdotal nature of ratings of "subjective" effects.
Some studies reported that hallucinogens produced different symptoms
than those patients were normally experiencing (Fink et al., 1966;
Turner et al., 1959), while others reported an exacerbation of
preexisting psychopathology (Hoch et al., 1952; MacDonald and
Galvin, 1956). A relatively consistent finding was that "burned
out," predominantly negative symptom-laden patients showed
blunted responses to hallucinogens (Boszormenyi and Szara, 1958;
Hoch et al., 1952). This latter finding supports lower levels
of 5-HT2 sites in the cortex of schizophrenics (Mita et al., 1986).
It also prompted a search for "endogenous schizotoxins,"
in which case "tolerance" to naturally occurring psychotomimetics
would confer resistance to exogenously administered agents in
patients.
The short-chained tryptamines, DMT and 5-methoxyDMT, were leading
candidates for endogenous hallucinogens (Corbett et al., 1978;
Franzen and Gross, 1965). Requisite enzymes for DMT biosynthesis
were found in human blood (Wyatt et al., 1973), brain (Saavedra
and Axelrod, 1972), and lung (Axelrod, 1962). Although correlations
were seen between acute symptomatology and DMT excretion in patients
(Murray et al., 1979), interest waned because peripheral DMT levels
were not consistently different between normal and psychotic subjects
(Gillin et al., 1976). However, peripheral levels do not accurately
reflect either concentrations at discrete brain areas, nor differential
sensitivity to comparable levels between normal subjects and patients
with psychoses. Lack of tolerance to its psychological effects,
given either twice daily for 5 days (Gillin et al., 1976) or every
30 minutes four times, strengthens its importance as a putative
schizotoxin.
Psychotherapy Research
Relatively few studies used LSD as a "psychopharmacotherapeutic"
agent in humans, i.e., daily dosing regimes. Daily LSD
elicited robust antidepressant responses in depressives in an
uncontrolled study, while tolerance to its psychedelic effects
developed rapidly (Savage, 1952). These data are consistent with
similar
effects of chronic LSD and antidepressants on 5-HT receptor function
(Buckholtz et al., 1990; Stolz et al., 1983). Beneficial responses
to daily dosing in some autistic children also were seen (Bender,
1966; Freedman et al., 1962; Simmons et al., 1966).
The first suggestion that LSD may hasten psychotherapy was made
in the early 1950s (Busch and Johnson, 1950), and series of cases
soon followed (Eisner and Cohen, 1958). LSD was believed useful
in recovering early memories, enhancing associative processes,
reducing repression, intensifying affective responses, and magnifying
aspects of the transference (Chandler and Hartman,1960; Hollister
et al., 1962; Snyder et al.,1968). These early protocols utilized
relatively low doses (25 to 100 mcg) within the context of ongoing
psychoanalytic psychotherapy. This was termed the psycholytic
approach, and utilized multiple sessions over months or years.
These studies were hampered by lack of adequate control groups
and impartial raters, small sample size, and primarily anecdotal
data. However, their emphasis on repeated sessions merits attention
when assessing results from "psychedelic" research protocols.
This latter approach, described below, may have limited efficacy
by depending inordinately upon one or two highly charged sessions,
without the benefit of "working through" available in
the psycholytic model.
The psychedelic approach, favored by North American researchers,
involved administration of a single, or at most a small number
of, high dose (300 to 1500 mcg) LSD session(s) after a relatively
short course of psychotherapy (Pahnke et al., 1970). This psychotherapy
encouraged the patient to undergo a "psychedelic experience,"
which had many aspects of a religious epiphany. As many "spontaneously
recovered" drug abusers report similar spiritual-mystical
experiences (Ludwig, 1985), this approach was turned to substance
abuse treatment (Hollister et al., 1969; Savage and McCabe, 1973).
Uncontrolled, often anecdotal reports from psychedelic studies
also demonstrated some promise in the treatment of sociopathy
(Shagass and Bittle, 1967), prisoner recidivism (Leary and Metzner,
1967-68), and the pain and despair associated with terminal illness
(Grof et al., 1973; Kast and Collins, 1964).
Substance abuse treatment studies were numerous, and while initial
reports were enthusiastic (Kurland et al., 1967; MacLean et al.,
1961; Smith, 1958), studies using control groups and longer follow-up
demonstrated less impressive results (Cheek et al., 1966; Hollister
et al., 1969; Johnson, 1969). However, a review of 31 studies
involving 1100 alcoholics concluded that meaningful generalizations
could not be reached because of the inconsistent designs and criteria
for improvement (Abuzzahab and Anderson, 1971).
In summary, many of the initial studies suggesting enhancement
of psychotherapy with hallucinogens were hampered by lack of methodological
rigor. However, placebo/control treatments are problematic. For
example, when 50 1lg of LSD were used as "active placebo"
against 450,ug of LSD in an alcoholism treatment study using the
psychedelic model, minimal differences in outcome among groups
were discerned (Kurland et al., 1971). That many of the low-dose
group also underwent a "peak experience" emphasizes
the importance of assessing the interplay between pharmacology,
psychotherapy, and subjective experience. Minimum requirements
for future studies should include independent raters of effects
and outcome, identical (nondrug) treatment in the control group,
and adequate follow-up (at least 1 year) (O'Brien and Jones, 1994).
The choice of inactive and/or active placebo must be given careful
consideration. Finally, a hybrid of the psychedelic and psycholytic
models, in which more frequent high-dose sessions are used, may
provide additional flexibility and allow more psychotherapeutic
work to take place than either model alone.
Adverse Effects
The profoundly altered mental status elicited by hallucinogens
requires astute clinical management, including thorough screening
and preparation of prospective patient or volunteer subjects,
careful supervision of drug sessions, and consistent and responsive
follow-up which may require psychotherapeutic intervention.
Early clinical investigators provided reassuring safety data.
A survey of American clinical research documented in normal volunteers
a rate of attempted suicide of 0/1,000, completed suicide of 0/1,000,
and "psychotic reactions over 48 hours" of.8/1,000.
Corresponding figures in patients were 1.2/1,000,.4/1,000, and
1.8/1,000 (Cohen, 1960). These data were derived from over 5,000
subjects who had received LSD or mescaline more than 25,000 times,
single individuals taking between 1 and 80 doses, using LSD doses
from 25 to 1,500 mcg. A British survey reported comparable results
(Malleson, 1971).
Once hallucinogens escaped from the laboratory, however, emergency
rooms and clinics were quickly impacted by adverse effects in
unprepared, unsupervised, and psychiatrically ill individuals
taking hallucinogens, especially LSD (Frosch, 1969; Ungerleider
et al., 1968). LSD was nearly always of uncertain quality and
dose, and combinations of LSD and other drugs and alcohol were
usual (Frosch et al., 1965).
These adverse consequences may be classified temporally as acute,
subacute, and chronic (Strassman, 1984).
Acute
Acute adverse effects include: a) brief panic reactions to effects
of the drug, which generally responded to verbal reassurance and
protection of the patient, and only in severe instances, to medication
(Taylor et al., 1970); and b) psychotic reactions, disorganized
states that lasted longer than 24 hours and required more intensive
management and often hospitalization. These psychotic reactions
usually were superimposed on preexisting psychotic disorders in
polydrug-abusing patients (Blumenfield and Glickman, 1967; Hekimian
and Gershon, 1968; Hensala et al., 1967; Vardy and Kay, 1983).
They typically responded to treatments appropriate to the non-drug-induced
syndromes they resembled (Strassman, 1984).
Toxicology laboratories now can measure sub-nanogram/milliliter
concentrations of LSD in body fluids (Nelson and Foltz, 1992),
aiding diagnosis of acute adverse reactions.
Subacute
Subacute effects requiring clinical intervention are flashbacks,
which refer to unbidden re-experiencing of certain aspects of
hallucinogen-induced effects, often visual, but partaking of all
psychic functions (Wesson and Smith, 1976). They occur after an
intervening period of normalcy after a drug experience (Horowitz,
1969). Not all flashbacks are felt to be adverse, and many members
of the psychedelic subculture find brief "free trips"
pleasurable (Wesson and Smith, 1976). The incidence is reported
to vary between 15% and 77% of individuals who have had at least
one LSD experience (Strassman, 1984).
In our DMT studies with experienced hallucinogen users, we have
seen an incidence of 5% to 10% in volunteers with at least one
high-dose DMT session. These sessions, it should be noted, are
almost uniformly regarded as "higher than I have ever been,"
and thus may be considered traumatic. Meditation, smoking marijuana,
and falling to or waking from sleep are the most common precipitants.
Several volunteers willfully attempt to re-experience aspects
of the DMT state by these means.
The etiology of flashbacks is not known, but organic, psychological,
and social hypotheses have been proposed (Alarcon et al., 1982).
Their presence in post-traumatic stress disorder and elicitation
by lactate infusion (Rainey et al., 1987) suggest a complex interaction
of anxiety and stress with memory processes (McGee, 1984). Flashbacks
are usually self-limited, if psychoactive drugs, especially hallucinogens
and marijuana, are avoided. Persistent or particularly disturbing
symptoms (Abraham, 1983) require a neurological evaluation.
Chronic
Chronic adverse effects may be divided into functional and organic.
Functional syndromes rarely may be quite debilitating and treatment
resistant, resembling an ego-syntonic, negative symptom-laden
schizophrenic disorder (Glass and Bowers, 1970).
More difficult to diagnosis confidently as directly related to
LSD use are changes in lifestyle and interpersonal behaviors associated
with hallucinogen use (Blacker et al., 1968). The confluence of
drugs and preexisting personality styles is suggested in McGlothlin
and Arnold's (1971) 10-year follow-up of psychotherapy patients
and normal volunteers who participated in sanctioned LSD studies.
This study suggested a catalytic effect of LSD use in individuals
predisposed to unconventional aesthetic and philosophic ideas
(McGlothlin and Arnold, 1971).
LSD-induced organic central deficits have been difficult to document
with certainty, because of no premorbid data and an inability
to control for other substances of abuse (Acord and Barker, 1973).
Statistically, but not clinically, significant decrements were
reported in several studies. Lower Halsteads' Category and Reitan's
Trail Making A test scores were reported in hallucinogen users
compared with control subjects; however, both of these tests were
within normal ranges in drug users (Culver and King, 1974; McGlothlin
et al., 1969). Nonspecific EEG changes also were described (Blacker
et al., 1968).
Chronic visual disturbances, posthallucinogen perceptual disorder,
akin to chronic flashbacks, may partake of functional and organic
bases. The validity of this diagnosis is uncertain because of
lack of premorbid data and inability to control for other drugs
of abuse. Its responsiveness to benzodiazepines (Abraham, 1983)
support an anxiety/functional rather than organic disorder (McGee,
1984).
Mutagenicity / Teratogenicity
Initial reports of chromosomal (Cohen et al., 1967) and
reproductive (Jacobson and Berlin, 1972) disorders in
LSD users were not replicated in later studies (Dishotsky et al.,
1971; Muneer, 1978). Until more controlled data
are forthcoming, however, woman who are pregnant or not using
reliable contraception are not suitable candidates for hallucinogen
research protocols.
Conclusions and Recommendations
Hallucinogens are powerful drugs, with the potential to elicit
or exacerbate psychiatric symptoms. Particularly aversive or overwhelming
acute effects may traumatize or sensitize the individual, setting
up the potential for flashbacks akin to those seen in post-traumatic
stress disorder. The use of experienced hallucinogen users may
reduce the traumatic nature of high-dose hallucinogen sessions,
and is recommended for psychopharmacological research. Additionally,
truly informed consent is possible only in experienced users.
Studies comparing responses in normal subjects with those in psychiatric
patients (see below) should use the lowest doses that will generate
requisite data.
Psychotherapy protocols require a careful assessment of risk to
benefit ratios balancing morbidity or mortality of an untreatable
psychiatric condition with the likelihood of psychological sequelae
of hallucinogen exposure. The risk associated with psychotherapy
research protocols may be lessened by using the lowest possible
dose of drug. If high-dose administration is necessary, it may
be prudent to gradually build up to this dose over several sessions.
Current Research
In the United States, we have been administering DMT since late
1990 (Strassman, 1991) in psychopharmacologic studies utilizing
experienced hallucinogen users (Strassman and Qualls, 1994; Strassman
et al., 1994). The University of Miami has begun phase I studies
of ibogaine in preparation for substance abuse treatment research.
Similar phase I studies have begun at UCLA with MDMA, also in
anticipation of therapeutic applications. Psychopharmacological
studies using subanesthetic, psychotomimetic doses of ketamine
in normal volunteers and patients with schizophrenia are ongoing
at Yale University (Krystal et al., 1994). A substance abuse treatment
amendment to the University of Maryland's inactive LSD protocol
has been approved, and may begin within a year.
In Europe, group and individual psychodynamic psychotherapy with
LSD or MDMA has been taking place in Switzerland since 1985, but
no research data have been generated. The University of Zurich
is studying the effects of psilocybin and ketamine on positron
emission tomography and neuropsychological responses in normal
volunteers (Vollenweider, 1994). In Germany, several sites are
studying mescaline and MDE (the N-ethyl derivative of MDMA) effects
in normal volunteers, studies in which multiple neurobiological
variables are characterized (Hermle et al., 1992, 1993).
Areas for Future Research
As described previously, a wide range of temporal characteristics
are available with the hallucinogens, and may be exploited for
research with different goals. For example, psychotherapy protocols
might be best served using short-acting drugs whose effects last
between 1 and 2 hours, while neuroendocrine challenge studies
would benefit from using ultra-short-acting drugs and keeping
interactions with the environment to a minimum. Protocols requiring
multiple within-individual assessments could use long-and ultra-long-acting
drugs.
Measurement Variables
Recent DMT studies demonstrate the superiority of subjective (HRS)
responses to biological ones with respect to subtle dose effects
(Strassman et al., 1994). Thus, despite better characterization
of mechanisms of action for neuroendocrine, cardiovascular, and
other autonomic variables, sensitivity for effects of experimental
manipulations is relatively low. This emphasizes the importance
of introspection and subjective data in characterizing the effects
of hallucinogens, especially using a within-subjects design.
Psychopharmacology
Human hallucinogen psychopharmacology requires further study,
for both clinical and heuristic purposes. Research should assess
the role of non-5-HT neurotransmitters, particularly dopamine.
Risperidone, with potent 5-HT2 and D2 antagonism, is more potent
than ritanserin, a pure 5-HT2A,( agent, in antagonizing animal
responses to LSD (Meert et al., 1989). The importance of combined
5-HT/DA antagonism corresponds to efficacy in schizophrenia treatment
with "atypical" antipsychotic medications (Meltzer,
1989), and suggests that antagonists to hallucinogens' behavioral
effects in humans may be efficacious in schizophrenia.
Pretreatment blockade studies, based upon relevant animal and
human data, will suggest interruption strategies for acute adverse
reactions in the emergency setting. Blockade strategies (Kosten
and Kosten, 1991) also could be utilized to prevent subjective
effects in those prone to chronic abuse of hallucinogens in a
manner similar to naltrexone.
Although most classical hallucinogens' qualitative psychopharmacological
properties are believed identical (Isbell, 1959), little data
exist for within-subject studies using multiple drugs. Many congeners
of classical compounds have been administered safely to humans
(Isbell et al., 1959b). Assessment of salient similarities and
differences will suggest structure-activity relationships for
design of drugs with desirable functional profiles for clinical
research purposes (Nichols, 1987).
Responses to hallucinogens in psychiatric populations with presumed
abnormalities in neurotransmitter systems relevant to hallucinogen
action may be tested, if appropriate safeguards are in place.
Such studies would generate unique human data relating disturbed
subjective experience in psychiatric patients to pharmacological
manipulations, generating both therapeutically and mechanistically
valuable data.
Studies exploiting recently developed hallucinogen-induced animal
models of information-processing defects in schizophrenia (Braff
and Geyer, 1990) could be applied to normal volunteers' responses
to these drugs, further comparing the two syndromes. In addition,
the HRS could be applied to more carefully characterized schizophrenic
patients at various stages of the disorder, allowing novel comparisons
between functional and drug-induced psychoses.
Advances in in vivo brain-imaging techniques may better
characterize hallucinogen effects and mechanisms of action. These
include topographic pharmacoelectroencephalography, positron emission
tomography (assessing metabolic effects of psychoactive doses,
and distribution of low doses of labeled compounds), and magnetic
resonance imaging (spectroscopy and functional imaging).
Psychotherapy
Economic constraints create increasing pressure for cost-effective
medical psychotherapy (Krupnick and Pincus, 1992). Sophisticated
psychotherapy protocols with proven efficacy (Frank et al., 1990)
provide a strong foundation upon which hallucinogen-assisted psychotherapy
research may be re-examined. Courses of therapy utilizing adjunctive,
high-dose, hallucinogen-assisted sessions should be considered
in a model combining the psychedelic and psycholytic models. This
would be a logical extension of earlier work that suggested robust
short-term improvement, but less impressive maintenance of therapeutic
effects, in high-dose models.
The growing numbers of terminally ill cancer and acquired immune
deficiency syndrome patients who require palliative, quality-of-life
treatment suggest additional areas for future psychotherapy research
that would build upon older, uncontrolled studies indicating beneficial
responses. The reported elements of increased pain control, improved
family relationships, and greater acceptance of illness and impending
death, if verified by controlled studies, would provide additional
clinical support for these patients. The use of "flooding"
to treat post-traumatic stress disorder in both combat veterans
(Grigsby, 1987) and others (Saigh, 1989) may also provide a unique
interfacing of hallucinogenic drug effects with an established
treatment modality for a particularly pernicious and common disorder.
Hallucinogen-enhanced imagery and associations, and associated
affective responses to these, could be used to enhance the efficacy
of this treatment.
Set and Setting
Although complex and potentially controversial, set and setting
issues require further study. Set refers to the personality, state,
and expectations of the subject, and setting to the environment
in which the session takes place. Setting partakes of the physical
surroundings, e.g., inpatient, high-technology research
unit or comfortable outpatient consultation suite; nuances of
the investigator/therapist presentation, including clothing, appearance,
odor, and other physical characteristics; being belted to the
bed (Smart et al., 1966) or able to move about freely; and eyes
open or blindfolded (Denber, 1958). In addition, it involves the
"set" of the research team members, including the nature
of countertransference and empathy (Day, 1957), type and amount
of training in psychotherapy and working with regressed/psychotic
individuals, and the theoretical model and expectations of the
research, psychotomimetic, psychedelic, or otherwise.
Finally, research team members' experience with hallucinogens
may affect the nature of the results of research/treatment protocols.
Swiss and German health authorities require that the principal
investigators first take study drugs at doses to be used in their
protocols, both for safety issues and to provide more adequate
informed consent.3 In the United States, self-experimentation
by research teams initially was encouraged (Cerletti and Rothlin,
1955; Johnson, 1969; Szara, 1957). However, in response to highly
publicized cases of self-experimentation and extraresearch drug
taking with volunteers (Leary, 1968), this practice was discontinued.
Future research must carefully account for these setting variables
in assessing outcome measures, and the European practice of "going
first" should be considered.
Training Issues
The small number of protocols using hallucinogens allows for very
close contact between investigators and regulatory agencies overseeing
this work. However, renewed examination of these compounds may
generate a large number of requests to use them in clinical studies.
State of the art methodologies are no guarantee against disasters
resulting from imprudent administration of hallucinogens to humans.
Transference and countertransference issues are rarely discussed
in psychopharmacology research, and increasingly less so in psychotherapy
research. However, the regressed, suggestible, and unusual behavior
of subjects under the influence of hallucinogens is easily observable.
Interpersonal exchanges that would be readily overlooked in a
normal state of awareness may assume extreme and confusing meaning.
The clinical investigator not only may become the object of infantile
wishes and fears, but may, in the subject's mind, actually look,
smell, feel, and sound identical to highly emotionally charged
people in his or her life. In addition, the clinical researcher
may have multiple, conflicting, and more-or-less conscious motivations
for administering incapacitating drugs to humans. These may include
narcissistic, grandiose or sadistic, and voyeuristic impulses.
Callous, offhand, or teasing remarks made for these and other,
less malignant, but similarly unexamined, motivations can dramatically
alter the course of a volunteer's hallucinogenic drug experience,
from a psychedelic to psychotomimetic. Sexual relations between
clinician and subject, during or after a hallucinogenic drug session,
the most disastrous acting-out of both parties' drug-altered sensibilities,
do occur.
Regulatory agencies determine professional qualifications and
adequacy of facilities for conducting this research. However,
I believe that specialized training, and perhaps certification,
is necessary for clinical investigators performing human hallucinogen
research. Such training/certification and ongoing periodic supervision
would reduce the likelihood of subtle or flagrant misuse of these
compounds by unknowing or unscrupulous clinical investigators.
Specific proposals regarding the nature of this training and supervision
is beyond the scope of this article. This suggestion is meant
to stimulate further debate and discussion at institutional and
governmental levels.
Conclusion
The renewal of human hallucinogen research is encouraging. However,
it must be tempered with an appreciation that the controversial
nature of these drugs caused a suspension of nearly a generation's
worth of research in the field (Dahlberg et al., 1968). Ongoing
studies are taking a painstaking, systematic approach, and are
avoiding claims that cannot be substantiated by data. Careful
attention to selection, screening, preparation, supervision, and
follow-up of subjects undergoing hallucinogenic drug sessions
is absolutely necessary. In addition, the training, characteristics,
and research setting of clinical investigators desiring to work
with these compounds must be addressed directly.
These precautions will provide a safety net to minimize many of
the mistakes and false leads that plagued the first round of human
studies. If appropriate circumspection is practiced, the re-examination
of the role of hallucinogens in clinical research and treatment
will be substantial.
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