Journal of the Neurological Sciences 411 (2020) 116715

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Journal of the Neurological Sciences

journal homepage: www.elsevier.com/locate/jns

Review Article

A review of emerging therapeutic potential of psychedelic drugs in the T

treatment of psychiatric illnesses
Tingying Chi⁎, Jessica A. Gold
Department of Psychiatry, Washington University School of Medicine, USA

ARTICLE INFO ABSTRACT

Keywords: Though there was initial interest in the use of psychedelic drugs for psychiatric treatment, bad outcomes and
Psychedelic drug research subsequent passage of the Substance Act of 1970, which placed psychedelic drugs in the Schedule I category,
MDMA significantly limited potential progress. More recently, however, there has been renewal in interest and promise
LSD of psychedelic research. The purpose of this review is to highlight contemporary human studies on the use of
Psilocybin
select psychedelic drugs, such as psilocybin, LSD, MDMA and ayahuasca, in the treatment of various psychiatric
Safety
illnesses, including but not limited to treatment-resistant depression, post-traumatic stress disorder, end-of-life
Emergent psychiatric therapy
anxiety, and substance use disorders. The safety and efficacy as reported from human and animal studies will
also be discussed. Accumulated research to date has suggested the potential for psychedelics to emerge as
breakthrough therapies for psychiatric conditions refractory to conventional treatments. However, given the
unique history and high potential for misuse with popular distribution, special care and considerations must be
undertaken to safeguard their use as viable medical treatments rather than drugs of abuse.

1. Introduction an adjunct to enhance psychoanalytic therapy. It was used to treat

Psychedelic medicines have a long, vibrant history in human civi-
lization; they have been used on all continents by both highly advanced
and preliterate cultures for centuries, if not millennia, for ritual, re-
creational and healing purposes [1]. In fact, per Oxford Dictionary, the
word “psychedelic” derives from ancient Greek and roughly means to
make manifest or reveal the mind, soul or spirit. Modern history of
psychedelics, however, began in 1943 when the renowned chemist
Albert Hoffman at Sandoz, now a division of Novartis, accidentally
discovered Lysergic acid diethylamide (LSD) while testing alkaloids
from rye ergot fungus. Interestingly, the same chemist also isolated
psilocybin, another psychedelic drug, in 1958. Sandoz marketed LSD
and psilocybin under the trade names of Delysid and Indocybin, re-
spectively, and widely distributed them to experts in fields of neurology
and psychiatry for basic investigative and therapeutic research. This led
to a quarter century of enthusiastic psychedelic research during an era
of rapid advancement in psychopharmacology, where medications such
as chlorpromazine and imipramine were first discovered and manu-
factured [2].
Early psychedelic research explored two treatment paradigms: the
psycholytic and the psychedelic model. The psycholytic model focuses
on administrating low doses of psychedelics during multiple sessions as
disorders such as personality disorders, anxiety, and somatization dis-
orders. The psychedelic model, on the other hand, utilizes higher doses
of psychedelic drugs administered in one or few sessions to induce a
“mystical”, “peak” or “psychedelic” experience. The goal of this method
is to evoke lasting changes in habitual patterns of thoughts and beha-
viors. This model, which has no parallel in modern psychiatric practice,
was studied predominantly among patients with substance use dis-
orders [3]. With clinically favorable profile and potency, these agents
were lauded by many prominent leaders in behavioral sciences as a
breakthrough therapy for intractable psychiatric disorders, such as
anxiety in patients suffering from terminal cancer. These research en-
deavors were widely supported by institutions such as the United States
National Institute of Mental Health, pharmaceutical companies, the
military, and intelligence agencies [4]. For example, in the 50s and 60s,
it was estimated that about 5000 human subjects in the United
Kingdom received LSD in more than 40,000 LSD sessions; during that
era, hundreds of papers were published on psychedelic research
worldwide [5].
In the 1960s, however, the promise of psychedelics for treatment
and therapy quickly turned sour as illicit manufacturing and distribu-
tion led to their widespread black-market use in uncontrolled settings,
often by individuals with significant premorbid psychiatric conditions.

⁎
Corresponding author at: 660 S. Euclid Ave, Saint Louis, MO 63110, USA.
E-mail addresses: t.chi@wustl.edu (T. Chi), jgold@wustl.edu (J.A. Gold).

https://doi.org/10.1016/j.jns.2020.116715
Received 17 August 2019; Received in revised form 3 November 2019; Accepted 29 January 2020
Available online 31 January 2020
0022-510X/ © 2020 Elsevier B.V. All rights reserved.
T. Chi and J.A. Gold
Reports of “bad trips”, characterized by hallucinations, overwhelming
anxiety to the point of panic, aggression, and depression with suicidal
ideation, raised serious concern about the safety of these substances.
The infrequent but often highly publicized homicide cases after “LSD
experiences” further incensed the public [2,6]. Powerful social and
political backlash ultimately led to the passing of Substances Act of
1970 in the United States (US). LSD, psilocybin and several other psy-
chedelic substances were placed in Schedule I by the Drug Enforcement
Administration (DEA), the most restrictive drug category. Per the DEA,
these substances “have no currently accepted medical use in the US, a
lack of accepted safety for use under medical supervision, and a high
potential for abuse” [7]. As a result of this classification, psychedelic
research on humans came to an abrupt halt; it became practically im-
possible to secure any government funding for new projects.
However, support for psychedelic medicines remained strong
among some prominent scientists and even politicians, notably Dr.
Albert Hoffman and Senator Robert Kennedy. In the 1980s, rigorous
research combining new techniques in molecular biology and neuroi-
maging began anew in a few laboratories. The decade saw the rise of
multiple non-profit organizations promoting psychedelic research, in-
cluding the Multidisciplinary Association for Psychedelic Studies
(MAPS), the Heffter Research Institute, and the Beckley Foundation, all
funded by private donors and organizations outside of government
structure [8]. Unlike clinical trials conducted in the 1960s that were
often uncontrolled and unblinded with inconsistent methods, con-
temporary psychedelic studies are carefully designed and subjected to
strict approval process by Institutional Review Boards. Proponents of
psychedelic research have argued that the basis of DEA's Schedule I
designation was politically driven instead of scientifically informed. For
example, prior research has not demonstrated that 5-HT2A agonists,
which included the classic psychedelic drugs such as LSD, psilocybin
and mescaline, reliably induce tolerance, withdrawal, and compulsive
drug-seeking behaviors like known addictive substances such as cocaine
and heroin [9–11]. In fact, some of these drugs may have anti-addictive
properties, as will be reviewed below. Secondly, marijuana, despite its
classification as a Scheduled I Substance, has been safely administered
in medical settings and is currently legalized in several states [12].
Finally, while administration of psychedelic medications does pose
some physiological risks (transient elevation in blood pressure and
heart rate) and unique psychological risk (overwhelming distress
during drug reaction), these risks can usually be effectively minimized
with close medical supervision [13]. As such, proponents argue that
these substances warrant further allowance for scientific study given
their potential promise for psychiatric treatment.
This review will focus on the potential psychiatric benefit of psy-
chedelic drugs. Today, the term “psychedelics” encompass a range of
substances that elicit a multifaceted clinical syndrome that may involve
changes across several cognitive and emotional domains. While there is
no widely accepted definition, generally psychedelic substances can be
classified into “classic psychedelics” and entactogens. The classic psy-
chedelics include LSD, psilocybin, dimethyltryptamine (DMT), and
mescaline. These drugs all act pharmacologically as agonists at the 5-
HT2A receptor. The entactogens include methylenediox-
ymethamphetamine (MDMA), which acts as a serotonin, dopamine and
noradrenaline agonist and has a significantly distinct mechanism of
action than the classic psychedelics [14]. Multiple recent studies have
found promising clinical benefits of psychedelic substances for a wide
range of mental illnesses, including end-of-life anxiety, treatment re-
sistant depression, post-traumatic stress disorder (PTSD), and substance
use disorders. While the pharmacodynamic and neurological under-
pinning of how these psychedelic drugs exert their therapeutic effects
remains unclear, current evidence suggests their possible role in
changing neuronal transcription, inducing entropic brain activities, and
activating cellular pathways distinct from those activated by traditional
psychotropic medications [15]. Specifically, one study showed that
psychedelic compounds representing all three classes of psychedelics,
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Journal of the Neurological Sciences 411 (2020) 116715
namely tryptamines (DMT, psilocybin), amphetamines (MDMA), and
ergolines (LSD), were capable of promoting neurite growth in vitro and
in fruit fly (Drosophila) larvae; additional experiments further demon-
strated mTOR (mammalian target of rapamycin) as a possible down-
stream mediator for the positive neurotropic effect [67]. Interestingly,
mTOR has also been theorized to be an important downstream mediator
for ketamine, despite the difference in target (NMDA versus 5-HT2A).
Another study has shown possible association of reduced amygdala
activity with administration of both psilocybin and LSD, which could
partly explain the euphoric effect these substances often have on mood
[16]. Of note, drugs such as ketamine, scopolamine, and ibogaine are
sometimes also classified as psychedelic. However, they will not be
discussed in this review. Instead, this review would focus on the recent
advancements and potential for use of selected classic psychedelics
(psilocybin, LSD, and DMT) and MDMA. It will highlight important
modern studies in the psychiatric literature for each drug, describing its
safety and efficacy in the treatment of psychiatric illnesses.
2. Methods
This is an expert review of major peer-reviewed studies and NIH-
registered clinical trials where the use of selected psychedelic drugs was
reported.
3. Psilocybin
Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine), known col-
loquially as “magic mushrooms” or “shrooms”, is a tryptamine-related
plant alkaloid that can be found in many species of mushrooms be-
longing to the genus Psilocybe. After ingestion, it is immediately de-
phosphorylated to psilocin (4-hydroxy-N,N-dimethyl-tryptamine),
which is structurally similar to serotonin, or 5-hydroxytryptamine [17].
It is considered a “classic psychedelic” as it exerts its effect mainly
through 5-HT2A agonism [18]. In humans, it may induce a transient
state of altered consciousness characterized by marked perceptual al-
terations, affective disturbance, and thought disorder that is rarely
experienced except in dreams and religious exaltation. As previously
mentioned, psilocybin is currently a Scheduled I substance. However,
multiple recent studies in both healthy volunteers and specific popu-
lations of patients have demonstrated generally good tolerability and
minimal adverse effects. Inspired by prior research in the 60s, several
contemporary research groups have conducted efficacy and feasibility
studies on use in specific psychiatric illnesses, including end-life an-
xiety, treatment-resistant depression, obsessive-compulsive disorder,
and tobacco use disorder.
3.1. Safety trials
Pulling raw data from eight double-blind, placebo-controlled studies
from 1999 to 2008 in Switzerland, Studerus et al. concluded that psi-
locybin is generally well tolerated by healthy volunteers both in the
short-and long-term. The studies include a total of 277 individual psi-
locybin sessions and 110 subjects evaluated with validated instruments
to assess a myriad of physical and psychological symptoms. Some
common short-term adverse effects include fatigue, headaches, and lack
of energy. The group found that most of these adverse effects tend to
resolve within the first few weeks subsequent to drug administration,
and that they are generally not life-interfering. Furthermore, they found
no change in drug-seeking behavior, persisting perception disorders,
prolonged psychosis, or other long-term impairment in function in all
subjects [19]. Of note, the authors did find one subject who had re-
quired professional help for emotional instability, depression, and an-
xiety that persisted several weeks post-experiment; this subject did re-
cover after few sessions of psychotherapy and had not relapsed on
follow-up. Another group, from Hopkins, specifically explored the re-
lationship between psilocybin and headache. Psilocybin, as a serotonin
T. Chi and J.A. Gold
receptor modulator, has many structural similarities with several mi-
graine medications; furthermore, headache is one of the most common
adverse effects of psilocybin. However, after administering a broad
range of psilocybin doses to 18 healthy volunteers, the group concluded
that these headaches are “neither severe nor disabling” [20]. The same
study also does not mention other significant adverse effects.
3.2. Anxiety and depression associated with terminal cancer
Clinically significant and disabling depressive and anxiety disorders
are common in patients with cancer. They are often missed due to
significant overlap between medical and psychiatric symptoms, and the
difficulty in differentiating pathological from normative reactions to
severe illness. Nonetheless, these psychiatric disorders have been as-
sociated with multiple predictors of poor outcome, such as decreased
treatment adherence, decreased quality of life, prolonged hospital stays,
and poor prognosis [21,22]. Despite the costs to individuals and the
society, there are currently few effective pharmacological treatments
for these patients. Conventional antidepressants have shown limited
efficacy compared to placebo [23], and benzodiazepines are generally
not recommended for chronic treatment given side effects and risks of
withdrawal.
In 2010, a group from Harbor-UCLA Medical Center conducted the
first double-blind, placebo-controlled pilot study to investigate the
safety and efficacy of psilocybin in treating anxiety and depression in
patients with advanced-stage cancer. Twelve subjects received two
experimental treatment sessions spaced several weeks apart and served
as their own control. Though the study found no statistically significant
reduction in anxiety and mood, it demonstrated that psilocybin can be
safely administered in this medically ill population with no reported
clinically significant adverse effects [24]. In 2016, two more studies
that involved larger number of subjects were published. A group from
Johns Hopkins conducted a randomized, double-blind, cross over trial
comparing the effects of a very low (placebo-like, 1–3 mg/70 kg) dose
vs very high dose (22–30 mg/70 kg) of psilocybin on 51 patients af-
flicted with advanced-stage cancer. The drug sessions lasted 8-hours
and were conducted in an aesthetic living room-like environment with
two monitors present the entire time. The group found a clinically
significant response for two of the primary outcome measures. Speci-
fically, 92% of the participants demonstrated either clinical remission
or a 50% reduction of depressive symptoms compared to baseline, as
measured by GRID-HAMD-17. More than 75% of the subjects also de-
monstrated similar response in anxiety as measured by HAM-A. Fur-
thermore, a large number of these subjects continued to exhibit reduced
symptom severity or remission at 5-week follow-up. Importantly, all
adverse events were medically non-serious [25]. In the same year, an-
other group from New York University conducted a randomized,
blinded, crossover study using niacin as the active control; study sub-
jects in both the experimental and control groups also received psy-
chotherapy. In this study, 29 patients were followed for 9 months. The
results showed significant improvement in both depression and anxiety;
specifically, more than 80% of study subjects receiving psilocybin met
criteria for antidepressant response, compared with 14% in the group
that received niacin (for anxiety, it was 58% for psilocybin and 14% for
niacin). At 6.5-month follow-up, after all subjects received psilocybin
from the crossover leg, the anti-depressant or anxiolytic response rate
were about 60–80% [26]. While it is unclear from the data whether the
beneficial outcome was secondary to psilocybin alone or some inter-
active effect of psilocybin plus targeted psychotherapy, the improve-
ment was vast and significant and, similar to the study conducted by the
group from Johns Hopkins, there were no serious adverse effects. The
authors did, however, recommended further research to elucidate the
contribution of each component alone.
All three of these studies share similar limitations in terms of patient
selection bias and suboptimal blinding. The study from Johns Hopkins,
for example, was conducted on subjects who are predominantly
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Journal of the Neurological Sciences 411 (2020) 116715
Caucasian, with almost half of the subjects having past exposure to
psychedelic substances. In other words, expectancy effect, where sub-
jects' expectations of certain result (e.g. taking psilocybin) could un-
consciously affect the outcome and could be an important contributor
to study results. However, some authors argue that psychological ex-
pectations can be therapeutic and should be considered as an active
part of treatment rather than a confounder [27]. As expected, there is
an inherent difficulty with blinding given the unique effect of psyche-
delic substances. Even when using an active placebo such as niacin,
which produces effect of warmth, arousal, and tingling sensation, post-
experiment analysis by the group from New York showed that the staff
had guessed the assignment correctly in 97% of the cases. Regardless of
these limitations, these studies have demonstrated not only feasibility
and safety, but potentially paradigm-altering benefits of psilocybin on a
refractory psychiatric disorder in a particularly ill population in need of
potential treatments.
3.3. Treatment resistant depression
A group from London conducted an open-label, non-controlled
study investigating possible benefits of administrating psilocybin to
twelve patients with treatment resistant depression. At the time of
participation, all twelve patients were in an active depressive episode
and had demonstrated no improvement after two adequate trials of
antidepressants from different pharmacological classes lasting more
than six weeks within the current episode. All patients were clinically
assessed to have moderate to severe depression at the time of enroll-
ment. After receiving two treatment sessions of psilocybin, 67% of the
patients achieved clinical remission and 58% continued to meet criteria
for response after three months [27]. No serious adverse events were
found other than transient confusion, anxiety, mild thought disorder,
headache, and mild nausea. This side effect profile compares extremely
favorably to currently available treatments such as electroconvulsive
therapy and vagal nerve stimulation. If further research continues to
reliably demonstrate safety and efficacy, psilocybin could potentially
become an invaluable treatment option for treatment resistant depres-
sion.
3.4. Obsessive-compulsive disorder
Obsessive-compulsive disorder (OCD) is a chronic illness with few
patients achieving true remission in their lifetime [28]. Though selec-
tive serotonin reuptake inhibitors (SSRIs) are potent and effective first-
line treatments, about 40–60% of patients do not respond to SSRI
therapy [29]. Other options for treatment refractory patients include
switching to another SSRI, augmenting with other agents, and adding
Cognitive Behavioral Therapy (CBT). However, a significant percentage
of these patients would remain treatment refractory; at that point, novel
or experimental drug treatments such as electroconvulsive therapy,
neurosurgery, or repetitive transcranial magnetic stimulation may be
considered. Yet these neurosurgical techniques are often invasive,
highlighting the need for other novel therapeutic options in this po-
pulation.
A group from University of Arizona recently conducted a small
proof-of-concept study on nine subjects with OCD who had failed at
least one first-line treatment. All of these subjects must have had prior
exposure to psychedelics and must abstain from antidepressants for at
least two weeks prior to treatment. They then received four escalating
doses of psilocybin in random order, from very low dose to high dose
(25 to 300 μg/kg body weight), in four sessions separated by at least
one week. Aggregate results from all dosing, even the very low dose,
showed a 23–100% reduction in symptoms as measured by the Yale-
Brown Obsessive-Compulsive Score (YBOCS) 24 h post-exposure [30].
The improvement, however, did not appear to persist beyond one week
as most subjects returned to baseline symptoms by the next session.
This preliminary study demonstrates acute, transient benefit of
T. Chi and J.A. Gold
psilocybin in patients with refractory OCD. While results from one small
pilot study is unlikely to be generalizable, the overall positive results do
at least warrant further research.
3.5. Smoking cessation
There is one open-label pilot study exploring the effect of psilocybin
on patients with Tobacco Use Disorder. In this study, fifteen psychia-
trically healthy subjects received three sessions of moderate or high
doses of psilocybin within a structured 15-week smoking cessation
treatment protocol consisting of four weekly meetings integrating CBT,
elements of mindfulness training, and guided imagery. Abstinence from
tobacco was monitored and confirmed by exhaled CO and urinary co-
tinine level. At 6-month follow-up, twelve out of fifteen (80%) of the
participants showed seven-day point prevalence abstinence [31]. The
cessation rate was significantly higher than commonly reported rate for
other available behavioral or pharmacology therapies, such as bupro-
pion, varenicline, and CBT (<35%). Notably, ten out of fifteen (67%)
participants continued to be abstinent at 12-month follow-up, at a rate
that also exceeded what was typically found with other smoking cession
aids (around 30%) [32]. Similar to other trials, there were no clinically
significant adverse events. One possible limitation of the study, how-
ever, was that it included a self-selected population that was motivated
to quit. Head-to-head trials comparing psilocybin and popular smoking
cessation aids are needed to contextualize these findings, yet these re-
sults show promise for use in tobacco cessation.
4. LSD
Lysergic acid diethylamide (LSD), often referred to by the street
name “acid”, is one of the most potent known hallucinogens. Similar to
psilocybin, it is a classic psychedelic as it exerts its effect through 5-
HT2A agonism. However, unlike psilocybin, it has also been shown to
indirectly affect dopaminergic neurotransmission without direct D2
receptor stimulation [33]. As aforementioned, LSD was first synthesized
by Albert Hofmann in 1938 from lysergic acid, a chemical derived from
ergot fungus (Claviceps purpurea) and several other fungal species. In
1947, the clinical similarity between the effect of LSD and schizo-
phrenia was noted, leading to its experimental use as a model for
psychosis. It has been found that animals chronically treated with low-
dose LSD (0.16 mg/kg every other day for more than three months)
exhibited symptoms of hyperactivity, irritability, anhedonia and im-
paired social interaction that persisted months after cessation of LSD
treatment; these symptoms mimic closely the negative symptoms of
chronic schizophrenia. Interestingly, these symptoms could be tran-
siently reversed by antipsychotics such as haloperidol and olanzapine
[34]. In humans, however, judicious ingestions of LSD had not been
shown to cause persistent psychosis, at least not in people without pre-
existing psychotic condition [35]. In fact, Albert Hofmann, who in-
tentionally ingested the substance at high dose as part of self-experi-
ment, described a sense of profound wellbeing after surviving the in-
itial, transient symptoms of unpleasant “altered perception, fear and
paranoia”. It is not surprising then that when LSD was first distributed
by Sandoz pharmaceuticals in 1948, the product guidelines had stipu-
lated “analytical psychotherapy” and “experiment studies on psychosis”
as two main applications [16].
While most early clinical trials used LSD, contemporary trials tend
to use psilocybin due to its shorter duration of action and less con-
troversial history [35]. For this reason, there are not as many studies
with LSD compared to those on psilocybin. Nonetheless, over the last
decade, multiple placebo-controlled studies on healthy volunteers and
one study on the effect of LSD on anxiety among patients with terminal
cancer have been conducted. This section will summarize findings from
these studies, in addition to provide one recent meta-analysis that pools
several well-designed studies conducted from 1966 to 1970 on the ef-
ficacy of LSD in patients with alcohol use disorder.
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Journal of the Neurological Sciences 411 (2020) 116715
4.1. Safety trials
Over the last five years, several placebo-controlled studies of LSD
have been conducted in Basel, London, and Zurich on about one hun-
dred healthy subjects. The dose ranges from low moderate (40–80 μg)
to relatively high dose (200 μg). These studies have provided several
insights into the psychological and medical effects of LSD. First, LSD
produces profound acute psychosis-like symptoms such as delusional
thinking, perceptual distortion, cognitive distortion, and paranoia. One
study found that LSD produces a mean Psychotomimetic States
Inventory (PSI) score that is much higher than what was found after
ketamine infusion, post-THC, and post cannabis use; fortunately, these
effects were found to be only transient [36]. The same study also noted
that for majority of the subjects, even those who experienced un-
pleasant psychotic symptoms, endorsed positive mood and other posi-
tive effects such as significant increases in optimism and personality
trait openness. The finding that LSD could cause “blissful state” is also
found in another study [30]. These results could explain why LSD was
found to be efficacious in treating anxiety and mood disorders and as a
psychotherapy adjunct in the 1960–1970s. Secondly, no serious adverse
physiological effect was observed other than transient increase in sys-
tolic blood pressure, heart rate, and temperature [37,38]. Common
post-experiment psychological adverse effects included headache, ex-
haustion, difficulty concentrating, and anxiety; these symptoms tended
to resolve by the end of experiment and were not life-impairing
[36,37,39].
4.2. Anxiety associated with terminal cancer/diseases
To date, there has been only one double-blind, active placebo-con-
trolled, randomized clinical trial exploring the feasibility of LSD on
patients with life-threatening illnesses. In this study, 12 subjects with
terminal cancer, autoimmune, and neurological diagnoses underwent a
3-month experiment that included 6–8 psychotherapy sessions com-
bined with two LSD experiences at 4 to 6-week intervals. The partici-
pants were randomized to full-dose group (200 μg) or active placebo
(20 μg). At baseline, all participants exhibited significant anxiety as
measured by the Spielberger State-Trait Anxiety Inventory, and all but
one subject had a history of being treated for major depressive disorder,
panic disorder, or generalized anxiety. On days of LSD administration,
subjects stayed overnight at the physician's office with attendant
nearby. 9 out of 12 subjects completed follow-ups at 1 week, 2 months,
and 12 months. Though the primary outcome measure was not statis-
tically significant (no clinical improvement in anxiety scores), there was
a positive trend towards improvement of anxiety. Perhaps more im-
portantly, the study found no patients experienced adverse effects that
are often attributed to LSD, such as prolonged anxiety (“bad trip”),
lasting psychotic or perceptual disorders, or clinically significant
changes in heart rate and blood pressure [40,41].
4.3. Alcohol use disorder
A recent meta-analysis of six double-blind, randomized control trials
from 1966 to 1970 yielded promising efficacy of LSD on reducing
problematic drinking behavior and total abstinence. The meta-analyses
included a total of 536 adults, where about 60% were randomized to
receive experimental dose of LSD. All subjects had listed “alcoholism”
as their primary problem and had been admitted to alcohol-focused
treatment programs prior to participation. All trials excluded patients
with known personal psychiatric conditions. Active LSD doses ranged
from 200 to 800 μg, while placebos included low-dose LSD, d-amphe-
tamine, inactive drug, or ephedrine. All subjects received one LSD dose
and were monitored during the active treatment phase. Though the
preparation and follow-up before and after the experimental session
varied between the studies (from very brief orientation and no de-
briefing to multiple clinical interviews plus psychotherapy), all trials
T. Chi and J.A. Gold
used clearly defined, standardized questionnaire to assess outcomes on
alcohol abuse. The outcomes were then dichotomized into “improved”
or “not improved”; improvement encompassed both abstinence and
reduction in binge drinking behaviors. The results showed a statistically
significant of improvement in problematic alcohol use. Specifically, at
2–6 months follow-up, LSD was associated with a reduction in proble-
matic drinking behavior with a number needed to treat (NNT) of 6. This
compares favorably with naltrexone, which has an NNT of 9 at similar
perimeters. LSD is also shown to have positive effect on abstinence that
is significant at least in short follow-up (1–3 months). Ultimately, it is
interesting to consider that a single dose of LSD may provide similar
effect as oral naltrexone, which requires daily dosing. However, one
could argue that, for possibly comparable benefit, Vivitrol injections are
more convenient and less controversial to administer on an outpatient
basis. Of course, there are no studies that compare LSD with monthly
Vivitrol injection. Even still, the study found no lasting harmful adverse
effects of LSD even in this large population. This suggests that the risk
as compared to vivitrol might be comparable. Regardless, the result of
this study points to potential benefits of LSD on an important, prevalent
substance use disorder [42].
5. MDMA
MDMA (3, 4-methylenedioxymethamphetamine), known commonly
by the street name “Molly” or “ecstasy”, was first synthesized in 1912
by pharmaceutical company Merck as a precursor to a new potential
hemostatic compound [43]. It is a ring-substituted methamphetamine
derivative but, unlike methamphetamine or amphetamine, it exerts its
effect mainly on the serotonin transporter. MDMA remained virtually
unknown, however, till the mid-1970s when its therapeutic potentials
were explored by a small group of therapists and researchers [44].
MDMA was described at the time as a relatively mild, short-acting drug
that promoted introspection, reduced fear response to perceived emo-
tional threats, and encouraged friendliness with others without the
troublesome perceptual alternation or emotional lability observed with
LSD [45]. About 500,000 doses of MDMA had been consumed between
early 1970s to 1980s with little to no negative publicity; side effects
were perceived to minimal at the time, presumably with judicious use
as prescribed by the therapists. However, the drug became increasingly
popular through word of mouth; by 1980s, aggressive marketing led to
a dramatic increase in recreational use. Interestingly, MDMA was al-
most marketed as “empathy”; however, the distribution network
thought that “ecstasy” would sell better even though “empathy” was
more appropriate [44]. Today, MDMA remained popular among young
people, especially in dance clubs and rave parties [46,47]. There is
ongoing controversy regarding the safety of MDMA, as will be discussed
below. While historically MDMA was used to treat a variety of disorders
including alcohol use disorder, OCD, end-of-life anxiety, and sequalae
to psychological trauma [44], contemporary MDMA research over the
last decade has been focusing on its potential as a novel therapy for
post-traumatic stress disorder (PTSD).
5.1. Safety trials
Over the last several decades, more than a thousand papers ex-
amining the potential short and long-term effect of MDMA use have
been published; however, results were inconsistent and at times con-
tradictory given wide variability in the type, quality, participant se-
lection criteria and methodologies utilized, generating considerable
controversy [46,48]. For example, there has long been concern about
MDMA-induced neurotoxicity based on prior studies on rodents and
primates. A group from Johns Hopkins has demonstrated that admin-
istrating squirrel monkeys at 2.5, 3.5, and 5.0 mg/kg of MDMA twice
daily for four days could result in significant serotonin depletion and
loss of serotonin-immunoreactive nerve fibers in dose-dependent
manner when the animal brains were removed and studied two weeks
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Journal of the Neurological Sciences 411 (2020) 116715
post-exposure [49]. Similar studies are obviously impossible to conduct
in humans. However, it turns out that serotonin plays an important role
in regulating the sensitivity of auditory neurons; in response to loud
noises, serotonin helps attenuating cortical response to protect neurons
from being damaged from overstimulation. Using electro-
encephalogram (EEG), a group from London was able to compare cor-
tical responses to loud auditory stimuli in the primary auditory cortex
between long-term MDMA users, long-term cannabis users, and con-
trols. The result showed impaired cortical responses in long-term
MDMA users, indirectly suggesting MDMA-induced neurotoxicity [50].
However, proponents of therapeutic MDMA research argued that ret-
rospective data on long-term users lacked validity, citing reasons such
as that the doses consumed are often much higher in naturalistic set-
tings, that street MDMA pills often contain other impurities, that self-
report of past usage is inherently subject to bias, and that many of the
subjects are multi-drug users.
Ideally, the effect of MDMA should be evaluated in prospective,
placebo-controlled trials with strict inclusion criteria, validated in-
struments for outcome measures, and standardized dosages. In 2006,
Dumont et al. screened over 1400 articles and found 29 studies (for a
total of around 300 subjects) from 1998 to 2004 that met the afore-
mentioned criteria. Physiologically, the authors found that MDMA most
often causes increase in cardiovascular markers (SBP, DBP, HR), pupil
size, and temperature. Notably, among the included studies there was
not enough reported evidence on the side effect of memory changes.
The authors had expressed surprise and disappointment over this
finding given the fact that retrospective studies have consistently cited
memory problem as one of the most concerning side effects [47]. Since
2006, about a dozen similarly-designed studies on healthy subjects have
been performed; however, they were small and not all of them had
specifically measured adverse side effects. In 2017, a group from Uni-
versity of Basel in Switzerland pooled data from 9 placebo-controlled,
crossover studies performed in the same laboratory on a total of 166
health subjects. Among them, 30 participants received a single 75 mg
dose of MDMA. Among the remaining 136 participants, MDMA was
administered as a single dose in 24 subjects and as two single-doses of
125 mg in 112 subjects, resulting in total exposure of 250 mg of MDMA
(time interval between the two doses was about 26 days). The study
again confirmed the dose-dependent effect on vital signs. Among all
subjects, no hypertensive urgencies or hyperpyrexia (> 40 degree
Celsius) was reported; however, maximal systolic and diastolic blood
pressure values were 196 and 130 mmHg, and maximal temperature
was 39.1 degree Celsius. Frequent acute adverse effects included lack of
appetite (59% of MDMA group versus 1% in placebo), dry mouth (55%
vs. 1%), difficulty concentrating (46% vs. 4%), and bruxism (40% vs.
2%). Subacute (up to 24 h) effects were similar. Chronic (around
30 days) effects on kidney and liver functions were nonexistent, though
there was a statistically significant decrease in hemoglobin and red
blood cells in women. Most side effects were found more commonly in
volunteers receiving higher doses of MDMA. No serious adverse effect
was reported [51]. Unfortunately, memory-related side effects were not
investigated in this study, presumably due to the short follow-up.
Overall, it would appear that prospective participants in any MDMA
trial will need to be carefully screened, especially for existing cardio-
vascular conditions, and that there are more regularly occurring, dose
dependent, side effects of MDMA than have been found for some other
psychedelics. Again, more high-quality long-term data is needed to
evaluate possible permanent adverse effects and to determine whether
there is a “safe” exposure dose for humans.
5.2. PTSD
Current guidelines for PTSD suggest psychotherapy as first-line
treatment over pharmacological monotherapies, namely the SSRIs ser-
traline and paroxetine, the only two Federal Drug Administration
(FDA)-approved medications for PTSD [52]. The effect size for both
T. Chi and J.A. Gold
exposure therapy and CBT, two popular psychotherapeutic options, was
about 8.0 when compared to waitlist or supportive counseling [53].
This is similar to the effect size of sumatriptan for temporary migraine
relief and levodopa for reduction of Parkinson's symptoms [54]. How-
ever, while effective, the response rate for participants who completed
the entire course of active psychotherapy treatment (usually
10–12 weeks) falls between 60 and 95% [53]. In other words, while
psychotherapy is an effective treatment for PTSD, studies indicate that
about 25 to 50% of participants who enrolled in clinical trials remained
refractory. This emphasized the need for further research into more
effective options for this chronic, debilitating illness [55].
The first modern pilot study of MDMA-assisted psychotherapy was
conducted in Spain in 2008; however, the study was prematurely ter-
minated due to political reasons [56]. Two years later, in 2010, the
MAPS completed the first clinical trial investigating the effect of MDMA
as psychotherapy adjunct. The study was a randomized, double-blind,
placebo-controlled pilot study with 20 participants, among whom the
majority had failed either multiple adequate medication trials or at
least one course of psychotherapy. Of note, all subjects were required to
taper and abstain from all psychotropic medications except sedative
hypnotics or anxiolytics given as needed between MDMA or placebo
sessions. All participants received manualized psychotherapy based on
prior LSD-assisted psychotherapy conducted during 1970s with PTSD-
specific modifications. MDMA (125 mg) or a placebo was administered
in two 8-hour experimental psychotherapy sessions followed by over-
night stay in the clinic with nurse on duty. The two sessions were about
four weeks apart, with three weekly psychotherapy sessions in between.
Primary outcome was measured by Clinician-Administered PTSD Scale
(CAPS), considered the gold standard in PTSD assessment, and was
obtained at baseline, 4 days after each experimental session, and
2 months after the second session. Clinical response was defined as
>30% reduction from baseline of CAPS total severity score. Significant
reduction was shown after 4 days post first experimental session; at 2-
month follow-up after the second experiment session, the clinical re-
sponse rate was 83% (10/12) in the MDMA group versus 25% (2/8) in
the placebo group. Ten participants in the MDMA group no longer met
DSM-IV criteria for PTSD compared to two in the placebo group. Fi-
nally, the study offered an open-label arm where the participants ran-
domized to the placebo group could cross-over. After crossing over, the
clinical response rate was found to be 100% [57]. Moreover, the im-
provement in symptoms appeared to be sustained when 16/20 of the
subjects were reassessed with CAPS at long-term follow up (between 17
and 74 months post study, with mean of 45 months) [58]. No lasting
medical or psychiatric adverse effects were observed in both studies.
Interestingly, a group from New Zealand replicated the study by
MAPS but did not find a statistically significance in MDMA-assisted
psychotherapy versus psychotherapy alone. The study did, however,
concur the overall tolerability of MDMA; there was no serious drug-
related adverse events. The authors cited baseline differences in sub-
jects (participants at the earlier study had higher baseline CAPS),
chance (given smaller number of subjects), and cross-cultural differ-
ences as possible reasons for the discrepancy [59].
Nonetheless, the MAPS group proceeded to conduct six phase two
trials at five study sites: three in the US, one in Canada, one in
Switzerland, and one in Israel, from 2004 to 2017. All six trials used a
randomized, double-blind design but with active doses varying between
75 and 125 mg and placebo or control doses from 0 to 40 mg. The six
studies enrolled a total of 105 patients, with 31 in the control group and
74 in the active treatment group. The patients had baseline CAPS score
similar to those in the pilot study and had failed at least one pharma-
cological therapy or psychotherapy. The design and primary outcome
measure were otherwise similar to what was previously described. The
authors found a significant difference in symptom reduction between
the control and treatment groups; in addition, more participants in the
active group no longer met PTSD criteria compared to the control group
(54% versus 23%) [60,61]. Regarding tolerability, there were four
6
Journal of the Neurological Sciences 411 (2020) 116715
serious adverse events. Three of them were considered unrelated to
treatment: one participant developed both suicidal ideation and major
depression in response to life event, and another developed appendi-
citis. The last serious adverse event occurred in one participant with
pre-existing premature ventricular contraction. This participant had
developed an acute increase in premature ventricular contraction after
receiving MDMA; fortunately, this participant recovered without any
permanent cardiac sequalae after staying overnight for cardiac mon-
itoring. Besides these isolated incidents, the studies also found a dose-
related common but non-serious side effects of jaw clenching and per-
spiration, in addition to transient elevation in vital signs that resolved
spontaneously by the end of the experimental session. Of note, in one of
the studies that was based in California, the authors mentioned no in-
crease in ecstasy-seeking behavior [61]. Based on the safety and effi-
cacy results, phase 3 trials are currently being conducted by the same
group. If the phase 3 trials continue to show similarly favorable results,
MDMA may become an FDA-approved treatment as a psychotherapy-
adjunct by 2021.
While promising for treatment resistant cases, MDMA will unlikely
become the first-line therapy for PTSD given the imaginable cost as-
sociated with the extensive monitoring protocols set forth by these
studies and the higher potential risk of use. Considering the high
number of study participants who achieved full remission after the
treatment, however, the potential is great for those failing other treat-
ments, particularly in addition to psychotherapy.
6. Ayahuasca
Ayahuasca is a brew used in traditional spiritual ceremonies by
indigenous people of the Amazon Basin and has been legal for ritual
purposes in Brazil since 1987. It is often prepared with mixture of two
plants, one containing the psychoactive substance dimethyltryptamine
(DMT), a serotonin and sigma-1 receptor agonist, and another con-
taining reversible monoamine oxidase inhibitors. There is currently one
completed NIH-registered clinical trial on the effect of ayahuasca on
patients with treatment-resistant depression. In 2016, a group from
Brazil conducted a double-blind, randomized placebo-controlled trial in
29 patients with treatment resistant depression, defined similarly as in
previously mentioned study with psilocybin. Participants received one
single dose of ayahuasca (0.36 mg/kg of N, N-DMT) or placebo in one 8-
hour supervised experimental session. Depression severity, measured
with the Montgomery-Asberg Depression Rating Scale (MADRS) and
Hamilton Depression Rating scale, was assessed at baseline and after
day 1, day 2, and day 7. Of note, it would appear that this study was
partially modeled after recent studies on ketamine, where subjects were
assessed similarly on day 1, 2, and only as long as 7 days after single
administration [62,63]. In other words, this study was designed to in-
vestigate the potential “rapid antidepressant” effect of ayahuasca. Re-
sult showed a statistically different response rate (defined as reduction
of 50% or more from baseline scores) at Day 7: 64% in the experimental
group and 27% in the placebo, with NNT of 2.66 [64]. However, the
authors noted strong placebo effect – in fact, response rate was 50% in
the experimental group and 46% in the placebo group after day 1, and
the rates remained high (77% in experimental and 64% in placebo) on
day 2. Other than vomiting, the authors did not mention other adverse
events that were more likely to associate with ayahuasca versus pla-
cebo, which was made to simulate the bitter taste and brownish color of
the brew. One interesting aspect of this study was that all subjects were
ayahuasca-naïve. Also interesting was the fact that about 76% of the
subjects had a diagnosis of personality disorder, mostly histrionic and
borderline; moreover, most of the participants came from lower so-
cioeconomic class. Authors speculated that these participant char-
acteristics could have accounted for the high placebo effect. Regardless,
this study showed some benefit in a clinically important population that
was different from previous psychedelic studies, which often recruited
highly educated, Caucasian participants with prior experience with the
T. Chi and J.A. Gold
psychedelic drug. As a possible treatment, however, the use of aya-
huasca is in its infancy and much more research needs to be done.
7. Conclusion
Based on the results from modern studies, including randomized
control trials, classical psychedelics (psilocybin, LSD, DMT) and en-
tactogens (MDMA) have demonstrated potential efficacy in patients
suffering from psychiatric illnesses refractory to conventional treat-
ments. For example, psilocybin may improve end-of-life anxiety and
depression that are minimally responsive to SSRI therapy. While clin-
ical trials are not numerous and limited by weaknesses (non-controlled
experimental set-up, strong placebo effect), there is hope that psilo-
cybin and ayahuasca could be effective in treatment-resistant depres-
sion. As we have seen with ketamine, it is quite interesting to consider
that single doses of a medication could possibly result in lasting effect;
this presents a drastic paradigm shift from contemporary practices of
psychiatry, where most available treatments require multiple regular
administrations over prolonged period of time to achieve maximal
benefit. Future research into psychedelic medicines, as with any other
emergent novel therapies, will require balancing between foreseeable
benefits, adverse effects, and feasibility.
Despite concern about side effects, particularly the fear of addiction
and abuse, psychedelics appear to be generally well-tolerated.
Physiological changes, such as elevation in cardiovascular perimeters,
were found to be transient and mostly non-medically serious except in
patients with pre-existing heart condition. Other side effects, both
physical and psychological, were usually mild and not functionally
impairing. Serious adverse events, such as persistent psychosis and
suicidality, have not been demonstrated. Some psychedelics, such as
psilocybin and LSD, have even been shown to have anti-addictive
property in patients with substance use disorders. One could argue that
it is still simpler, safer, and perhaps more cost-effective to take a pill
every day than to receive one dose of controlled substance, given the
extensive amount of time, monitoring, and preparation required.
However, if taking a pill is ineffective, the promise of these medications
may outweigh the fear of potential risk. Additionally, psychedelic re-
search is still at its preliminary stage; in the future, it is possible that
these substances may be administered in less and less restrictive settings
as more information about their safety, pharmacology and mechanism
of action comes to light.
The recent renewed interest in psychedelics has already begun to
capture public imagination, inspiring anecdotal reports, popular gen-
eral-audience books, and dedicated psychedelic research centers in
major academic institutions [66]. Given the unique history of psyche-
delics, special precaution must be taken in the dissemination of these
findings to the general population and their subsequent implementation
as therapies. The history of psychedelic research has demonstrated
unequivocally that rampant, uncontrolled usage of these powerful
substances can lead to harm and also hindrance to bona fide scientific
research. We also know that the opinions of the public, politicians, and
medical professionals do not always align as we saw with the re-
classification of psychedelics as Schedule I drugs. As such, care must be
taken to conduct controlled studies on these medications, and as new
data continue to emerge and treatments are being evaluated by the
FDA, consideration must be given to safety, diversion, and abuse stra-
tegies for medication dissemination. We live in an time where access to
information is easier and faster than ever; however, it is also becoming
increasingly more difficult for lay public to distinguish evidence-based
knowledge from misinformation. Currently, there is already a struggle
between physicians and the public regarding the use of marijuana, a
Schedule I Substance that has been legalized in many states. The public
misinformation about psychedelics is no different. This is best illu-
strated by the recent emergence of the concept “micro-dosing”, which
has garnered enthusiastic public interest even with very limited scien-
tific support [65]. As physicians, we must continue to critically appraise
7
Journal of the Neurological Sciences 411 (2020) 116715
available data and discuss its meaning to our patients and the public.
From panacea to drugs of abuse, psychedelics have played an im-
portant role in our culture since the dawn of civilization. With the help
from modern technology, we may be able to successfully and safely
harness their powerful effect to alleviate suffering from specific psy-
chiatric illnesses while minimizing the known risks and negative social
repercussions.
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