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A Review of Lysergic Acid Diethylamide (LSD) in the Treatment of Addictions:

Historical Perspectives and Future Prospects

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146 Current Drug Abuse Reviews, 2014, 7, 146-156

A Review of Lysergic Acid Diethylamide (LSD) in the Treatment of

Addictions: Historical Perspectives and Future Prospects
Mitchell B. Liester*

P.O. Box 302, 153 N. Washington Street, Suite 103, Monument, CO 80132, USA

Abstract: Lysergic acid diethylamide (LSD) is a semisynthetic compound with strong psychoactive
properties. Chemically related to serotonin, LSD was initially hypothesized to produce a psychosis-
like state. Later, LSD was reported to have benefits in the treatment of addictions. However,
widespread indiscriminate use and reports of adverse affects resulted in the classification of LSD as
an illicit drug with no accepted medical use. This article reviews LSD’s storied history from its
discovery, to its use as a research tool, followed by its widespread association with the counterculture
movement of the 1960s, and finally to its rebirth as a medicine with potential benefits in the treatment
of addictions. LSD’s pharmacology, phenomenology, effects at neurotransmitter receptors, and
effects on patterns of gene expression are reviewed. Based upon a review of the literature, it is
concluded that further research into LSD’s potential as a treatment for addictions is warranted.
Keywords: Addiction, entheogen, ergot, hallucinogen, lysergic acid, lysergic acid diethylamide, LSD, psychedelic drugs.

THE DISCOVERY OF LSD alkaloids, and a diethylamine group, which is added in the
laboratory. Alkaloids are naturally occurring, nitrogen
LSD was first synthesized in 1938, while Hoffman was containing organic compounds and include nicotine,
attempting to synthesize a circulatory and respiratory stimulant morphine, atropine, cocaine, and caffeine. Ergot alkaloids
derived from ergot [1]. After Hoffman synthesized the twenty- have a variety of medicinal effects. These include producing
fifth compound in a series of lysergic acid derivatives, it was uterine contractions, stopping uterine bleeding, and reducing
named “lysergsäure-diethylamid-25” (German) or “lysergic migraine headaches.
acid diethylamide-25” (English). More commonly known as
“LSD” or “LSD-25”, this chemical was found to have strong LSD’s psychoactive effects begin within 20-60 minutes
effects on the uterus. However, it also caused restlessness in of ingesting the drug and typically last 8-12 hours. The
experimental animals, which resulted in the suspension of effects are dependent upon dosage, body weight, age, and
further testing with this compound [1]. tolerance [2]. The plasma half-life is 5.1 hours, with a peak
plasma concentration at 3 hours post-dose [3]. In humans,
In 1943, Hoffman synthesized LSD a second time [1]. the effective dose range is 0.0003-0.001 mg/kg. The minimal
After inadvertently absorbing a small amount through his psychoactive dose in adult humans is generally considered to
skin, he deliberately self-administered an extremely small be 25 micrograms [4].
dose of this medicine to further explore its effects. After
ingesting 250 micrograms, which was the lowest dose he Tolerance to LSD’s effects develops rapidly, if
expected would produce an effect, Hoffman experienced a administration is repeated with too short an interval between
mixture of confusion, dizziness, perceptual distortion, and a doses. For example, if LSD is administered daily, no reaction
fear of going insane. However, he also experienced periods will occur by the third day [5]. The LD50 varies widely
of clear thinking and a perception that his consciousness between animal species. In mice the LD50 is 50-60 mg/kg
existed outside of his body [1]. IV whereas in rabbits it is 0.3 mg/kg [1]. A single elephant
died after being administered 0.06 mg/kg [6], a dose that was
Subsequently, studies were performed on a variety of considered 99 times too large [7].
animals including mice, cats, dogs, chimpanzees, fish, and
spiders. In the latter, it was observed that low doses of LSD Although the lethal dose in humans is not known, it is
resulted in the production of webs that were better estimated to be at least 0.2 mg/kg [4]. This means an
proportioned than normal webs. However, at higher doses, overdose of 300-600 times the normal effective dose would
the webs were poorly constructed [1]. be required to cause death in humans. To date, there have
been no known deaths resulting purely from LSD overdose.
However, fatalities have resulted from behaviors that
PHARMACOLOGY OF LSD occurred while individuals were under the influence of LSD.
LSD is a semisynthetic compound consisting of naturally
occurring lysergic acid, which is found in all major ergot LSD’S EFFECTS ON NEUROTRANSMITTERS AND
THEIR RECEPTORS
*Address correspondence to this author at the P.O. Box 302, 153 N.
LSD is believed to exert its pharmacologic properties
Washington Street, Suite 103, Monument, CO 80132, USA;
Tel: 719-488-0024; Fax: 719-488-6672; E-mail: [email protected] primarily through its effects on the serotonin system. LSD

1874-4745/14 $58.00+.00 © 2014 Bentham Science Publishers

LSD in the Treatment of Addictions Current Drug Abuse Reviews, 2014, Vol. 7, No. 3 147

binds to 5-HT1A/1B/1D, 5-HT2A/2C, 5-HT5A, 5-HT6, and 5-HT7 behavioral effects of hallucinogens [19]. These findings
receptors [8]. However, the psychedelic effects of LSD are suggest that the 5-HT2AR/mGluR2 complexes may be one of
generally attributed to its partial agonist effects at 5-HT2A the molecular sites responsible for the actions of
receptors. Psychedelics share a common biochemical action hallucinogenic drugs [19].
in that they all act as agonists at 5-HT2A receptors [5, 9]. Svenningsson et al. proposed another possible mechan-
Antagonists of 5-HT2A receptors are known to block the
ism for LSD’s psychoactive effects. They hypothesized
psychedelic properties of LSD [8].
LSD’s effects are mediated through dopamine- and cAMP-
5-HT2 receptors are known to activate phospholipase C regulated neuronal phosphoprotein (DARPP-32) [20].
(PLC); a membrane bound enzyme that catalyzes the
degradation of phosphatidylinositol 4,5-biphosphate (PIP2) LSD’S AFFECTS ON GENE EXPRESSION
to inositol 1,4,5-triphosphate (IP3) and diacyglycerol (DAG). PATTERNS
IP3 triggers the release of calcium from intracellular stores.
These calcium ions then activate calcium/calmodulin LSD alters the expression of genes within cells. Even a
kinases, a group of enzymes that phosphorylate other single dose of LSD has been demonstrated to alter gene
proteins involved in the regulation of cellular functions. expression patterns [21]. Genes that exhibit differential
DAG activates protein kinase C (PKC), which stimulates the expression following treatment with LSD include: c-fos,
production of arachidonic acid. The latter facilitates the krox-20, NOR-1, arc, IΚβ-α, sgk, and Ania3 [21]. Increased
production of prostaglandins and prostacyclins, which exert expression of these genes, which are involved in a wide
numerous effects on cellular processes [10]. variety of cellular functions, alters synaptic plasticity,
glutamatergic signaling, cytoskeletal architecture, as well as
5-HT2A receptors also activate the phospholipase A2
communication between the synapse and nucleus [21].
(PLA2) signaling pathway and subsequent release of
arachidonic acid [5]. Although LSD stimulates the PLA2
pathway to a greater extent that the PLC pathway, the PHENOMENOLOGY OF LSD
significance of this finding remains unclear [11].
LSD can produce a profound altered state of
5-HT2A receptors have also been found to couple to consciousness characterized by changes in physiology,
phospholipase D (PLD). This enzyme catalyzes the perceptions, emotions, and cognition. Some individuals
hydrolysis of the terminal diester bond of phosphatidyl report transcendent or mystical experiences [22]. Specific
choline, producing phosphatidic acid and choline [5]. effects of LSD may include the following:
The relationship between LSD’s agonist activity at 5-
HT2A receptors and its psychedelic effects on human Somatic Effects
consciousness has not yet been elucidated. LSD has been
found to affect a wide array of neurotransmitter systems in Subjects may experience: changes in heart rate and blood
addition to the serotonergic system. LSD binds to adrenergic pressure, dilation of the pupils, sweating, hypersalivation,
receptors (α1 and α2) [5] and inhibits NMDA transmission in piloerection, nausea, diarrhea, vomiting, fatigue, increased
the prefrontal cortex [12]. LSD acts as an agonist at D1 and muscular tension, tremors, headache, heaviness of the
D2 receptors [8, 13, 14]. extremities, and sexual feelings. These effects may result from
stimulation of both the sympathetic and parasympathetic
The role of glutamate in LSD’s action on the central nervous systems [4]. Analgesia may occur as well [23].
nervous system has been the focus of increased interest in
recent years. LSD enhances glutamatergic transmission in
Perceptual Changes
the cerebral cortex via stimulation of presynaptic 5-HT2A
receptors [11]. Aghajanian and Marek suggested the release Perceptual changes occur frequently following the
of glutamate in the cerebral cortex might be responsible for ingestion of LSD [4]. The visual pathway is the sensory
the alterations in cognition, perception, and emotions modality most commonly affected. Visual changes
following administration of LSD [15]. associated with LSD include: blurring of vision, distortion of
Metabotropic glutamate receptors, or mGluRs, have been three-dimensional space, changes in faces and objects, colors
studied as a mediator of LSD’s actions. mGluRs are involved may change or be brighter, and halos or areas of light or
in a wide variety of functions including memory, anxiety, color may surround objects. Illusions, hallucinations, and
learning, and the perception of pain [16]. It has been changes in the intensity of light may occur. Visual
demonstrated that mGluRs activate biochemical cascades, perseveration or after-images may be present [4].
which effect neuronal excitability [17]. Auditory changes are less common and include:
A subset of mGluRs, known as mGluR2s, couple with 5- increased or decreased sensitivity to sound, inability to
HT2A receptors to form functional complexes in the brain localize the source of sound, confusion or inability to
cortex. These 5-HT2A/mGluR2 complexes have been understand sounds, and auditory hallucinations [4].
demonstrated to play an important role in the action of Tactile changes are the next most commonly reported
hallucinogenic drugs. For example, activation of mGlu2 sensory modality changes [4]. Kinesthetic changes also occur
receptors inhibits hallucinogen-specific neuronal signaling and include: shaking or vibration phenomena, sensations of
pathways induced by hallucinogenic 5-HT2A receptor pressure, and light-headedness. Changes in body image and out
agonists [18]. Furthermore, mice with disrupted mGluR2 of body experiences are reported [4]. Synesthesias are described
signaling capacity are insensitive to the cellular and as well [4].
148 Current Drug Abuse Reviews, 2014, Vol. 7, No. 3 Mitchell B. Liester

Emotional Effects psychopathic antisocial trends, abandonment of social

responsibilities, and paranoid reactions [29].
Emotional responses following the ingestion of LSD vary
widely and include: euphoria, depression, anxiety, panic, and
irritation [4, 22]. If psychiatric patients are administered Set and Setting
LSD, the frequency of negative moods is increased [22]. The effects of LSD are strongly influenced by the set and
Suicidal ideation may occur [22]. setting in which the drug is utilized [30]. The term “set”
refers to the mindset or mental state of the individual at the
Cognitive Effects time of ingestion. This includes the mood, thoughts, and
expectations of the individual. As Von Barr and colleagues
Cognitive changes include: impaired judgment, shortened pointed out, the phenomena induced by LSD cannot be
concentration span, interposed thoughts, mind wandering, predicted or understood solely in terms of its
wavelike changes in thoughts, inability to control thoughts, pharmacological properties, because the personality of the
and memory changes. Abnormal thought content includes: individuals plays a critical role in determining the drug’s
ideas of reference, bizarre ideas, and delusions [4]. Increased effects [31].
suggestibility has been reported as well [24]. Positive
cognitive changes are also reported. Previously unconscious “Setting” refers to the physical, social, and cultural
or preconscious material may emerge into consciousness environment in which the medicine is ingested. “Social
[25]. New insights into one’s self or others are described. learning,” which results from modeling and observational
learning, plays an important role by influencing the
subjective experience with LSD [30].
Other Effects
Additional effects of LSD include its consciousness- USES OF LSD
altering effects. These include: a dream-like character to
consciousness and lowering of psychological defenses. Following the synthesis of LSD in 1938, human trials
Creativity may be enhanced as well [4]. were initiated. Stoll administered forty-nine doses of LSD in
doses of 20-130 micrograms to twenty-two schizophrenic
Subjective awareness of the passage of time is frequently and healthy subjects. Stoll reported the emotional state of the
altered [4]. Time may appear to speed up, slow down, stop, subjects was “predominantly euphoric” [32].
or run backwards. Some individuals experience themselves
as existing outside of time. One of the topics raised in Stoll’s paper was the potential
use of LSD as a research tool in psychiatry. Similarities were
Transcendental or mystical experiences have been noted to the effects of mescaline, which induced
described. These experiences include: 1) a sense of unity or hallucinations. Additionally, low doses of LSD appeared to
oneness, 2) insightful knowledge and a certainty that such facilitate psychotherapy by allowing repressed material to
knowledge is truly real, 3) transcendence of time and space, flow more easily into consciousness [32].
4) sense of sacredness, 5) deeply felt positive mood, 6)
paradoxicality, 7) ineffability, 8) transiency, and 9) positive Sandoz began providing LSD at no charge to physicians
changes in attitude and/or behavior [26]. and research institutes around the world as an experimental
drug for research. It was given the trade name “Delysid” [1].
The prospectus for this medicine suggested it might be
ADVERSE EFFECTS useful in analytical psychotherapy as well as in experimental
Cohen was the first to systematically investigate the studies on the nature of psychosis [1].
potential side effects of psychedelic therapy [27]. He This latter indication formed the basis for LSD’s initial
conducted a survey of 62 investigators who had studied use by researchers, who hoped it would provide an
psilocybin or LSD. Forty-four researchers replied to his opportunity to study mental illnesses such as schizophrenia.
questionnaire. The responses included data on psychedelic This idea, known as the “model psychosis” concept [1, 4],
therapy with nearly 5000 individuals on more than 25,000 suggested LSD might provide new insights into the nature of
occasions. The findings indicated that psychotic breaks, psychosis by mimicking the psychotic state, an effect known
panic attacks, and other psychiatric reactions lasting over 48 as the “psychotomimetic effect” of LSD [4]. Sandoz
hours occurred in 0.8 per 1000 normal volunteers and 1.8 per proposed that psychiatrists take LSD in order to experience
1000 patients undergoing therapy [27]. what their patients were experiencing. It was believed this
In 1962, Cohen and Ditman described an increasing experience would allow them to gain a greater understanding
number of adverse effects associated with LSD-25 of their patient’s mental state. In addition, it was theorized
administration [28]. They warned that the unsupervised use that administering LSD to non-psychotic subjects would
of LSD increased its potential for serious adverse cause them to experience a schizophrenia-like state. It was
consequences including antisocial acting-out behaviors, hoped this would provide a model for studying this disease
misuse of LSD as part of a pattern of multidrug use, and and potentially discovering new and improved treatments for
abuse of the euphoriant property of LSD [28]. schizophrenia and related psychotic disorders. The model
psychosis theory did not begin with LSD, however. Ten
The following year, these same authors published a years prior to the synthesis of LSD, Beringer suggested
follow up report describing nine cases involving different mescaline might be used to help psychiatrists better
types of adverse effects including: prolonged psychotic understand the psychotic experiences of their patients [33].
decompensation, depressive reactions, release of preexisting
LSD in the Treatment of Addictions Current Drug Abuse Reviews, 2014, Vol. 7, No. 3 149

Based upon the observed effects of LSD in experimental treatment resistant alcoholics they could find, to compensate
sessions, and a rudimentary understanding of the for the lack of a control group. They selected alcoholics who
phenomenology induced by this medicine, LSD and related had failed every available treatment and whose therapists
compounds were referred to as “hallucinogens.” In 1957, viewed them as having a very poor prognosis [4].
Osmond offered “psychedelic” as a replacement term, Twenty-four inpatients were selected. The researchers
contending these medicines did much more than "mimic
spent 2-4 weeks establishing a psychotherapeutic
psychosis." He preferred the term “psychedelics” because
relationship with each of the subjects. Subjects were
these medicines did not necessarily produce a predictable
educated regarding the typical effects of LSD. Each subject
and pathological sequence of events, but rather could
was then administered a single dose of 200 to 400
catalyze a "mind manifesting" state involving an enriching
micrograms of LSD in a hospital setting. Patients typically
and life changing vision [34]. spent the day of their LSD treatment in either a private room
In 1979, Ruck proposed a new term, “entheogen,” to or a doctor’s office. A nurse and/or a psychiatrist stayed with
describe this class of medicines [35]. Entheos is a Greek them throughout the day. Initially, there were no efforts
word which means “god within” and gen denotes the action made to alter the environment. However, as the study
of becoming. Thus, an entheogen is a medicine that progressed, the researchers began bringing in fresh cut
facilitates the experiencing of opening to the god within. flowers, paintings, and other visual aids to create a more
therapeutic environment. The next day, subjects were
One outgrowth of the recognition that these medicines
encouraged to write about their experience.
did more than produce hallucinations was a decline in the
model psychosis concept [24, 36]. Researchers increasingly The results of this study showed that none of the
recognized numerous differences between the psychotic state alcoholics were worse after treatment with LSD. Of the 24
and the state of consciousness induced by LSD. Bleuler alcoholics treated, 12 (50%) were unchanged, 6 (25%) were
claimed that psychedelic drugs “contributed nothing to the “improved,” and the other 6 (25%) were “much improved.”
understanding of the pathogenesis of schizophrenia” [37]. The criteria utilized to define “much improved” included 1)
Eventually, most scientists renounced the model psychosis complete abstinence from alcohol for the duration of the
theory. follow-up period and 2) lifestyle changes including more
stable personal relationships and regular employment [39].
In the 1950‘s, researchers in Europe and North America
began exploring LSD’s therapeutic potential [24, 38, 39]. Based upon this early research, Hoffer and Osmond
Early reports suggested LSD could enhance the developed a treatment model for patients suffering from
psychotherapeutic process. Not only did LSD appear to addictions. This model, known as “psychedelic therapy,”
expedite psychotherapy, it also showed promise in treating involved one to three sessions in which 300 to 1500
patients who were previously considered poor candidates for micrograms of LSD was administered each session [4]. The
psychotherapy. This latter group included alcoholics and goal was to induce a so-called “psychedelic peak
narcotic-drug addicts. experience” in order to assist the individual in overcoming
their addiction. The concept of a psychedelic peak
LSD AS A TREATMENT FOR ALCOHOLISM experience was modeled after Maslow’s concept of the peak
experience [41].
Among the physicians who initially focused on LSD’s
Grof, defined a “psychedelic peak experience” as:
“psychomimetic properties” were Osmond and Smythies.
These researchers proposed a biochemical hypothesis to An ecstatic state, characterized by the loss of boundaries
explain the origin of schizophrenia, suggesting the body between the subject and the objective world, with ensuing
might produce an endogenous hallucinogen during times of feelings of unity with other people, nature, the entire
stress. Their theory was based upon the similarity in Universe, and God. In most instances this experience is
chemical structure between adrenaline and mescaline [40]. contentless and is accompanied by visions of brilliant white
With time, interest in the model psychosis theory diminished or golden light, rainbow spectra or elaborate designs
as it was discovered that subjects’ experiences with LSD resembling peacock feathers. It can, however, be associated
depended greatly on the therapists’ and the subjects’ with archetypal figurative visions of deities or divine
objectives [41]. personages from various cultural frameworks [41].
In 1953, Osmond and Hoffer began examining the According to Grinspoon, the primary goal of psychedelic
possibility that LSD might produce a controlled experience therapy was the induction of a mystical experience that
similar to delirium tremens. They proposed alcoholics who would change the way a person sees himself and the world
were administered LSD might have a “hitting bottom [24]. Grof offered a slightly different explanation,
experience” that would deter them from ever drinking again identifying the main goal of psychedelic therapy as the
[4]. The first two subjects in their study were inpatients facilitation of “ego death and the subsequent transcendence
suffering from alcoholism. Each was administered 200 into the so-called psychedelic peak experience” [41].
micrograms of LSD. One was a male who remained sober Psychedelic peak experiences were viewed as profound
for several months after discharge. The other was a female experiences that catalyzed recovery from addictions.
who continued to drink with the same intensity for six In 1959, O’Reilly et al. began exploring LSD as a
months, and then stopped drinking. treatment for alcoholism [42, 43]. They administered 200
Based upon the results of this preliminary investigation, a micrograms of LSD to 68 chronic alcoholic patients who had
larger study was designed. The researchers selected the most not responded to other forms of treatment [44]. Fifteen of the
150 Current Drug Abuse Reviews, 2014, Vol. 7, No. 3 Mitchell B. Liester

patients received more than one dose of LSD. Patients experience showed greater improvement than patients who
suffering from any form of psychotic disorder were did not experience a psychedelic peak experience [47]. This
eliminated from the study. Sixty percent of the patients had study involved a randomly assigned, double blind protocol
been drinking for more than 10 years. Follow-up occurred at with controls. In the active treatment group, 117 subjects
varying lengths of time, ranging from two months to 34 received a single 350-450 mg dose of LSD. Control subjects
months. The results showed that 26 patients (38%) had been received 50 mg of LSD. A team of independent raters
abstinent from alcohol during the two months prior to performed evaluations before treatment and 6 months post-
follow-up. The other 42 (62%) were non-abstainers. The treatment. They evaluated “global adjustment” (defined as
only variable reported to correlate with future abstinence was occupational, interpersonal, and residential functioning as
a “transcendental” experience, which the researchers defined well as the subject’s reaction to alcohol) and “drinking
as, “a new way of looking at one’s life, with a loss of behavior.” These evaluations found a statistically significant
previous defensive meanings or perceptions of oneself” [43]. (p < 0.05) improvement at six-month follow-up in the
Unfortunately, the conclusions of this study were limited by treatment group compared with the control group.
methodological problems including: lack of clarity regarding
Summarizing the existing research into the use of LSD as
subjects’ diagnoses, variable severity of alcoholism,
a treatment for alcoholism in 1967, Hoffer and Osmond
inconsistent follow-up periods, and absence of a control
reported LSD, when used in combination with other forms of
group treatment and supportive measures, “results in marked
In 1962, Jensen published the first controlled trial of LSD improvement in the recovery rate that would be otherwise
as a treatment for alcoholism [45]. This trial was a pilot study obtained” [4]. Grinspoon and Balakar subsequently reported
involving 145 patients. Subjects were placed in three treatment nearly fifty percent of “severe chronic alcoholics” treated
groups. The first group (65 subjects) received standard with a single dose of LSD remained sober 1-2 years after
inpatient therapy including occupational therapy, two hours of treatment [24]. The early results from studies utilizing LSD
group psychotherapy, three weekly Alcoholics Anonymous therapy as a treatment for alcoholism were so encouraging,
meetings, and bimonthly movies with discussion. Near the end by the late 1960s there were six alcoholism treatment
of the three weeks of treatment, 200 mg of LSD was programs in North America utilizing LSD [35].
administered. The second group (35 subjects) received the
The encouraging results from these early studies resulted
same therapy without LSD. The third group (45 subjects)
in a growing number of researchers administering LSD to
received one-on-one psychotherapy and milieu therapy in an alcoholics. However, not everyone shared in the optimism
inpatient setting. They did not receive LSD. This was a two-
regarding LSD’s effectiveness in the treatment of addictions.
year study with follow-up periods ranging from 6 to 18
Early enthusiasm stemming from promising results was
months. Of the 65 subjects in the active treatment group (i.e.
tempered by subsequent criticisms of methodological flaws
received LSD), seven (11%) were lost to follow up. Results
and inconclusive results.
from the remaining 58 subjects showed 38 (66%) were
abstinent throughout the follow-up period, 7 (12%) were For example, in an effort to isolate the pharmacological
improved, and 13 (22%) were unimproved. Among the 35 actions of LSD from environmental influences, Smart et al.
subjects in the control group (i.e. those receiving the same blindfolded subjects and/or restrained them to prevent
therapy but no LSD), 18 were lost to follow up. Results from movement during LSD sessions. Observers were instructed
the remaining 17 subjects showed 7 (41%) were abstinent, 4 not to interact with subjects who were under the effects of
(24%) were improved, and 9 (53%) were unimproved. Of the LSD. Although subjects in this study showed some
45 subjects in the third group (i.e. individual psychotherapy improvement, the results were less positive than in previous
and milieu therapy, but no LSD), 23 were lost to follow up. studies [48].
Among the remaining 22 subjects, 7 (32%) were abstinent, 3
(14%) were improved, and 12 (55%) were unimproved. REVIEWS OF RESEARCH USING LSD AS A
Based on the findings of this pilot study, Jensen and TREATMENT FOR ALCOHOLISM
Ramsay modified their study design. Their next study Several reviews examining the effectiveness of LSD in
involved 125 patients divided into two groups. The treatment
the treatment of alcohol dependence have been published
group consisted of 70 patients who received milieu therapy,
[24, 49-54]. Mangini published a review in 1998 that found
AA group meetings, and LSD treatment. The control group
studies of LSD’s effectiveness in the treatment of alcoholism
of 55 patients received no LSD. Eight of the treatment group
were inconclusive [50]. Problems with the reviewed studies
and 26 of the control group were lost to follow-up. Of the
included non-random assignment of subjects to treatment
remaining subjects, 46 (74%) of the treatment group and 12 groups, failure to use placebo groups or control groups, lack
(41%) of the control group were improved at six to 18
of standardized therapies, absence of blind raters, lack of
months post-discharge [46]. This study suffered from
regard for environmental influences, and inconsistent follow-
multiple methodological flaws including lack of diagnostic
up.
specificity, variable periods of follow-up, loss of a large
number of subjects to follow-up, and a lack of clarity Abuzzahab and Anderson reviewed 31 studies from 1953
regarding how improvement was measured. to 1969 involving 1105 alcoholics [54]. They examined five
studies involving a single dose of LSD and three studies
LSD AND PEAK EXPERIENCES involving multiple doses of LSD. The authors’ conclusion
was that meaningful generalizations could not be reached
In 1970, Pahnke et al. published a study investigating because of inconsistent study designs and criteria for
whether alcoholic patients who reported a psychedelic-peak improvement.
LSD in the Treatment of Addictions Current Drug Abuse Reviews, 2014, Vol. 7, No. 3 151

Krebs and Johansen performed a meta-analysis of six offer unique perspectives on potential mechanisms by which
randomized controlled trials (5 of which were double-blind) LSD may aid in the treatment of addictions. These
examining the efficacy of LSD in the treatment of hypotheses, which exhibit some degree of overlap (i.e.
alcoholism [52]. These trials involved 536 adult subjects individuals may experience anti-addictive effects via more
who suffered from “alcoholism.” Of these subjects, 325 than one mechanism of action), include biochemical,
received a single dose of LSD at a dose ranging from 210- psychological, and transcendent mechanisms of action.
800 micrograms. The control group consisted of 211 subjects
who received low-dose LSD (25 or 50 micrograms), d- Biochemical Hypothesis Regarding LSD’s Anti-Addictive
amphetamine (60 milligrams), ephedrine sulphate (60 Properties
milligrams), or non-drug control. The conditions during the
LSD sessions varied widely as did the preparation and On a biochemical level, addiction has been linked to
debriefing of subjects. The authors concluded: “The alterations in the mesolimbic dopamine pathway (MDP) of
effectiveness of a single dose of LSD compares well with the the brain. Also known as the “reward pathway,” the MDP is
effectiveness of daily naltrexone, acamprosate, or associated with motivation, pleasure, and reward [57]. The
disulfiram” [52]. MDP consists of dopaminergic neurons whose cell bodies
are located in the ventral tegmental area (VTA) and axonal
More than 20 research articles examining the effects of
LSD as a treatment for alcoholism were published from the projections that extend to the limbic system both directly and
indirectly via the nucleus accumbens (NAc) [58].
1950’s through the 1970’s. However, research with LSD and
other psychedelic medicines slowed dramatically in the Pleasurable stimuli, including drugs of abuse, release
1970’s. dopamine (DA) in the mesolimbic pathway [58, 59]. This
release of DA in the MDP has been proposed as the common
LSD AS A TREATMENT OF NARCOTIC ADDICTIONS final pathway for the reinforcing effects of all drugs of abuse
[58]. Following its release, DA binds to G-protein coupled
Although LSD was studied primarily as a treatment for receptors. It is believed that this release and subsequent
alcoholism, a few studies examined its potential as a binding of DA to receptors is responsible for the “rush” or
treatment for opiate addiction. Ludwig and Levine explored “high” associated with drugs of abuse and leads to their
the use of LSD to treat “narcotic addicts” by administering reinforcing effects [59].
moderate doses (2ug/kg) to 70 subjects following With repeated and chronic administration of drugs of
detoxification [55]. The subjects were randomly assigned to
abuse, dopamine levels in the MDP become depleted [60]
one of five treatment groups: 1) LSD, 2) LSD with
and DA receptors are reduced in number [61]. This
psychotherapy, 3) LSD with psychotherapy and hypnosis, 4)
decreased level of dopaminergic tone, which has been
psychotherapy without LSD, and 5) psychotherapy with
termed “allostasis” [62], has been proposed to produce
hypnosis. At two-week follow up, subjects demonstrated a
anhedonia and drug craving [62].
significant improvement in self-concept and coping attitudes.
However, at two-month follow up, no significant differences One proposed treatment model involves utilizing DA
were found between the groups. Unfortunately, drug agonists to reduce the craving and withdrawal symptoms
abstinence and behavioral changes were not assessed. associated with discontinuation of DOA’s, thereby reducing
self-administration [63]. This model is complicated by the
Savage and McCabe examined the use of LSD to treat
fact that DA agonists can themselves become DOA’s if they
narcotic addiction [56]. Seventy-four subjects were release too much DA. Thus, if DA agonists are to be utilized
randomly assigned to a treatment group. Subjects in one
as effective treatments for addictions, they must release
group were placed in a halfway house for six weeks where
enough DA to return MDP DA to a normal level, but not
they received psychotherapy followed by a single dose of
release too much DA, which would lead to reinforcement
200-500 micrograms of LSD. The control group was placed
and subsequent addiction.
in an outpatient clinic program where they received weekly
group psychotherapy. Daily urine samples were used to One method of modulating DA levels in the MDP is to
monitor drug abstinence. After one year, significant administer a 5-HT agonist along with a DA agonist [64].
differences were found between the treatment group and the This concept is based upon the finding that some serotonin
control group. In the group who received LSD with neurons exhibit inhibitory effects on DA neurons in the
psychotherapy, 25% remained abstinent whereas in the MDP, thus attenuating the reinforcing effects of DA agonists
control group, only 5% remained abstinent. Of the 13 [64].
subjects who had perfect community adjustment scores after 5-HT agonists exhibit mixed effects on DA release in the
one year, 12 reported having had a psychedelic peak MDP, depending upon the particular 5-HT receptor
experience during their treatment with LSD. involved. 5-HT2C agonists decrease DA release in the MDP
[65]. LSD acts as an agonist at D1 and D2 receptors [8, 13-
HYPOTHESES REGARDING LSD’S MECHANISM 14], as well as 5-HT2C receptors [8]. Via these actions, LSD
OF ACTION AS A TREATMENT FOR ADDICTIONS is proposed to modulate the release of DA in the MDP, thus
alleviating allostasis and restoring homeostasis. This
Three hypotheses are suggested to explain LSD’s restoration of dopaminergic homeostasis in the MDP would
possible mechanism of actions as a treatment for addictions. be expected to decrease the reinforcing properties of drugs of
These hypotheses are not mutually exclusive. Rather, they abuse.
152 Current Drug Abuse Reviews, 2014, Vol. 7, No. 3 Mitchell B. Liester

Psychological Hypothesis Regarding LSD’s Anti- However, they totally abandoned the scientific method,
Addictive Properties which they viewed as a “game” they no longer wanted to
play. This eventually led to their termination by Harvard
The psychological hypothesis regarding LSD’s anti- [69].
addictive properties is based upon the benefits derived from
using LSD in conjunction with psychotherapy. This model of Even within the psychiatric community, the use of LSD
therapy was developed after researchers found that provoked controversy. Grinker, the first editor of the
individuals who ingested LSD frequently talked more openly Archives of General Psychiatry, wrote an editorial chastising
about their problems and exhibited increased insight into the psychiatrists who administered the drug to themselves,
emotional meaning of their symptoms. They also claiming they were unqualified as competent investigators
experienced reduced depression, anxiety, and [70]. A year later, Grinker wrote in the Journal of the
compulsiveness, as well as an increased sense of well-being American Medical Association that researchers were using
and increased access to previously unconscious memories [1, uncontrolled, unscientific methods. He claimed their
4]. These findings lead researchers to develop a form of conclusions were biased by their self-administration of LSD
treatment involving low doses of LSD integrated with [71].
psychotherapy. This was termed “psycholytic therapy.” Numerous social and political issues fueled the growing
Psycholytic comes from the Greek psyche meaning “soul” or controversy surrounding LSD. When the Baby Boomer
“personality” and lysis meaning “dissolution.” Psycholytic generation came of age in the mid 1960s, they rebelled
therapy was reported to produce dissolution of psychic against their parents’ values. A growing dissatisfaction with
conflicts or release emotional tension [22]. In doing so, LSD the status quo resulted in the same corporations that
was believed to help resolve the underlying emotional produced an economic boom in the 1950s being blamed for
conflicts that perpetuate the addictive cycle. the Vietnam War in the 1960s. A counterculture movement
developed that fought for women’s rights, civil rights, and
Transcendent Hypothesis Regarding LSD’s Anti- free speech. A growing sense of rebellion among America’s
Addictive Properties youth produced anti-war protests and an outgrowth of the
Beat Generation known as the “hippies.” Fanning the flames
A third hypothesis regarding LSD’s potential mechanism of fear about LSD were unsubstantiated claims that this
of action as an anti-addiction medicine stems from its medicine caused brain damage. Such exaggerations were
reported ability to produce transcendent, mystical, or peak intensified by the thalidomide scare of the late 1950s and
experiences [22]. Transcendent experiences can produce early 1960s [67]. The failure of the media and politicians to
transformative effects on those who undergo them. A classic distinguish monitored, therapeutic use of LSD from
example is the transcendent experience of Bill W., the unmonitored, recreational use fostered increasingly negative
founder of Alcoholics Anonymous. While receiving perceptions of this medicine.
inpatient treatment for severe alcoholism, Bill W. underwent
a profound transcendent experience. As a result of that
LEGAL STATUS OF LSD
experience, he stopped drinking alcohol [66].
The burgeoning recreational use of hallucinogens and
RECREATIONAL USE OF LSD other drugs in the 1960’s created escalating social and
political pressures to control the use of these drugs. Prior to
In the 1960’s, the use of LSD spread from research 1966, there were no state or federal criminal penalties for the
laboratories and psychiatric hospitals to the streets of unauthorized possession, manufacture, or sale of LSD [24].
America. This created a “psychedelic movement” in which
people began using LSD for recreational or spiritual However, in 1965 the U.S. Congress passed the Drug
purposes [67]. Hundreds of thousands of people were drawn Abuse Control Amendments. These amendments, which
to San Francisco in 1967 for the “summer of love” [2]. went into effect in 1966, modified the Food, Drug, and
Cosmetics Act and allowed the Secretary of Health,
Unsupervised use by individuals who lacked medical Education, and Welfare to designate hallucinogenic drugs (as
supervision or adequate preparation resulted in widespread well as certain stimulant and depressant drugs) as controlled,
abuse and “bad trips.” The popular media provided thus requiring licensing for their manufacture, sale, or
sensationalized stories about how LSD was corrupting distribution. The Drug Abuse Control Amendments still
America’s youth. In April 1966, a Harvard graduate and permitted possession of these drugs for personal
former medical student was dubbed the “LSD slayer” after consumption or for administration to animals, however [72].
he confessed to stabbing and killing his mother-in-law under
the influence of LSD. However, it later turned out that he In the spring of 1966, Senator Robert Kennedy, called for
was not under the influence of LSD at the time of the congressional hearings. Senator Kennedy, whose wife had
murder. Instead, he suffered from chronic schizophrenia. been treated with LSD, spoke in favor of additional research
Nonetheless, Time magazine fueled the hysteria by reporting rather than greater controls on LSD. Kennedy expressed
in 1966 that an LSD epidemic was sweeping across America, concern with the FDA’s interference with the scientific
producing rampant psychosis in America’s youth [68]. investigation of LSD [73]. That same year, Sandoz halted the
production and distribution of LSD [24]. This resulted in a
Adding to the controversy over LSD was its use by two marked reduction in the number of research studies
high profile individuals at Harvard University, Timothy investigating LSD’s potential therapeutic effects.
Leary and Richard Alpert. Leary and Alpert were strong
proponents of the use of LSD in non-medical settings.
LSD in the Treatment of Addictions Current Drug Abuse Reviews, 2014, Vol. 7, No. 3 153

In 1968, President Lyndon Johnson issued an executive psychoanalysis, and Jungian psychotherapy [4]. This use of
order creating the Bureau of Narcotics and Dangerous Drugs LSD stemmed from early researchers’ discovery that the
(BNDD). The BNDD was formed by merging the Bureau of effects of LSD were sometimes quite different from those
Narcotics, which was responsible for the control of predicted by the “model psychosis theory”. For example,
marijuana and narcotics such as heroin, with the Bureau of rather than being guarded or paranoid, some subjects were
Drug Abuse Control (BDAC), which had been responsible able to talk more easily about their problems during their
for handling hallucinogens, depressants, and stimulants. The LSD sessions. Increased insight into the emotional meaning
BNDD was responsible for enforcing the Drug Abuse of symptoms, improvements in depression, reduced anxiety,
Control Amendments of 1965. In 1970, the Controlled reduced compulsions, increased sense of well-being, and
Substances Act created five schedules for controlled increased access to previously repressed memories were
medicines [74]. LSD was placed in Schedule I, the most additional unexpected findings [1, 4]. Busch and Johnson felt
restrictive of the five schedules. In 1973, the Drug LSD might serve as a tool for shortening psychotherapy [81].
Enforcement Agency (DEA) was established. The DEA A Czechoslovakian study reported LSD produced “good”
assumed responsibility for enforcing the Drug Abuse Control results as a treatment for personality disorders [82].
Amendments of 1965, which had previously been the
LSD has been investigated as a treatment for non-
responsibility of the BNDD.
psychiatric disorders as well. In the 1960’s, LSD was studied
While greater restrictions were being placed on LSD in as an analgesic. Administered at doses below psychedelic
the United States, controversy over the drug was growing levels, LSD was found to exhibit potent analgesic properties.
internationally as well. In 1971, the United Nations’ Kast and Collins administered 100 micrograms of LSD to 50
Convention on Psychotropic Substances established four patients with severe, intolerable pain. The analgesic effects
Schedules of controlled substances. LSD was placed in were stronger than the effects derived from traditional
Schedule I, the most restrictive of the Schedules [75]. opiates and provided longer lasting reductions in pain [23].
In addition to the increasing legal restrictions placed on Pahnke et al. reported about two-thirds of terminal cancer
LSD, another result of the growing political and social patients experienced improved mood, reduced anxiety,
polarization of psychedelics was a perceived schism between decreased fear of death, and decreased use of analgesic
“good medicines” and “bad drugs”. This lead to the so-called medication following the administration of LSD [83].
“War on Drugs”, a term first coined by President Richard LSD has also been used as a treatment for cluster
Nixon. The War on Drugs was an effort to stem the tide of
headaches. Sewell et al. studied 53 patients who suffered
illegal drug traffic through military intervention and military
from cluster headaches. They selected individuals who had
aid to foreign countries.
used LSD or psilocybin specifically to treat their condition.
The increasingly restrictive legal climate and social They found 7 of 8 LSD users reported cluster period
stigmatization of LSD contributed to a precipitous drop in termination and 4 of 5 LSD users reported remission period
the number of research studies involving LSD in the 1970’s. extension following self-administration of LSD [84].
This decline in research was not permanent, however.
CONCLUSION
RESURGENCE OF RESEARCH
Addictions constitute a global health crisis. The 2012
In 1988, the Swiss Federal Office for Public Health gave World Drug Report estimated 230 million people use illicit
special permission to resume research with LSD. Research drugs each year and almost 200,000 die from drugs [85]. In
continued in Switzerland until 1993, when all research with 2009, close to 30% of the world population used illicit drugs,
psychedelics was again prohibited [76]. alcohol, or nicotine. In areas of Europe, South Asia, and
Africa, the rate of prescription drug abuse exceeds the rate of
In 2007, a group of Swiss psychiatrists was granted
abuse of certain illicit drugs such as cocaine or heroin [86].
permission to study the effects of LSD on anxiety in patients
with life-threatening illnesses. This research began in 2008 The situation is no better in the US. Prescription drug
and ended in 2011. Twelve subjects underwent 30 sessions. abuse and dependency are growing at alarming rates. Nearly
Twenty-two sessions involved a therapeutic dose of 200 2 million persons age 12 or older are estimated to have
micrograms of LSD and 8 sessions involved a placebo dose abused or been dependent upon prescription pain relievers in
of 20 micrograms of LSD. All 12 subjects reported benefits the last year [87]. From 1999 to 2006, the number of fatal
from the treatment and none reported any serious adverse poisonings involving opioid analgesics more than tripled in
effects [77]. the US from 4,000 to 13,800 deaths [88]. Excessive
consumption of alcohol is now the third leading cause of
OTHER USES OF LSD death in the US, with more than 75,000 deaths attributed to
excessive drinking in 2001 [89]. The high failure rate of
In addition to its role as a treatment for addictions, LSD existing pharmacologic interventions for addictions
also has been studied as a treatment for other psychiatric and highlights the need for new, more effective treatments.
medical conditions. For example, Obsessive-Compulsive
Early optimism regarding LSD’s potential as a treatment
Disorder (OCD) and depression have been suggested to
for addictions was later replaced by skepticism generated by
respond to treatment with LSD [78-80].
methodologically flawed studies, widespread misuse, and an
LSD was utilized as an adjunct to various forms of increasingly restrictive legal climate. However, a
psychotherapy including individual psychotherapy, reevaluation of the historical context in which early research
154 Current Drug Abuse Reviews, 2014, Vol. 7, No. 3 Mitchell B. Liester

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Received: August 19, 2014 Revised: August 28, 2014 Accepted: September 4, 2014

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