Psilocybin-assisted treatment for alcohol dependence: A proof-of-concept study

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DOI: 10.1177/0269881114565144 · Source: PubMed
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Abstract
Several lines of evidence suggest that classic (5HT2A agonist) hallucinogens have clinically relevant effects in alcohol and drug addiction. Although recent studies have investigated the effects of psilocybin in various populations, there have been no studies on the efficacy of psilocybin for alcohol dependence. We conducted a single-group proof-of-concept study to quantify acute effects of psilocybin in alcohol-dependent participants and to provide preliminary outcome and safety data. Ten volunteers with DSM-IV alcohol dependence received orally administered psilocybin in one or two supervised sessions in addition to Motivational Enhancement Therapy and therapy sessions devoted to preparation for and debriefing from the psilocybin sessions. Participants' responses to psilocybin were qualitatively similar to those described in other populations. Abstinence did not increase significantly in the first 4 weeks of treatment (when participants had not yet received psilocybin), but increased significantly following psilocybin administration (p < 0.05). Gains were largely maintained at follow-up to 36 weeks. The intensity of effects in the first psilocybin session (at week 4) strongly predicted change in drinking during weeks 5-8 (r = 0.76 to r = 0.89) and also predicted decreases in craving and increases in abstinence self-efficacy during week 5. There were no significant treatment-related adverse events. These preliminary findings provide a strong rationale for controlled trials with larger samples to investigate efficacy and mechanisms. NCT02061293. © The Author(s) 2015.
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DOI: 10.1177/0269881114565144
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Introduction
In the 1950s through early 1970s there was extensive research
on the use of LSD and other classic (5HT2A agonist or partial
agonist) hallucinogens in the treatment of addiction (Abuzzahab
and Anderson, 1971; Dyck, 2006; Grinspoon and Balakar, 1997;
Halpern, 1996; Mangini, 1998), existential distress in dying
patients (Grof et al., 1973; Pahnke et al., 1969; Richards, 1975;
Richards et al., 1977), pain (Kast, 1966; Kast and Collins, 1964),
and other conditions (Grinspoon and Balakar, 1997; Grof, 2008).
A recent meta-analysis (Krebs and Johansen, 2012) examined
the six published randomized trials (Bowen et al., 1970; Hollister
et al., 1969; Ludwig et al., 1969; Pahnke et al., 1970; Smart
et al., 1966; Tomsovic and Edwards, 1970) of LSD treatment of
alcoholism. A total of 325 participants received active treatment
with LSD, and 211 received control treatment. At the first post-
treatment follow-up (ranging from 1 month to 12 months) the
odds ratio for improvement was 1.96, favoring LSD (95% confi-
dence interval 1.36–2.84, Z = 3.59, p = 0.0003).
The past decade has seen a rapid growth of interest in poten-
tial clinical applications of the classic hallucinogen psilocybin
(Bogenschutz, 2012; Burdick and Adinoff, 2013; Carhart-Harris
et al., 2012, 2013; Garcia-Romeu et al., 2013; Grob et al., 2011;
Kometer et al., 2012; Nichols, 2014). Using a double-blind,
cross-over design, Grob et al. administered psilocybin 0.2 mg/kg
vs. placebo to 12 patients with anxiety related to advanced cancer
(Grob et al., 2011). Participants showed significant improvement
with time, and there were statistical trends suggesting a positive
effect of psilocybin on mood. Additional clinical trials in cancer
patients are currently nearing completion at Johns Hopkins
University and New York University (Nichols, 2014). A recent
pilot study of psilocybin as an adjunct in smoking cessation treat-
ment resulted in remarkable rates of abstinence (80% point absti-
nence at 6-month follow-up) (Johnson et al., 2014). Extensive
clinical research with the classic hallucinogens (LSD, psilocybin,
DMT, mescaline) has established their relative safety within a
clinical research setting when subjects are carefully screened,
supervised, and followed up (Strassman, 1984). A number of arti-
cles and chapters have reviewed the literature on the use of hal-
lucinogens in the treatment of addictions (Abuzzahab and
Anderson, 1971; Dyck, 2006; Grinspoon and Balakar, 1997;
Halpern, 1996; Mangini, 1998), with the recent addition of two
reviews that incorporate current research on the effects of classic
hallucinogens more generally and discuss possible mechanisms of
action (Bogenschutz and Pommy, 2012; Ross, 2012).
Psilocybin-assisted treatment for alcohol
dependence: A proof-of-concept study
Michael P Bogenschutz1, Alyssa A Forcehimes1, Jessica A Pommy1,
Claire E Wilcox1, PCR Barbosa2 and Rick J Strassman1
Abstract
Several lines of evidence suggest that classic (5HT2A agonist) hallucinogens have clinically relevant effects in alcohol and drug addiction. Although
recent studies have investigated the effects of psilocybin in various populations, there have been no studies on the efficacy of psilocybin for alcohol
dependence. We conducted a single-group proof-of-concept study to quantify acute effects of psilocybin in alcohol-dependent participants and to
provide preliminary outcome and safety data. Ten volunteers with DSM-IV alcohol dependence received orally administered psilocybin in one or
two supervised sessions in addition to Motivational Enhancement Therapy and therapy sessions devoted to preparation for and debriefing from the
psilocybin sessions. Participants’ responses to psilocybin were qualitatively similar to those described in other populations. Abstinence did not increase
significantly in the first 4 weeks of treatment (when participants had not yet received psilocybin), but increased significantly following psilocybin
administration (p < 0.05). Gains were largely maintained at follow-up to 36 weeks. The intensity of effects in the first psilocybin session (at week 4)
strongly predicted change in drinking during weeks 5–8 (r = 0.76 to r = 0.89) and also predicted decreases in craving and increases in abstinence self-
efficacy during week 5. There were no significant treatment-related adverse events. These preliminary findings provide a strong rationale for controlled
trials with larger samples to investigate efficacy and mechanisms.
TRIAL REGISTRATION: NCT02061293
Keywords
Addiction treatment, alcoholism, hallucinogens, psilocybin, clinical trial, motivational interviewing
1
Department of Psychiatry, University of New Mexico Health Sciences
Center, Albuquerque, NM, USA
2
Departamento de Filosofia e Ciencias Humanas Ilheus, Universidade
Estadual de Santa Cruz, Bahia, Brazil
Corresponding author:
Michael P Bogenschutz, Department of Psychiatry, Center for
Psychiatric Research, University of New Mexico Health Sciences
Center, MSC11 6035, 1 University of New Mexico, Albuquerque, NM
87131-0001, USA.
Email: mbogenschutz@salud.unm.edu
565144JOP0010.1177/0269881114565144Journal of PsychopharmacologyBogenschutz et al.
research-article2014
Original Paper
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2 Journal of Psychopharmacology
Biological mechanisms
Although classic hallucinogens bind to many serotonin receptor
subtypes and other receptors (Ray, 2010), the psychoactive
effects of all classic hallucinogens appear to depend primarily on
their actions at 5HT2A receptors (Nichols, 2004; Vollenweider
and Kometer 2010; Vollenweider et al., 1998). Administration of
classic hallucinogens in rat models has been shown to induce
down-regulation of 5HT2A receptors, particularly those in the
anterior cingulate and frontomedial cortex, likely accounting for
the rapid development and reversal of behavioral tolerance to
most classic hallucinogens (Buckholtz et al., 1990; Gresch et al.,
2005).
The behavioral correlates and effects of 5HT2A receptor
activity are complex. Increased 5HT2A receptor binding has
been found in relation to pathological conditions in humans
including depression (Shelton et al., 2009), impulsive aggres-
sion (Rosell et al., 2010), neuroticism (Frokjaer et al., 2008),
borderline personality disorder (Soloff et al., 2007), and suicide
(Anisman et al., 2008). The relationship of 5HT2A receptor
binding/activity and alcoholism or alcohol exposure is less clear.
Family history of alcoholism may be associated with lower
5HT2A binding (Underwood et al., 2008), and alcoholism is not
consistently associated with change in 5HT2A receptor levels
(Thompson et al., 2012; Underwood et al., 2008). Among alcohol-
ics, one small post-mortem study reported that higher impulsivity
was associated with increased 5HT2A receptor binding
(Thompson et al., 2012). In animal models, alcohol exposure has
been associated with region-specific increases (Akash et al.,
2008) and decreases (George et al., 2010) in 5HT2A receptors
binding. Studies indicate that increased activity in 5HT2A-
mediated pathways relative to 5HT2C activity increases cue
response and impulsivity in rat models of cocaine addiction
(Cunningham and Anastasio, 2014). 5HT2A antagonists suppress
alcohol consumption in animal models (Johnson, 2008).
However, two large trials of the 5HT2A antagonist ritanserin
failed to demonstrate beneficial effects in people with alcohol
dependence (Johnson et al., 1996; Wiesbeck et al., 1999).
Animal studies suggest mechanisms by which acute activa-
tion of 5HT2A receptors could activate intracellular signaling
pathways resulting in persisting changes in cellular structure
and synapses. The classic hallucinogen DOI increases expres-
sion of glial cell line-derived neurotrophic factor (GDNF)
mRNA in glioiblastoma cells by a 5HT2A-dependent mechanism
(Tsuchioka et al., 2008). Through its action on 5HT2A receptors,
DOI has also been shown to increase levels of mRNA for brain-
derived neurotrophic factor (BDNF) in rat parietal cortex and
other neocortical regions, with decreases in the hippocampus
and no change in piriform cortex (Vaidya et al., 1997). These
findings are relevant because levels of BDNF and GDNF
are inversely related to alcohol consumption and conditioned
place preference in animal models (Ghitza et al., 2010). DOI
activates intracellular signaling cascades associated with den-
dritic spine remodeling on rat pyramidal cells, and transiently
increases the size of dendritic spines on cortical neurons (Jones
et al., 2009).
Psychological models of psychedelic treatment
Clinical work with classic hallucinogens has emphasized the cen-
tral role of the altered state of consciousness experienced during
the drug’s acute effects (Grof, 2008; Hoffer, 1967; Masters and
Houston, 2000; Pahnke et al., 1970; Sherwood et al., 1962). The
“psycholytic” model of treatment emphasized the use of classic
hallucinogens to enhance the process of psychodynamic psycho-
therapy by making unconscious material more accessible
(Leuner, 1967). The “psychedelic” treatment model on the other
hand emphasized the use of relatively high doses of classic
hallucinogens (usually LSD) to occasion a “peak-psychedelic” or
mystical experience of ego loss, often likened to psychological
death and rebirth (Kurland et al., 1967). The latter model was
used in most of the clinical studies conducted in North America
using LSD in the treatment of addiction or existential anxiety in
the dying. The concept of a singular transformative experience
leading to lasting behavior change is consistent with classic
descriptions of religious conversion (James, 1902), “spiritual
awakening” in the context of Alcoholics Anonymous (Forcehimes,
2004), and spontaneous Quantum Change experiences (Miller
and C’de Baca, 2001). Recent studies have demonstrated that the
self-reported “mystical” dimension of the psilocybin experience
(feelings of unity, sacredness, ultimate reality, transcendence of
time and space, deeply felt positive mood, and ineffability
(Pahnke, 1963)) significantly predicts the lasting personal sig-
nificance of the experience (Griffiths et al., 2008) and personality
change (Maclean et al., 2011) in normal volunteers receiving
psilocybin.
The evidence summarized above provides a convincing
rationale for investigating whether a classic hallucinogen can
improve treatment response among patients with alcohol depend-
ence. In spite of the accumulating evidence that psilocybin has
clinically relevant effects and is safe under controlled conditions,
there are no prior studies of psilocybin in the treatment of alcohol
dependence. We therefore undertook a proof-of-concept study
which aimed to quantify the psychoactive effects and tolerability of
oral psilocybin in alcohol-dependent participants, and to evaluate
outcomes during and after completion of treatment.
Methods
Study design
The study employed a single-group, within-subjects design.
Participants received a 12-week, 14-session manualized inter-
vention including two open-label psilocybin sessions in which
psilocybin was administered: the first after 4 weeks of psychoso-
cial treatment, the second after 8 weeks. Outcome data were
collected for a total of 36 weeks.
Participants
Participants were recruited from the community using advertise-
ments in local media and flyers. They were males and females
age 25–65 with a diagnosis of active alcohol dependence, ascer-
tained using the Structured Clinical Interview for DSM-IV
(SCID) (First et al., 1996), and at least two heavy drinking days
in the past 30 days, who were concerned about their drinking and
not currently in treatment. Participants were excluded if screen-
ing showed them to have exclusionary medical or psychiatric
conditions; family history of schizophrenia, bipolar disorder, or
suicide; cocaine, psychostimulant, or opioid dependence; or his-
tory of using hallucinogens more than 10 times (or any use in the
past 30 days). Participants were required to be abstinent and not
in alcohol withdrawal at the time of the psilocybin sessions.
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Bogenschutz et al. 3
Participants provided written informed consent, and all study
procedures were reviewed and approved by the IRB of the
University of New Mexico Health Sciences Center.
Interventions
Psychosocial intervention. The psychosocial intervention
comprised a total of 12 sessions: seven sessions of Motivational
Enhancement Therapy (MET: a structured approach using the
principles of motivational interviewing (Miller and Rolnick,
2013)), three preparation sessions, and two debriefing sessions.
Four sessions occurred before the first psilocybin session, four
sessions between the first and second psilocybin sessions, and
four sessions after the second psilocybin session. The psychoso-
cial intervention was conducted by a team of two therapists. One
performed the seven MET sessions focused on changing drinking
behavior, while the other was responsible for preparation before,
support during, and debriefing after the psilocybin sessions. Both
therapists were present for the preparation and debriefing sessions,
as well as the psilocybin sessions. Three of the authors (MB, AF,
CW) served as study therapists. Therapy sessions were audiore-
corded. The first and third MET sessions were coded using the
Motivational Interviewing Treatment Integrity (MITI 3.1) coding
system (Moyers et al., 2005) by a rater trained to reliability.
Dosing and administration of study medications. On the
morning of the psilocybin sessions, participants were required
to be afebrile, non-hypertensive, non-tachycardic, abstinent
from alcohol for at least 24 hours, and without evidence of alco-
hol withdrawal. Urine drug screens were negative for cocaine,
psychostimulants, and opioids, and breath was negative for
alcohol. The psilocybin sessions took place in a room that was
specially prepared to provide a living-room-like environment
for the sessions. Individualized doses of psilocybin (based on
participant weight) were prepared by the study pharmacist on the
morning of the session, and placed in a single gelatin capsule.
Participants ingested the psilocybin capsule followed by 4
ounces of water. They were instructed to lie on a couch wearing
eyeshades and headphones (providing a standardized program
of music), and to direct their attention toward their internal
experience. Participants remained under observation for at least
8 hours following psilocybin administration. Both therapists
were present throughout the session. Interactions with the par-
ticipants were supportive and non-directive. Medications were
available for administration if needed to treat hypertension
(sublingual nitroglycerin 0.4 mg), anxiety (lorazepam 1–2 mg
PO/IM), or acute psychosis (ziprasidone 10–20 mg PO/IM).
Beginning 7 hours after drug administration, participants com-
pleted questionnaires and assessments, and a brief clinical inter-
view was performed, including mental status exam. Participants
were escorted home at the end of the session by a family member
or friend, who stayed with the participant overnight.
For the first psilocybin session, participants received a dose of
0.3 mg/kg. For the second session, the dose was increased to 0.4 mg/
kg unless the participant (i) was unwilling to increase the dose; (ii)
experienced adverse effects during the first session which suggested
that a higher dose would pose significant risk; or (iii) reported a
“complete” mystical experience during the first session (Griffiths
et al., 2006), indicating very strong effects from 0.3 mg/kg.
Assessments
Medical evaluation. Medical screening consisted of medical
history and physical examination, ECG, liver function tests,
complete blood count, blood chemistries, urinalysis, serum
pregnancy test, and body mass index. Women of childbearing
potential completed a menstrual calendar at each assessment
visit, and urine pregnancy tests were completed prior to each
drug administration session. The Clinical Institute Withdrawal
Scale—Alcohol, revised (CIWA-Ar) (Sullivan et al., 1989) was
used to assess alcohol withdrawal at screening and before the
psilocybin sessions.
Psychiatric and substance use disorder diagnoses. The
SCID (First et al., 1997) was used to diagnose DSM-IV Axis I
disorders including substance abuse and dependence diagnoses.
Acute hallucinogen effects. Self-report scales (administered 7
hours after drug administration) and monitor ratings (0–6 hours
after drug administration) were used to quantify acute subjective
effects. The Intensity subscale of the Hallucinogen Rating Scale
(HRS) (Strassman et al., 1994) was used as a global measure of
the intensity of the drug experience. The 5-Dimensional Altered
States of Consciousness Scale (5D-ASC) (Dittrich, 1998) has 94
items using the visual analog scale format, yielding five primary
dimensions: “Oceanic Boundlessness,” “Dread of Ego Dissolu-
tion,” “Visionary Restructuralization,” “Auditory Alterations,”
and “Altered Vigilance.” The States of Consciousness Scale is a
100-item questionnaire which has been used extensively to measure
states of consciousness in hallucinogen administration experi-
ments (Griffiths et al., 2006; Pahnke, 1963, 1969; Richards et al.,
1977; Turek et al., 1974). This scale contains the 43 items of the
Pahnke–Richards Mystical Experience Questionnaire (MEQ)
(Griffiths et al., 2006). The Addiction Research Center Inventory
(ARCI), 49-item version (Martin et al., 1971) was also adminis-
tered following each drug administration session. In addition, a
Monitor Session Rating Form (Griffiths et al., 2006) was com-
pleted by both monitors at intervals during the psilocybin sessions
to provide ratings of participants’ behavior and affect during the
session.
Substance use and consequences. The Time-Line Follow-
Back (TLFB) (Sobell and Sobell, 1992, 1995) procedure was
used to assess drinking behavior at baseline (covering the 12 weeks
preceding enrollment) and follow-up visits. Heavy drinking days
were defined as days during which participants consumed five or
more standard drinks if the participant was male, or four or more
standard drinks if the participant was female, a standard drink
being defined as 14 g of alcohol. Drinking days were defined as
days during which participants consumed any amount (even a
sip) of an alcoholic beverage. The Short Inventory of Problems
(SIP) (Miller et al., 1995), past 3 month version, was used to
measure consequences of alcohol use. Breath Alcohol Concen-
tration (BAC) was measured at each visit, but was used to ensure
safety of treatment and validity of assessments rather than as an
outcome measure.
Psychological assessments. The Stages of Change Readiness
and Treatment Eagerness Scale (SOCRATES 8A) (Miller and
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4 Journal of Psychopharmacology
Tonigan, 1996) was used as a measure of motivation. The Alcohol
Abstinence Self-Efficacy Scale (AASE) (Diclemente et al.,
1994) was used as a measure of self-efficacy to abstain from
drinking. The Penn Alcohol Craving Scale (PACS) (Flannery
et al., 1999) was used to assess craving. The Profile of Mood
States (POMS) (Mcnair et al., 1981) was used as a measure of
mood. Additional measures of persisting psychological effects
obtained but not discussed in this publication were the Hood
Mysticism Scale (Hood et al., 2001), the Persisting Effects
Questionnaire (Griffiths et al., 2006), the ASPIRES Spiritual
Transcendence Scale (Piedmont, 1999), the Brief Multidimen-
sional Measure of Religiousness/Spirituality (Fetzer Institute,
1999), the NEO Personality Inventory 3 (NEO-PI-3) (Mccrae
et al., 2005), and the Schwartz Value Survey (Schwartz, 1992,
2006).
Safety assessment. Vital signs were obtained at each visit and
measured frequently during psilocybin sessions: every half
hour for the first 2 hours, then hourly for the next 4 hours, with
more frequent readings as needed. Adverse events (AEs), when
present, were collected on an AE case report form at the end of
the psilocybin sessions and at all subsequent visits, including
assessment of clinical significance and relatedness to treatment.
Statistical analysis and power
Statistical analyses for this open-label pilot study were primarily
descriptive, but two a priori hypotheses were tested. To test for
changes in drinking behavior (percent heavy drinking days and
percent drinking days), consequences of drinking, and psycho-
logical outcomes, scores at follow-up time points were contrasted
with baseline and week 4 values using paired t-tests, and effect
sizes (Cohen’s d) (Cohen, 1988) were computed with correction
for correlation between time points (Morris and Deshon, 2002).
The primary drinking outcome was percent heavy drinking days,
and the primary contrast was baseline vs. weeks 5–12. With a
sample size of n = 10, the study had power of 0.803 to detect pre-
post changes of effect size d = 1.0, with α = 0.05 (2-tailed) prior to
correction for multiple comparisons. For drinking outcomes, the
Benjamini–Hochberg procedure (Benjamani and Hochberg,
1995) was used to control the false discovery rate at the 0.05 level.
Results
Participants
In total 70 individuals were screened for the study, of whom 10
were included in the study (Figure 1). Participants were four
women and six men with DSM-IV alcohol dependence. Two
participants were Native American/Alaska Native, one was
African American, four were Hispanic, and three were white
non-Hispanic. Four were single, three were married, and three
were divorced. Four were working full-time, five part-time, and
one was unemployed. Mean household income was $47,023 (SD
$35,262). Participants averaged 15.1 (SD 3.7) years of education
(12 years representing graduation from high school), and three
were college graduates.
Mean age was 40.1 years (SD 10.3, range 25–56), and mean
duration of alcohol dependence was 15.1 years (SD 11.5, range
4–32). Participants had a mean of 5.0 dependence criteria (SD
1.2, range 3–7). Eight out of 10 had evidence of physical depend-
ence (tolerance or withdrawal), but none had alcohol withdrawal
symptoms requiring treatment during the trial.
Treatment exposure and follow-up
Figure 1 summarizes participation in treatment and follow-up.
Ten participants completed the first psilocybin session. Of the
seven participants completing the second psilocybin session, six
received psilocybin 0.4 mg/kg and are included in analysis of
second session effects. One received psilocybin 0.3 mg/kg due to
meeting criteria for “complete mystical experience” in the first
session. Nine participants completed all follow-up assessments
and are included in outcome analyses. One participant discontin-
ued participation shortly after the first psilocybin session and did
not provide usable outcome data. A total of 14 MET sessions
were coded for fidelity using the MITI 3.1. Mean (SD) global
scores ranged from 4.43 (0.76) to 5.00 (0.00), well above the
proficiency benchmark of 4.0.
Acute effects
Figure 2 illustrates physiologic effects and monitor ratings dur-
ing the first psilocybin session, in which all participants
received psilocybin 0.3 mg/kg, and during the second psilocy-
bin session for the six participants who received psilocybin 0.4
mg/kg. Systolic or diastolic blood pressure was modestly but
significantly increased from 30 minutes to 180 minutes in one
or both conditions. Heart rate (not shown) did not change sig-
nificantly. Monitor ratings of global drug effect and “distance
from ordinary reality” peaked between 120 and 180 minutes,
and were significantly elevated at most time points. Differences
in these measures between the two doses were not statistically
significant (paired t-tests, df = 5).
Table 1 shows mean scores on self-report measures of sub-
jective experience obtained 7 hours following administration
of psilocybin 0.3 mg/kg in the first session and for the six par-
ticipants who received psilocybin 0.4 mg/kg in the second session.
Intensity of effects varied markedly from patient to patient. On
average, acute effects on the MEQ and HRS are numerically
lower in magnitude than those seen at comparable doses in normal
volunteers (Griffiths et al., 2011). For the six participants who
received psilocybin 0.4 mg/kg in the second session, subjective
ratings were not significantly different between the two sessions
(paired t-tests, df = 5), but were strongly correlated between
the sessions for most of the scales intended to measure halluci-
nogen effects.
Clinical outcomes
Percent heavy drinking days decreased during weeks 5–12 rela-
tive to baseline (mean difference (SD) = 26.0 (22.4), 95% CI
8.7–43.2, t(8) = 3.477, p = 0.008), and also decreased relative to
weeks 1–4 (during psychosocial treatment but prior to psilocy-
bin) (mean difference (SD) = 18.2 (20.0), 95% CI 2.8–33.5, t(8)
= 2.723, p = 0.026). Percent drinking days also decreased during
weeks 5–12 relative to baseline (mean difference (SD) = 27.2
(23.7), 95% CI 9.0–45.4, t(8) = 3.449, p = 0.009) and relative to
weeks 1–4 (mean difference (SD) = 21.9 (21.8), 95% CI 5.1–
38.6, t(8) = 3.010, p = 0.017). Figure 3 illustrates change in
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Bogenschutz et al. 5
percent heavy drinking days and percent drinking days over the
course of the study. Improvement is not statistically significant
during the first 4 weeks of participation, when participants
received weekly counseling but had not yet received psilocybin.
Following the first psilocybin session, percent heavy drinking
days and percent drinking days are significantly lower than
baseline at all follow-up points. Further, these measures are
significantly decreased relative to weeks 1–4 with the exception
of heavy drinking days during weeks 9–12 (p = 0.059). Fifteen
out of 16 contrasts were significant at the nominal 0.05 level,
and all of these remained significant at a false discovery rate of
0.05. Effect sizes are large (greater than 0.8) with one exception,
Cohen’s d ranging from 0.75 to 1.38. Table 2 summarizes addi-
tional outcomes for study participants. Significant improvement
70 began screening
51 excluded prior to consent
16 declined participation/lost to follow-up
11 exclusionary psychiatric or drug use disorder
9 lifetime hallucinogen use more than 10 occasions
5 exclusionary medications
4 exclusionary medical conditions
3 age greater than 65
2 did not meet current drinking inclusion criteria
1 active legal issues
19 consented
9 excluded
3 lost to follow-up/declined participation
2 reported family history of suicide
1 did not meet current drinking inclusion criteria
1 excluded for medical condition
1 reported past suicide attempt
10 received
psilocybin
10 completed first psilocybin session (week 4, psilocybin 0.3 mg/kg)
7 completed second psilocybin session (week 8)
6 received psilocybin 0.4 mg/kg
1 received psilocybin 0.3 mg/kg
3 did not complete second psilocybin session
1 missed second session due to unrelated medical condition but completed all other aspects of the study
1 dropped out of treatment after week 7 but completed follow-up assessments
1 withdrew participation after week 4
10 included in analyses of first session acute effects
9 included in analyses of drinking outcomes
9 completed all follow-up assessments
1 withdrew participation after week 4
Figure 1. Participant flow.
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6 Journal of Psychopharmacology
relative to baseline and/or week 4 is noted at multiple time
points for drinking consequences, craving, self-efficacy, and
motivation. Changes in POMS scores were not significant with
one exception (increased Vigor at week 24 relative to baseline).
Relationships between acute effects and
treatment response
Because the acute effects of psilocybin were quite variable, it was
possible to explore the relationships between the intensity of
acute effects and changes in drinking behavior. Table 3 shows
correlations between three summary measures of the intensity of
acute effects in the first psilocybin session and short-term clinical
outcomes. Large correlations were observed between measures
of acute effect intensity and change in drinking behavior, as well
as changes in craving and self-efficacy in some cases.
Supplemental Figure 1 displays scatterplots of the individual data
points underlying these correlations.
Treatment-related adverse events
Five participants reported mild headaches which resolved within
24 hours following psilocybin administration, consistent with
prior reports (Johnson et al., 2012). One participant had nausea
with one episode of emesis during one psilocybin session. One
participant with irritable bowel syndrome experienced diarrhea
during one psilocybin session. One participant reported insomnia
on the night following a psilocybin session. No participant
required medication or other intervention for blood pressure,
anxiety, or other psychiatric symptoms. There was no report
of illicit hallucinogen use by any participant during study
participation.
Discussion
Overall, the response of our alcohol-dependent participants to psil-
ocybin was qualitatively similar to that which has been reported in
other samples (Hasler et al., 2004; Griffiths et al., 2006, 2011;
Grob et al., 2011). Medication-related AEs were transient and
mild. However, subjective response was highly variable among
participants in this study, and numerically weaker on average for
some of the measures than that reported in normal volunteers at
comparable doses (Griffiths et al., 2011). This is consistent with
observations beginning in the 1950s that alcoholics tended to
require larger doses of LSD to have a strong effect (Chwelos et al.,
1959). Our findings suggest that some alcohol-dependent patients
are relatively insensitive to the effects of psilocybin, although
larger samples will be necessary to confirm this. The lack of sig-
nificant differences between the 0.3 mg/kg and 0.4 mg/kg doses is
most likely accounted for by the small sample size (n = 6) and/or
idiosyncratic responses in a small number of participants.
Participants exhibited significant improvement in drinking,
with large pre–post effect sizes, as well as significant changes in
psychological measures relevant to drinking. Importantly, much
of the improvement occurred following the administration of
psilocybin, at which time participants had already received 4
weeks of psychosocial treatment and 4–6 hours of assessment.
Also, strong correlations were observed between measures of
intensity of the acute drug effects and clinical outcomes. Although
change in drinking was correlated with the mystical quality of the
experience, it was similarly associated with ratings of other acute
effects. More work will necessary to determine whether there are
particular characteristics of the acute psilocybin experience that
are predictive of therapeutic benefit in alcohol use disorder.
While clearly demonstrating feasibility, this study has major,
self-evident limitations including small sample size, lack of a
control group or blinding, and lack of biological verification of
alcohol use. Due to these limitations, it is not possible to separate
unequivocally the effects of attention, psychosocial treatment,
and time; expectancy effects related to knowledge of receiving
psilocybin; and the specific effects of psilocybin. However, the
70.00
80.00
90.00
100.00
110.00
120.00
130.00
140.00
150.00
160.00
Systolic Session1
Diastolic Session1
Systolic Session2
Diastolic Session2
Blood Pressure
0
0.5
1
1.5
2
2.5
Overall EffectSession 1
Distance fromOrdinary Reality Session1
Overall EffectSession 2
Distance fromOrdinary Reality Session2
Monitor Rangs
Figure 2. Within-session objective effects. Blood pressure (mm Hg)
monitor ratings (0–4 Likert Scale).
Means are shown for 10 participants receiving psilocybin 0.3 mg/kg in the first
session (solid lines), and the six participants who received psilocybin 0.4 mg/
kg in the second session (n = 6, dashed line) during the 6 hours following drug
administration. Solid markers indicate significant difference from baseline value.
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Bogenschutz et al. 7
Table 1. Acute effects of psilocybin 0.3 mg/kg and 0.4 mg/ kg.
0.3 mg/kg
Session 1 (n = 10)
0.4 mg/kg
Session 2 (n = 6)
r Sig.
Mean (SD) Min. Max. Mean (SD) Min. Max. (n = 6)
ASC OBN 960.4 (518.8) 91 1798 785.0 (977.3) 79 2107 0.649 0.163
ASC DED 499.6 (515.8) 38 1515 340.1 (445.2) 26 1021 0.808 0.052
ASC VRS 923.5 (396.8) 61 1516 610.2 (543.5) 188 1462 0.670 0.145
ASC AUA 302.5 (380.9) 26 1166 182.0 (288.5) 18 766 0.960 0.002
ASC VIR 394.2 (268.1) 49 819 244.4 (333.0) 36.5 883 0.828 0.042
G-ASC 2383.5 (1347.7) 235 4628 1735.3 (1761.1) 337.5 4590 0.827 0.042
MEQ total 0.473 (0.217) 0.016 0.768 0.387 (0.347) 0.011 0.924 0.843 0.035
HRS intensity 2.43 (1.03) 0 3.5 2.00 (1.14) 0.25 3.25 0.902 0.014
ARCI PCAG 8.00 (3.06) 3 12 5.50 (4.04) 1 12 0.287 0.581
ARCI BG 5.40 (1.58) 3 8 5.83 (2.99) 2 11 0.167 0.752
ARCI A 4.78* (2.37) 0 8 4.50 (2.88) 2 9 0.198 0.707
ARCI MBG 5.33* (3.61) 4 12 6.33 (4.55) 2 13 0.388 0.448
ARCI LSD 8.10 (3.21) 1 13 8.17 (2.99) 4 12 0.405 0.425
Shown are scores for all 10 participants in session 1, scores for the six participants who received psilocybin 0.4 mg/kg in the second session, and correlations between
scores for the two sessions for these six participants.
*n = 9 due to incomplete questionnaire from one participant.
ASC: 5-Dimensional Altered States of Consciousness Scale; OBN: Oceanic Boundlessness subscale; DED: Dread of Ego Dissolution subscale; VRS: Visionary Restructuraliza-
tion subscale; AUA: Auditory Alterations subscale; VIR: Vigilance Reduction subscale; G-ASC: summary score (sum of OBN, DED, and VRS); MEQ: Mystical Experience Ques-
tionnaire; HRS Intensity: Intensity subscale of the Hallucinogen Rating Scale; ARCI: Addiction Research Center Inventory; PCAG: Phenobarbital, Chlorpromazine, Alcohol
Group subscale (sedation); BG: Benzedrine group subscale (stimulant); A: Amphetamine subscale (stimulant); MBG: Morphine-Benzadrine group subscale (euphoria); LSD:
LSD subscale (dysphoria). Instruments are described in Methods section.
0
5
10
15
20
25
30
35
40
45
BaselineWeeks 1-4Weeks 5-8Weeks 9-12 Weeks13-24 Weeks25-36
%DrinkingDays
%Heavy Drinking Days
Drinking Days
Baselinevs.
Weeks 1-4 p= .164 d= 0.490
Weeks 5-8 p= .009 d= 1.194
Weeks 9-12 p= .015 d= 1.033
Weeks13-24 p= .006 d= 1.332
Weeks25-36 p= .007 d= 1.187
Weeks1-4 vs.
Weeks 5-8 p= .016 d= 1.109
Weeks 9-12 p= .033 d= 0.869
Weeks13-24 p= .014 d= 1.163
Weeks25-36 p=. 013 d= 1.036
HeavyDrinkingDays
Baselinevs.
Weeks 1-4 p= .158 d= 0.492
Weeks 5-8 p= .007 d= 1.249
Weeks 9-12 p= .019 d= 0.985
Weeks13-24 p= .010 d= 1.161
Weeks25-36 p= .004 d= 1.383
Weeks1-4 vs.
Weeks5-8 p= .022 d= 1.046
Weeks9-12 p= .059 d= 0.750
Weeks13-24 p= .038 d= 0.876
Weeks25-36 p= .018 d= 1.040
First
psilocybin
treatment
following
Week 4
assessment
Percent Drinking Days/Percent HeavyDrinkingDays
Figure 3. Drinking outcomes and effect sizes.
Means shown are for all available data (n = 10 at baseline, n = 9 at all other time points). p-values are from paired t-tests (df = 8). Cohen’s d is shown for the contrast
between baseline or weeks 1–4 and each follow-up time point.
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8 Journal of Psychopharmacology
Table 2. Secondary outcomes.
Baseline Week 4 Week 5 Week 8 Week 9 Week 12 Week 24 Week 36
Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD)
SIP
Physical 4.60 (2.27) 4.89 (3.14) 2.78 (2.95) 2.78 (3.35)
Interpersonal 4.80 (2.57) 4.44 (3.17) 2.56 (3.05)** 2.56 (2.88)**
Intrapersonal 7.30 (1.70) 6.00 (3.12) 3.89 (3.76)* 3.67 (3.74)*
Impulse control 2.90 (1.29) 3.89 (2.47) 2.56 (2.24) 2.56 (3.05)
Responsibility 4.50 (2.37) 4.22 (3.46) 3.67 (3.81) 2.67 (2.87)
PACS 16.00 (5.59) 14.10 (7.17) 11.89 (8.64) 11.56 (5.85)* 10.00 (6.61)**,§12.11 (8.28)* 13.00 (9.59) 8.11 (9.16)***,§
AASE
Temptation 38.30 (12.80) 38.10 (18.17) 28.11 (18.86) 32.78 (21.09) 24.56 (16.80)*,§32.56 (21.67) 26.63 (18.70)* 27.22 (21.86)§
Confidence 40.10 (12.58) 40.30 (16.66) 55.56 (10.88)*,§§ 49.00 (11.90) 53.67 (12.76)§50.00 (13.21) 50.44 (13.09) 54.00 (19.87)§
SOCRATES
Recognition 31.80 (3.22) 31.10 (5.26) 31.11 (5.33) 31.78 (5.89) 31.89 (5.33) 30.38 (8.02) 28.67 (7.89) 26.78 (9.56)
Ambivalence 15.70 (3.65) 13.90 (5.93) 14.22 (5.31) 14.56 (5.81) 13.11 (6.13) 13.00 (6.48) 12.00* (5.20) 11.56* (4.90)
Taking Steps 32.30 (3.20) 34.00 (5.03) 36.33 (2.65)* 36.33 (2.65)** 37.33 (3.46)**,§35.78 (3.80)* 36.00 (4.12)* 33.78 (5.36)
POMS
Tension 7.20 (5.27) 6.22 (3.42) 4.67 (3.54) 5.78 (4.44) 5.89 (4.88) 8.00 6.06 5.78 (5.97) 5.33 (6.04)
Depression 6.50 (5.60) 3.40 (4.45) 4.89 (6.41) 4.44 (3.50) 3.22 (4.38) 6.78 7.45 6.11 (6.11) 5.00 (4.58)
Anger 4.40 (4.09) 2.40 (3.13) 4.67 (4.61) 3.89 (4.62) 2.22 (2.64) 4.50 (6.61) 3.56 (5.48) 4.56 (6.46)
Vigor 5.60 (4.01) 6.50 (3.34) 8.56 (4.61) 8.11 (5.46) 9.00 (5.85) 7.75 4.10 9.56 (4.90)* 7.50 (2.78)
Fatigue 8.70 (5.79) 6.60 (5.78) 6.22 (6.44) 5.44 (4.75) 5.56 (4.28) 7.67 6.28 6.67 (5.96) 6.89 (4.08)
Confusion 6.10 (2.69) 3.90 (1.79)* 4.67 (2.96) 5.33 (3.71) 5.56 (3.43) 5.13 3.36 5.56 (2.19) 4.44 (2.51)
SIP: Short Inventory of Problems; PACS: Penn. Alcohol Craving Scale; AASE: Alcohol Abstinence Self-Efficacy; SOCRATES: Stages of Change Readiness and Treatment Eagerness Scale; POMS: Profile of Mood States.
*Different from baseline, p < 0.05; **Different from baseline, p < 0.01; ***Different from baseline, p < 0.001; §Different from week 4, p < 0.05; §§Different from week 4, p < 0.01.
n = 10 at baseline and 4 weeks, and n = 9 at weeks 5–36 with the following exceptions due to missing questionnaire items: n = 9 for PACS baseline; n = 8 for SOCRATES Recognition week 12, AASE Confidence week 12, AASE
Temptation week 24, POMS Anger week 12, POMS Confusion week 12, POMS Vigor week 12, and POMS Vigor week 36.
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Bogenschutz et al. 9
Table 3. Correlations between acute effects and change in drinking, craving, and self-efficacy (n = 9).
PDD PHDD PACS AASE
(wk. 8 – wk. 4) (wk. 8 – wk. 4) (wk. 5 – wk. 4) (wk. 5 – wk. 4)
HRS Intensity r = –.844 r = –.763 r = –.823 r = .753
(wk. 4) p = .004 p = .017 p = .006 p = .019
MEQ total r =–.885 r = –.852 r = –.810 r = .762
(wk. 4) p = .002 p = .004 p = .008 p = .017
G-ASC r =–.838 r =–.893 r =–.654 r =-.555
(wk. 4) p = .005 p = .001 p = .056 p = .121
PDD: Percent Drinking Days; PHDD: Percent Heavy Drinking Days; PACS: Penn Alcohol Craving Scale; 4AASE = Alcohol Abstinence Self-Efficacy Confidence score; HRS:
Hallucinogen Rating Scale Intensity score; MEQ: Mystical Experience Questionnaire; G-ASC: Altered States of Consciousness Scale summary score.
time course of the observed changes and the striking relation-
ship between intensity of response and clinical improvement
provide support for the concept that psilocybin may produce
lasting benefits in alcohol use disorder when administered
under controlled conditions to carefully screened patients,
in the context of appropriate psychosocial interventions.
Adequately powered randomized trials will be necessary to test
this hypothesis rigorously. Neuroimaging studies in alcohol use
disorder trial participants would help characterize the persisting
effects of psilocybin on brain activity (e.g. resting state func-
tional connectivity, cue response, stress response, response to
emotional stimuli, and inhibitory control). Studying the genetics
of response to psilocybin may shed light on the variability of
response, ultimately aiding in dose selection or identifying
patients particularly likely to benefit.
Acknowledgements
We wish to thank the following persons for their contributions to the
study. From the University of New Mexico, Albuquerque, NM: for data
collection, Rose C. Bigelow, MS; for fidelity monitoring, Christina E.
Ripp, MA; for data entry and cleaning, Robert G. Voloshin, DO, Alex M.
Pogzeba, BA, Christina E. Ripp, MA, Lindsay M. Worth, MPA; for qual-
ity assurance and regulatory compliance, Linda A. Schenkel; CCRC,
CPhT; for service on the Data and Safety Monitoring Committee for the
study, Jan A. Fawcett, MD, Theresa B. Moyers, PhD. From the University
of North Carolina: for providing the psilocybin used for this study, David
E. Nichols, PhD. From Johns Hopkins University: for providing training
for study interventionists, William A. Richards, PhD; for guidance on
intervention and assessment procedures, Roland R. Griffiths, PhD. From
the Heffter Research Institute: for advice and support in the design and
conduct of the study, George R. Greer, MD.
Declaration of Conflicting Interests
The authors declared the following potential conflicts of interest with
respect to the research, authorship, and/or publication of this article: Dr.
Bogenschutz reports grants from National Institute on Drug Abuse, dur-
ing the conduct of the study; and grants from the Lundbeck Foundation
and the Heffter Research Institute, outside the submitted work.
Funding
The authors disclosed receipt of the following financial support for the
research, authorship, and/or publication of this article: The study was
supported by a grant from the Heffter Research Institute and NIH grant
1UL1RR031977.
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  • ... The prodrug psilocybin, from Psilocybe mushrooms (Figure 1), is demonstrating therapeutic potential for the treatment of psychiatric conditions including alcohol use disorder (Bogenschutz et al., 2015), tobacco addiction (Garcia-Romeu, Griffiths, & Johnson, 2014), depression and existential anxiety in palliative care Grob et al., 2011;Ross et al., 2016). In many of these clinical studies, subjects' mystical-type experiences have been correlated with therapeutic outcomes and improvements in various aspects of mental well-being such as reductions in anxiety and an increase in the personality domain of openness Johnson, Garcia-Romeu, & Griffiths, 2017;MacLean, Johnson, & Griffiths, 2011). ...
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    Objective Research into psychedelic therapy models has shown promise for the treatment of specific psychiatric conditions. Mystical‐type experiences occasioned by psilocybin have been correlated with therapeutic benefits and long‐term improvements in positive mental outlook and attitudes. This article aims to provide an overview of the topic, highlight strengths and weaknesses in current research, generate novel perspectives and discussion, and consider future avenues for research. Design This narrative review was designed to summarise and assess the state of research on psilocybin occasioned mystical‐type experiences and applications for the treatment of specific psychiatric conditions. Results Contemporary methods on the quantification of mystical‐type experiences and their acute subjective effects are discussed. Recent studies provide some understanding of the pharmacological actions of psychedelics although the neurological similarities and differences between spontaneous and psychedelic mystical‐type experiences are not well described. Applicability to modern clinical settings is assessed. Potential novel therapeutic applications include use in positive psychology interventions in healthy individuals. Conclusions Since 2006 significant advancements in understanding the therapeutic potential of psilocybin‐assisted psychotherapy have been made; however, more work is required to understand the neuromechanistic processes and applicability in modern clinical settings. Despite promising results in recent studies, funding issues for clinical trials, legal concerns and socio‐cultural resistance provide a counterpoint to experimental evidence.
  • ... For the meta-analysis we only included datasets where the effects of orally administered psilocybin were investigated in healthy participants and any of the below specified questionnaires were applied. We therefore excluded the following datasets: Grob et al., Bogenschütz et al., Griffiths et al. [15][16][17] because these studies investigated the effects of psilocybin in patient populations; Griffiths et al. [18] because psilocybin administration was combined with meditation; Carhart-Harris et al. [19] because psilocybin was administered intravenously (i.v.) and it is unclear how the dose compares to oral administration. Three publications were duplicates, meaning data from the same experiment was reported (see Table 1). ...
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    Psilocybin is the active component of magic mushrooms and is well known for its psychoactive properties. Different questionnaires have been developed to systematically quantify altered states of consciousness induced by psychoactive drugs. The aim of this study was to obtain the dose-response relationships of the subjective experiences induced by psilocybin in healthy study participants. For this purpose, we applied a linear meta-regression approach on questionnaire ratings after oral administration of psilocybin in a controlled setting. Data was obtained from The Altered States Database, which contains psychometric data extracted from peer-reviewed articles published in MEDLINE-listed journals that used standardized and validated questionnaires. Our meta-analysis included data of the Altered States of Consciousness Rating Scale, the Mystical Experience Questionnaire (MEQ30), and the Hallucinogen Rating Scale (HRS). We used the Robust Variance Estimation Framework to obtain linear dose-response relationship estimates for each dimension of the given questionnaires. Ratings on most dimensions and subscales of the included questionnaires correlated positively with dose. Since subjective experiences are not only determined by dose, but also by individual differences and environmental factors, our results do not necessarily generalize to recreational use, as our analyses are based on data from controlled laboratory experiments. The paper at hand could serve as a general literature citation for the use of psilocybin in experimental and clinical research, especially for the comparison of expected and observed subjective drug experiences.
  • ... Pilot studies indicate psychedelics may also hold promise in the treatment of clinical-level depression, anxiety, or addictions (Bogenschutz et al. 2015;Carhart-Harris et al. 2018;Gasser, Kirchner, and Passie 2014;Griffiths et al. 2016;Grob et al. 2011;Palhano-Fontes et al. 2019;Ross et al. 2016). ...
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    Despite their acutely inebriating and sometimes unpleasant effects, some people report positive changes in life satisfaction, well-being, or mental health after taking psychedelic drugs. One explanation may be the ability of psychedelics to trigger mystical-type experiences. We examined the validity, reliability, and factor structure of a novel Finnish translation of the Revised Mystical Experiences Questionnaire (MEQ30) among 288 people retrospectively reporting on their first time using a psychedelic. We found evidence for internal consistency reliability and preliminary evidence for criterion and discriminant validity of the Finnish MEQ30. A four-factor structure with factors for mystical qualities, positive mood, transcendence, and ineffability had the best, fair to reasonable fit to the data. MEQ30 scores and having a full mystical experience were highly associated with describing the experience as mystical, spiritual, or religious, and as personally significant, and somewhat associated with the experience being sad or difficult. Mystical experiences were especially associated with positive changes in relationships with nature and oneself and in creativity. Mystical experiences were more common with larger doses. Increasing research suggests mystical-type experiences to relate to positive changes after taking psychedelics. The Finnish MEQ30 is able to tap into relevant information about this aspect of people’s psychedelic experiences.
  • ... Psychedelic experiences: mysticism, awe, and ego dissolution Classic serotonergic psychedelics (CSPs) are a group of psychoactive drugs the acute effects of which include substantial changes to sensory perception, mood, sense of self, relationship to external reality and sense of passage of time (Preller and Vollenweider 2016). Clinical research suggests that CSPassisted therapy-in which patients take a relatively mild or a large dose of psychedelics under the supervision of a therapist-can help to alleviate psychological distress and different mental health problems (see Carhart-Harris and Goodwin 2017 for an overview), including distress associated with life-threatening illness (Griffiths et al. 2016;Ross et al. 2016), various forms of addiction including alcoholism and tobacco addiction (Bogenschutz et al. 2015;Johnson et al. 2017; Morgan et al. 2017) and recurrent and treatmentresistant anxiety and depression disorders (Carhart-Harris et al. 2018a;Palhano-Fontes et al. 2019). ...
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  • ... Another addiction trial was subsequently reported by Bogenschutz et al. [28]. They examined the possibility that psilocybin-assisted psychotherapy could be beneficial in alcohol use disorder. ...
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    Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is an indole-based secondary metabolite produced by numerous species of mushrooms. South American Aztec Indians referred to them as teonanacatl, meaning “god’s flesh,” and they were used in religious and healing rituals. Spanish missionaries in the 1500s attempted to destroy all records and evidence of the use of these mushrooms. Nevertheless, a 16th century Spanish Franciscan friar and historian mentioned teonanacatl in his extensive writings, intriguing 20th century ethnopharmacologists and leading to a decades-long search for the identity of teonanacatl. Their search ultimately led to a 1957 photo-essay in a popular magazine, describing for the Western world the use of these mushrooms. Specimens were ultimately obtained, and their active principle identified and chemically synthesized. In the past 10–15 years several FDA-approved clinical studies have indicated potential medical value for psilocybin-assisted psychotherapy in treating depression, anxiety, and certain addictions. At present, assuming that the early clinical studies can be validated by larger studies, psilocybin is poised to make a significant impact on treatments available to psychiatric medicine.
  • ... Studies have shown that psychedelics have a profound effect on neural activity, and are felt to 'deconstrain' networks in the brain, including those responsible for selfrelated processing. 17,18 There have been promising early results in recent open-label studies in alcohol dependence, 19,20 tobacco addiction, 21,22 obsessive-compulsive disorder, 23,24 existential anxieties in the context of terminal illness, [25][26][27] and unipolar depression. 28,29 Leading on from this, a further two pilot studies using ayahuasca in major depressive disorder have also been published, 30,31 and placebo-controlled RCTs are currently underway to investigate psilocybin use in treatment refractory depression. ...
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    Functional neurological disorder (FND), formerly known as conversion disorder, causes a high burden of disability and distress, and is amongst the most commonly encountered conditions in neurology clinics and neuropsychiatric services, yet the therapeutic evidence base is somewhat limited. There has been recent interest in the therapeutic potential of psychedelics such as psilocybin and lysergic acid diethylamide (LSD), and in recent studies psychedelics have shown promise in treating a range of neuropsychiatric conditions. Modification of neural circuits associated with self-representation is thought to underlie some of this effect, and as some contemporary theories of FND focus on aberrant somatic self-representation, psychedelics may therefore represent an unexplored treatment option for FND. We systematically reviewed studies involving the use of psychedelics in FND. Nine studies published between 1954 and 1967, with a total of 26 patients, were identified. Due to restriction of licencing of psychedelic drugs since this period, no modern studies were identified. In most cases, patients received a course of psychotherapy with variable adjunctive administration of psychedelics (in a combination known as ‘psycholytic therapy’), with protocols varying between studies. Of those treated, 69% (n = 18) were found to have made at least some recovery on heterogeneous and subjective clinician-rated criteria. Adverse events were mostly mild and transient; however, at least one patient terminated the study due to distressing effects. All included studies were of low quality, often lacking control groups and valid outcome measures. Although no conclusions on efficacy may be drawn from these data, further research may help to determine whether psychedelics offer a feasible, safe and effective treatment for FND.
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    The relative value of and motivation for abused drugs often increases with drug experience and differs based on drug availability. Here, we determined how different intake patterns of fentanyl, a μ‐opioid agonist, alter economic demand for fentanyl and how 5‐HT2A receptor stimulation affects economic demand for fentanyl. We used a within‐session demand threshold procedure to characterize changes in economic demand for fentanyl before and after intermittent or continuous access schedules. We subsequently tested the acute effects of 5‐HT2A receptor stimulation with psychedelic 2,5‐dimethoxy‐4‐iodoamphetamine (DOI) on economic demand for fentanyl. Extended fentanyl experience with both intermittent and continuous schedules increased fentanyl consumption at low cost (Q0), increased total fentanyl consumption, and decreased demand elasticity (α), indicating both schedules elevated motivation to self‐administer fentanyl. Overall, the two schedules produced similar alterations in economic demand for fentanyl, although low‐cost consumption (Q0) increased more in the continuous access group. Systemic injections of DOI (0.0‐0.4 mg/kg, i.p.) dose‐dependently produced economic demand changes in the opposite direction produced by fentanyl experience. DOI decreased motivation (increased “α”), decreased Q0, and decreased total fentanyl consumption. The selective 5‐HT2A antagonist, M100907 (0.3 mg/kg, i.p.), blocked the effects of DOI, indicating that DOI is acting through 5‐HT2A receptors to alter economic demand for fentanyl. In an economic food demand experiment, DOI (0.4 mg/kg) also increased demand elasticity and reduced food consumption. These results demonstrate that both intermittent and continuous fentanyl experience raise the economic demand for fentanyl, and acute 5‐HT2A receptor activation reduces economic demand for fentanyl and food.
  • Article
    Background Psychedelic drugs have shown an efficacy in some psychiatric disorders and have an original mechanism of action with a 5-HT 2A agonism. Aim The aim of this meta-analysis was to assess by a quantitative analysis the putative efficacy of psychedelic drugs on depressive symptoms and to investigate the kinetic of this efficacy. Methods We searched the MEDLINE and PsycINFO databases through April 2019, without limits on year of publication. Means and standard deviations were extracted to calculate standardized mean differences (SMD). Scores of depressive symptoms were compared with baseline scores at days 7, 14, and 21; weeks 4–5 and 6–8; and months 3 and 6. Results Eight studies were included in this meta-analysis. A significant decrease of depressive symptoms was found from day 1 ( n = 5 studies; SMD = ‒1.4, 95% confidence interval (CI): ‒2.33 to ‒0.48, p = 0.003) to 6 months ( n = 4 studies; SMD = ‒1.07, 95% CI: ‒1.44 to ‒0.7, p < 0.001) after psychedelic sessions. No serious adverse effect was reported in all included studies. A transient increase of the heart rate, blood systolic, and diastolic pressure were found after psychedelics compared with placebo. Conclusion This meta-analysis shows that psychedelic treatments were safe and could contribute to a rapid improvement of depressive symptoms.
  • Article
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    Psychedelic drugs, including the serotonin 2a (5-HT2A) receptor partial agonist psilocybin, are receiving renewed attention for their possible efficacy in treating a variety of neuropsychiatric disorders. Psilocybin induces widespread dysregulation of cortical activity, but circuit-level mechanisms underlying this effect are unclear. The claustrum is a subcortical nucleus that highly expresses 5-HT2A receptors and provides glutamatergic inputs to arguably all areas of the cerebral cortex. We therefore tested the hypothesis that psilocybin modulates claustrum function in humans. Fifteen healthy participants (10M, 5F) completed this within-subjects study in which whole-brain resting-state blood-oxygenation level-dependent (BOLD) signal was measured 100 min after blinded oral administration of placebo and 10 mg/70 kg psilocybin. Left and right claustrum signal was isolated using small region confound correction. Psilocybin significantly decreased both the amplitude of low frequency fluctuations as well as the variance of BOLD signal in the left and right claustrum. Psilocybin also significantly decreased functional connectivity of the right claustrum with auditory and default mode networks (DMN), increased right claustrum connectivity with the fronto-parietal task control network (FPTC), and decreased left claustrum connectivity with the FPTC. DMN integrity was associated with right-claustrum connectivity with the DMN, while FPTC integrity and modularity were associated with right claustrum and left claustrum connectivity with the FPTC, respectively. Subjective effects of psilocybin predicted changes in the amplitude of low frequency fluctuations and the variance of BOLD signal in the left and right claustrum. Observed effects were specific to claustrum, compared to flanking regions of interest (the left and right insula and putamen). This study uses a pharmacological intervention to provide the first empirical evidence in any species for a significant role of 5-HT2A receptor signaling in claustrum functioning, and supports a possible role of the claustrum in the subjective and therapeutic effects of psilocybin.
  • Article
    For most psychiatric disorders, including alcohol use disorder (AUD), approved pharmacological treatments are limited in their effectiveness, and new drugs that can easily be translated into the clinic are needed. Currently, great hope lies in the potential of psychedelics to effectively treat AUD. The primary hypothesis is that a single session of psychedelic-guided psychotherapy can restore normal brain function in AUD individuals and thereby reduce the risk of relapse in the long run. Here we applied three different treatment schedules with psilocybin/LSD in order to investigate relapse-like drinking in the alcohol deprivation effect (ADE) model. In contrast to the primary hypothesis, psychedelics had no long-lasting effects on the ADE in male and female rats, neither when administered in a high dosage regime that is comparable to the one used in clinical studies, nor in a chronic microdosing scheme. Only sub-chronic treatment with psilocybin produced a short-lasting anti-relapse effect. However, it is not a translatable treatment option to give psychedelics sub-chronically for relapse prevention. In conclusion, our results in the ADE model do not support the hypothesis that microdosing or high doses of psychedelic reduce relapse behavior. This conclusion has to be confirmed by applying other animal models of AUD. It could also well be that animal models of AUD might be unable to fully capture the therapeutic potential of psychedelic drugs and that only future large-scale clinical trials will be able to demonstrate the efficacy of psychedelics as a new treatment option for AUD.
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    Rationale: Serotonin (5-Hydroxytryptamine, 5-HT) receptors play an important role in perception, affect regulation and attention. Pharmacological challenge with the 5-HT2A agonist psilocybin (PY) is useful in studying the neurobiological basis of cognition and consciousness. Objective: Investigation of dose-dependent effects of PY on psycho(patho)logical and physiological parameters. Methods: Eight subjects received placebo (PL), and 45 ("very low dose, VLD”), 115 ("low dose, LD”), 215 ("medium dose, MD”), and 315 ("high dose, HD”) μg/kg body weight PY. The "Altered States of Consciousness Rating Scale” (5D-ASC), the "Frankfurt Attention Inventory” (FAIR), and the "Adjective Mood Rating Scale” (AMRS) were used to assess the effects of PY on psycho(patho)logical core dimensions, attention, and mood. A 24-h electrocardiogram (EKG) was recorded and blood pressure was measured. Plasma concentrations of thyroid-stimulating hormone (TSH), prolactin (PRL), cortisol (CORT), adrenocorticotropic hormone (ACTH), and standard clinical chemical parameters were determined. Results: PY dose dependently increased scores of all 5D-ASC core dimensions. Only one subject reacted with transient anxiety to HD PY. Compared with PL, MD and HD PY led to a 50% reduction of performance in the FAIR test. "General inactivation”, "emotional excitability”, and "dreaminess” were the only domains of the AMRS showing increased scores following MD and HD PY. The mean arterial blood pressure (MAP) was moderately elevated only 60min following administration of HD PY. Neither EKG nor body temperature was affected by any dose of PY. TSH, ACTH, and CORT plasma levels were elevated during peak effects of HD PY, whereas PRL plasma levels were increased following MD and HD PY. Conclusion: PY affects core dimensions of altered states of consciousness and physiological parameters in a dose-dependent manner. Our study provided no cause for concern that PY is hazardous with respect to somatic health
  • Article
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    Background: Validation of animal models of hallucinogenic drugs' subjective effects requires human data. Previous human studies used varied groups of subjects and assessment methods. Rating scales for hallucinogen effects emphasized psychodynamic principles or the drugs' dysphoric properties. We describe the subjective effects of graded doses of N,N-dimethyltryptamine (DMT), an endogenous hallucinogen and drug of abuse, in a group of experienced hallucinogen users. We also present preliminary data from a new rating scale for these effects. Methods: Twelve highly motivated volunteers received two doses (0.04 and 0.4 mg/kg) of intravenous (IV) dimethyltryptamine fumarate "nonblind," before entering a doubleblind, saline placebo-controlled, randomized study using four doses of IV DMT. Subjects were carefully interviewed after resolution of drug effects, providing thorough and systematic descriptions of DMT's effects. They also were administered a new instrument, the Hallucinogen Rating Scale (HRS). The HRS was drafted from interviews obtained from an independent sample of 19 experienced DMT users, and modified during early stages of the study. Results: Psychological effects of IV DMT began almost immediately after administration, peaked at 90 to 120 seconds, and were almost completely resolved by 30 minutes. This time course paralleled DMT blood levels previously described. Hallucinogenic effects were seen after 0.2 and 0.4 mg/kg of dimethyltryptamine fumarate, and included a rapidly moving, brightly colored visual display of images. Auditory effects were less common. "Loss of control," associated with a brief, but overwhelming "rush," led to a dissociated state, where euphoria alternated or coexisted with anxiety. These effects completly replaced subjects' previously ongoing mental experience and were more vivid and compelling than dreams or waking awareness. Lower doses, 0.1 and 0.05 mg/kg, were primarily affective and somaesthetic, while 0.1 mg/kg elicited the least desirable effects. Clustering of HRS items, using either a clinical, mental status method or principal components factor analysis provided better resolution of dose effects than did the biological variables described previously. Conclusions: These clinical and preliminary quantitative data provide bases for further psychopharmacologic characterization of DMT's properties in humans. They also may be used to compare the effects of other agents affecting relevant brain receptors in volunteer and psychiatric populations.
  • Article
    The history of research with psychedelic drugs has produced a variety of methods for their use and conflicting claims about results. First came the wave of excitement among experimentalists in the 1950s when it was claimed that lysergic acid diethylamide (LSD) could produce a model psychosis which might be useful in understanding schizophrenia. While this promise was fading, enthusiastic reports about the possibility of LSD as an aid to psychotherapy in the treatment of alcoholism and other psychiatric disorders appeared. All these approaches were represented in 1959 at the first international conference devoted entirely to LSD.1 Since then, there have been at least five more published proceedings of such conferences on various aspects of psychedelic drugs.2-6 The most recent conference on various means of producing states of consciousness was sponsored by the Menninger Foundation and the American Association of Humanistic Psychology on April 7 to 11, 1969, in