psilocybin-assisted treatment for alcohol dependence - a proof-of-concept study (pdf)
pdf version

bookmarks

search on psilosophy:  
   



Psilocybin-assisted treatment for alcohol dependence

A proof-of-concept study

by

Michael P Bogenschutz1, Alyssa A Forcehimes1, Jessica A Pommy1, Claire E Wilcox1, PCR Barbosa2 and Rick J Strassman1

Journal of Psychopharmacology 1-11

© The Author(s) 2015

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

sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/0269881114565144

Table of Contents:
Abstract
Introduction
 Biological mechanisms
 Psychological models of psychedelic treatment
Methods
 Study design
 Participants
 Interventions
  Psychosocial intervention
  Dosing and administration of study medications
 Assessments
  Medical evaluation
  Psychiatric and substance use disorder diagnoses
  Acute hallucinogen effects
  Substance use and consequences
  Psychological assessments
  Safety assessment
 Statistical analysis and power
Results
 Participants
 Treatment exposure and follow-up
 Acute effects
 Clinical outcomes
 Relationships between acute effects and treatment response
 Treatment-related adverse events
Discussion
Acknowledgements
References

Abstract

Several lines of evidence suggest that classic (5-HT2A 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

Introduction

In the 1950s through early 1970s there was extensive research on the use of LSD and other classic (5-HT2A 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% confidence interval 1.36-2.84, Z = 3.59, p=0.0003).

The past decade has seen a rapid growth of interest in potential 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 treatment resulted in remarkable rates of abstinence (80% point abstinence 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 articles and chapters have reviewed the literature on the use of hallucinogens 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).

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 5-HT2A 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 5-HT2A 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 5-HT2A receptor activity are complex. Increased 5-HT2A receptor binding has been found in relation to pathological conditions in humans including depression (Shelton et al., 2009), impulsive aggression (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 5-HT2A receptor binding/activity and alcoholism or alcohol exposure is less clear. Family history of alcoholism may be associated with lower 5-HT2A binding (Underwood et al., 2008), and alcoholism is not consistently associated with change in 5-HT2A receptor levels (Thompson et al., 2012; Underwood et al., 2008). Among alcoholics, one small post-mortem study reported that higher impulsivity was associated with increased 5-HT2A 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 5-HT2A receptors binding. Studies indicate that increased activity in 5-HT2Amediated pathways relative to 5-HT2C activity increases cue response and impulsivity in rat models of cocaine addiction (Cunningham and Anastasio, 2014). 5-HT2A antagonists suppress alcohol consumption in animal models (Johnson, 2008). However, two large trials of the 5-HT2A 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 activation of 5-HT2A receptors could activate intracellular signaling pathways resulting in persisting changes in cellular structure and synapses. The classic hallucinogen DOI increases expression of glial cell line-derived neurotrophic factor (GDNF) mRNA in glioiblastoma cells by a 5-HT2A-dependent mechanism (Tsuchioka et al., 2008). Through its action on 5-HT2A 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 dendritic 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 central 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 psychotherapy 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 significance 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 dependence. 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 intervention including two open-label psilocybin sessions in which psilocybin was administered: the first after 4 weeks of psychosocial treatment, the second after 8 weeks. Outcome data were collected for a total of 36 weeks.

Participants

Participants were recruited from the community using advertisements in local media and flyers. They were males and females age 25-65 with a diagnosis of active alcohol dependence, ascertained 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 screening showed them to have exclusionary medical or psychiatric conditions; family history of schizophrenia, bipolar disorder, or suicide; cocaine, psychostimulant, or opioid dependence; or history 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. 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 psychosocial 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 audiorecorded. 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 alcohol 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 participants 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 completed questionnaires and assessments, and a brief clinical interview 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 Dissolution," "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 experiments (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 administered following each drug administration session. In addition, a Monitor Session Rating Form (Griffiths et al., 2006) was completed 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 Concentration (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 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 Multidimensional 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 psychological 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 dependence (tolerance or withdrawal), but none had alcohol withdrawal symptoms requiring treatment during the trial.


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
9 completed all 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

Figure 1. Participant flow.

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 discontinued 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 during the first psilocybin session, in which all participants received psilocybin 0.3 mg/kg, and during the second psilocybin 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 significantly. 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).

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.

Table 1 shows mean scores on self-report measures of subjective experience obtained 7 hours following administration of psilocybin 0.3 mg/kg in the first session and for the six participants 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 hallucinogen effects.

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)
rSig.
Mean(SD)Min.Max.Mean(SD)Min.Max.(n=6)
ASC OBN960.4(518.8)911798785.0(977.3)7921070.6490.163
ASC DED499.6(515.8)381515340.1(445.2)2610210.8080.052
ASC VRS923.5(396.8)611516610.2(543.5)18814620.6700.145
ASC AUA302.5(380.9)261166182.0(288.5)187660.9600.002
ASC VIR394.2(268.1)49819244.4(333.0)36.58830.8280.042
G-ASC2383.5(1347.7)23546281735.3(1761.1)337.545900.8270.042
MEQ total0.473(0.217)0.0160.7680.387(0.347)0.0110.9240.8430.035
HRS intensity2.43(1.03)03.52.00(1.14)0.253.250.9020.014
ARCI PCAG8.00(3.06)3125.50(4.04)1120.2870.581
ARCI BG5.40(1.58)385.83(2.99)2110.1670.752
ARCI A4.78*(2.37)084.50(2.88)290.1980.707
ARCI MBG5.33*(3.61)4126.33(4.55)2130.3880.448
ARCI LSD8.10(3.21)1138.17(2.99)4120.4050.425
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 Restructuralization subscale; AUA: Auditory Alterations subscale; VIR: Vigilance Reduction subscale; G-ASC: summary score (sum of OBN, DED, and VRS); MEQ: Mystical Experience Questionnaire; 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.

Clinical outcomes

Percent heavy drinking days decreased during weeks 5-12 relative 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 psilocybin) (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 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 additional outcomes for study participants. Significant improvement 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).

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.

Table 2. Secondary outcomes.
Baseline
Mean (SD)
Week 4
Mean (SD)
Week 5
Mean (SD)
Week 8
Mean (SD)
Week 9
Mean (SD)
Week 12
Mean (SD)
Week 24
Mean (SD)
Week 36
Mean (SD)
SIP
Physical4.60 (2.27)4.89 (3.14)2.78 (2.95)2.78 (3.35)
Interpersonal4.80 (2.57)4.44 (3.17)2.56 (3.05)**2.56 (2.88)**
Interpersonal7.30 (1.70)6.00 (3.12)3.89 (3.76)*3.67 (3.74)*
Impulse control2.90 (1.29)3.89 (2.47)2.56 (2.24)2.56 (3.05)
Responsibility4.50 (2.37)4.22 (3.46)3.67 (3.81)2.67 (2.87)
PACS16.00 (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
Temptation38.30 (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)§
Confidence40.10 (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
Recognition31.80 (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)
Ambivalence15.70 (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 Steps32.30 (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
Tension7.20 (5.27)6.22 (3.42)4.67 (3.54)5.78 (4.44)5.89 (4.88)8.00 6.065.78 (5.97)5.33 (6.04)
Depression6.50 (5.60)3.40 (4.45)4.89 (6.41)4.44 (3.50)3.22 (4.38)6.78 7.456.11 (6.11)5.00 (4.58)
Anger4.40 (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)
Vigor5.60 (4.01)6.50 (3.34)8.56 (4.61)8.11 (5.46)9.00 (5.85)7.75 4.109.56 (4.90)*7.50 (2.78)
Fatigue8.70 (5.79)6.60 (5.78)6.22 (6.44)5.44 (4.75)5.56 (4.28)7.67 6.286.67 (5.96)6.89 (4.08)
Confusion6.10 (2.69)3.90 (1.79)*4.67 (2.96)5.33 (3.71)5.56 (3.43)5.13 3.365.56 (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.

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.

Table 3. Correlations between acute effects and change in drinking, craving, and self-efficacy (n = 9).
PDD
(wk. 8 - wk. 4)
PHDD
(wk. 8 - wk. 4)
PACS
(wk. 5 - wk. 4)
AASE
(wk. 5 - wk. 4)
HRS Intensityr = -.844r = -.763r = -.823r = .753
(wk. 4)p = .004p = .017p = .006p = .019
MEQ totalr =-.885r = -.852r = -.810r = .762
(wk. 4)p = .002p = .004p = .008p = .017
G-ASCr =-.838r =-.893r =-.654r =-.555
(wk. 4)p = .005p = .001p = .056p = .121
PDD: Percent Drinking Days; PHDD: Percent Heavy Drinking Days; PACS: Penn Alcohol Craving Scale; AASE = 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.

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 psilocybin 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 significant 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 time course of the observed changes and the striking relationship 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 functional 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 quality 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, during 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.

References

  1. Abuzzahab FS, Sr. and Anderson BJ (1971) A review of LSD treatment in alcoholism. Int Pharmacopsychiatry 6: 223-235.
  2. Akash KG, Anju TR, Peeyush KT, et al. (2008) Enhanced dopamine D2 receptor function in hypothalamus and corpus striatum: Their role in liver, plasma and in vitro hepatocyte ALDH regulation in ethanol treated rats. J Biomed Sci 15: 623-631.
  3. Akash KG, Balarama KS and Paulose CS (2008) Enhanced 5-Ht(2a) receptor status in the hypothalamus and corpus striatum of ethanol-treated rats. Cell Mol Neurobiol 28: 1017-1025.
  4. Anisman H, Du L, Palkovits M, et al. (2008) Serotonin receptor subtype and P11 mRNA expression in stress-relevant brain regions of suicide and control subjects. J Psychiatry Neurosci 33: 131-141.
  5. Benjamani Y and Hochberg Y (1995) Controlling the false discovery rate: A practical and powerful approach to multiple testing. J Royal Stat Soc Series B (Method) 57: 289-300.
  6. Bogenschutz MP (2012) Effects of psilocybin in the treatment of addictions: A review and preliminary results from two ongoing trials. Neuropsychopharmacology 38: S15-S16.
  7. Bogenschutz MP and Pommy JM (2012) Therapeutic mechanisms of classic hallucinogens in the treatment of addictions: From indirect evidence to testable hypotheses. Drug Test Anal 4: 543-555.
  8. Bowen WT, Soskin RA and Chotlos JW (1970) Lysergic acid diethylamide as a variable in the hospital treatment of alcoholism: A follow-up study. J Nerv Ment Dis 150: 111-118.
  9. Buckholtz NS, Zhou DF, Freedman DX, et al. (1990) Lysergic acid diethylamide (LSD) administration selectively downregulates serotonin2 receptors in rat brain. Neuropsychopharmacology 3: 137-148.
  10. Burdick BV and Adinoff B (2013) A proposal to evaluate mechanistic efficacy of hallucinogens in addiction treatment. Am J Drug Alcohol Abuse 39: 291-297.
  11. Carhart-Harris RL, Erritzoe D, Williams T, et al. (2012) Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proc Natl Acad Sci U S A 109: 2138-2143.
  12. Carhart-Harris RL, Leech R, Erritzoe D, et al. (2013) Functional connectivity measures after psilocybin inform a novel hypothesis of early psychosis. Schizophr Bull 39: 1343-1351.
  13. Chwelos N, Blewett DB, Smith CM, et al. (1959) Use of D-lysergic acid diethylamide in the treatment of alcoholism. Q J Stud Alcohol 20: 577-590.
  14. Cohen J (1988) Statistical Power Analysis for the Behavioral Sciences (2nd Edn). Hillsdale, NJ: Lawrence Erlbaum Associates, Inc.
  15. Cunningham KA and Anastasio NC (2014) Serotonin at the nexus of impulsivity and cue reactivity in cocaine addiction. Neuropharmacology 76 Pt B: 460-478.
  16. Dittrich A (1998) The standardized psychometric assessment of altered states of consciousness (ASCS) in humans. Pharmacopsychiatry 31: 80-84.
  17. Dyck E (2006) 'Hitting highs at rock bottom': LSD treatment for alcoholism, 1950-1970. Soc Hist Med 19: 313-329.
  18. Fetzer Institute (1999) Multidimensional Measurement of Religiousness/Spirituality for Use in Health Research. Kalamazoo, MI: Fetzer Institute.
  19. Diclemente CC, Carbonari JP, Montgomery RP, et al. (1994) The Alcohol Abstinence Self-Efficacy Scale. J Stud Alcohol 55: 141-148.
  20. First MB, Spitzer RL, Gibbon M, et al. (1996) Structured Clinical Interview for DSM-IV Axis I Disorders-Patient Edition (Scid-I/P, Version 2.0). New York, NY: Biometrics Research Department, New York State Psychiatric Institute.
  21. First MB, Spitzer RL, Gibbon M, et al. (1997) Structured Clinical Interview for DSM-IV Axis I Disorders-Patient Edition. New York, NY: Biometrics Research Department, New York State Psychiatric Institute.
  22. Flannery BA, Volpicelli JR and Pettinati HM (1999) Psychometric properties of the Penn Alcohol Craving Scale. Alcohol Clin Exp Res 23:1289-1295.
  23. Forcehimes AA (2004) De profundis: Spiritual transformations in Alcoholics Anonymous. J Clin Psychol 60: 503-517.
  24. Frokjaer VG, Mortensen EL, Nielsen FA, et al. (2008) Frontolimbic serotonin 2a receptor binding in healthy subjects is associated with personality risk factors for affective disorder. Biol Psychiatry 63:569-576.
  25. Garcia-Romeu AP, Johnson MW and Griffiths RR (2013) Examining the psychological mechanisms of psilocybin-assisted smoking cessation treatment: A pilot study. Abstract book. San Diego, CA: CPDD conference, June 16-20, 2013.
  26. George AK, Paul J, Kaimal SB, et al. (2010) Decreased cerebral cortex and liver 5-HT2a receptor gene expression and enhanced ALDH activity in ethanol-treated rats and hepatocyte cultures. Neurol Res 32: 510-518.
  27. Ghitza UE, Zhai H, Wu P, et al. (2010) Role of BDNF and GDNF in drug reward and relapse: A review. Neurosci Biobehav Rev 35: 157-171.
  28. Gresch PJ, Smith RL, Barrett RJ, et al. (2005) Behavioral tolerance to lysergic acid diethylamide is associated with reduced serotonin-2a receptor signaling in rat cortex. Neuropsychopharmacology 30:1693-1702.
  29. Griffiths R, Richards W, Johnson M, et al. (2008) Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later. J Psychopharmacol 22: 621-632.
  30. Griffiths RR, Johnson MW, Richards WA, et al. (2011) Psilocybin occasioned mystical-type experiences: Immediate and persisting dose-related effects. Psychopharmacology (Berl) 218: 649-665.
  31. Griffiths RR, Richards WA, Mccann U, et al. (2006) Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology (Berl) 187: 268-283; discussion 284-292.
  32. Grinspoon L and Balakar JB (1997) Psychedelic Drugs Reconsidered. New York: The Lindesmith Center.
  33. Grob CS, Danforth AL, Chopra GS, et al. (2011) Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiatry 68: 71-78.
  34. Grof S (2008) LSD Psychotherapy. 4 edn. Ben Lomond, CA: Multidisciplinary Association for Psychedelic Studies.
  35. Grof S, Goodman LE, Richards WA, et al. (1973) LSD-assisted psychotherapy in patients with terminal cancer. Int Pharmacopsychiatry 8:129-144.
  36. Halpern JH (1996) The use of hallucinogens in the treatment of addiction. Addict Res 4: 177-189.
  37. Hasler F, Grimberg U, Benz MA, et al. (2004) Acute psychological and physiological effects of psilocybin in healthy humans: A double-blind, placebo-controlled dose-effect study. Psychopharmacology (Berl) 172: 145-156.
  38. Hoffer A (1967) A program for treatment of alcoholism: LSD, malvaria, and nicotinic acid. In: Abramson HA (ed) The Use of LSD in Psychotherapy and Alcoholism. Indianapolis: Bobbs-Merrill. pp. 343-406.
  39. Hollister LE, Shelton J and Krieger G (1969) A controlled comparison of lysergic acid diethylamide (LSD) and dextroamphetmine in alcoholics. Am J Psychiatry 125: 1352-1357.
  40. Hood RWJ, Ghorbani N, Watson PJ, et al. (2001) Dimensions of the mysticism scale: Confirming the three-factor structure in the United States and Iran. J Sci Study Relig 40: 691-705.
  41. James W (1902) The Varieties of Religious Experience. Cambridge, MA: Harvard University Press.
  42. Johnson BA (2008) Update on neuropharmacological treatments for alcoholism: Scientific basis and clinical findings. Biochem Pharmacol 75: 34-56.
  43. Johnson BA, Jasinski DR, Galloway GP, et al. (1996) Ritanserin in the treatment of alcohol dependence - a multi-center clinical trial. Ritanserin Study Group. Psychopharmacology (Berl) 128: 206-215.
  44. Johnson MW, Andrew Sewell R and Griffiths RR (2012) Psilocybin dose-dependently causes delayed, transient headaches in healthy volunteers. Drug Alcohol Depend 123: 132-140.
  45. Johnson MW, Garcia-Romeu A, Cosimano MP, et al. (2014) Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. J Psychopharmacol 28: 983-992.
  46. Jones KA, Srivastava DP, Allen JA, et al. (2009) Rapid modulation of spine morphology by the 5-HT2A serotonin receptor through kalirin-7 signaling. Proc Natl Acad Sci U S A 106: 19575-19580.
  47. Kast EC (1966) Pain and LSD-25: A theory of attenuation of anticipation. In: Solomon D (ed) LSD: The Consciousness-Expanding Drug. New York, NY: GP Putnam, 239-254.
  48. Kast EC and Collins VJ (1964) Study of lysergic acid diethylamide as an analgesic agent. Anesth Analg 43: 285-291.
  49. Kometer M, Schmidt A, Bachmann R, et al. (2012) Psilocybin biases facial recognition, goal-directed behavior, and mood state toward positive relative to negative emotions through different serotonergic subreceptors. Biol Psychiatry 72: 898-906.
  50. Krebs TS and Johansen PO (2012) Lysergic acid diethylamide (LSD) for alcoholism: Meta-analysis of randomized controlled trials. J Psychopharmacol 26: 994-1002.
  51. Kurland AA, Unger S, Shaffer JW, et al. (1967) Psychedelic therapy utilizing LSD in the treatment of the alcoholic patient: A preliminary report. Am J Psychiatry 123: 1202-1209.
  52. Leuner H (1967) Present state of psycholytic therapy and its possibilities. In: Abramson HA (ed) The Use of LSD in Psychotherapy and Alcoholism. Indianapolis: Bobbs-Merrill, pp. 101-116.
  53. Ludwig A, Levine J, Stark L, et al. (1969) A clinical study of LSD treatment in alcoholism. Am J Psychiatry 126: 59-69.
  54. Maclean KA, Johnson MW and Griffiths RR (2011) Mystical experiences occasioned by the hallucinogen psilocybin lead to increases in the personality domain of openness. J Psychopharmacol 25: 1453-1461.
  55. Mangini M (1998) Treatment of alcoholism using psychedelic drugs: A review of the program of research. J Psychoactive Drugs 30: 381-418.
  56. Martin WR, Sloan JW, Sapira JD, et al. (1971) Physiologic, subjective, and behavioral effects of amphetamine, methamphetamine, ephedrine, phenmetrazine, and methylphenidate in man. Clin Pharmacol Ther 12: 245-258.
  57. Masters R and Houston J (2000) The Varieties of Psychedelic Experience: The Classic Guide to the Effects of LSD on the Human Psyche. Rochester, Vermont: Park Street Press.
  58. Mccrae RR, Costa Jr, PT and Martin TA (2005) The Neo-Pi-3: A more readable revised neo personality inventory. J Pers Assess 84: 261-270.
  59. Mcnair DM, Lorr M and Droppleman LF (1981) Profile of Mood States. San Diego, CA: Educational and Industrial Testing Service.
  60. Miller WR and C'de Baca J (2001) Quantum Change : When Epiphanies and Sudden Insights Transform Ordinary Lives. New York: Guilford Press.
  61. Miller WR and Rolnick S (2013) Motivational Interviewing: Helping People Change. 3rd. ed. New York, NY: Guilford Press.
  62. Miller WR and Tonigan JS (1996) Assessing drinker's motivation for change: The Stages of Change Readiness and Treatment Eagerness Scale (Socrates). Psychology of Addictive Behaviors 10: 81-89.
  63. Miller WR, Tonigan JS and Longabaugh R (1995) The Drinker Inventory of Consequences (Drinc): An Instrument for Assessing Adverse Consequences of Alcohol Abuse. Test Manual (Vol. 4). Rockville, MD: US Government Printing Office.
  64. Morris SB and Deshon RP (2002) Combining effect size estimates in meta-analysis with repeated measures and independent-groups designs. Psychological Methods 7: 105-125.
  65. Moyers TB, Martin T, Manuel JK, et al. (2005) Assessing competence in the use of motivational interviewing. J Subst Abuse Treat 28: 19-26.
  66. Nichols DE (2004) Hallucinogens. Pharmacol Ther 101: 131-181.
  67. Nichols DE (2014) The Heffter Research Institute: Past and hopeful future. J Psychoactive Drugs 46: 20-26.
  68. Pahnke W (1963) Drugs and mysticism: An analysis of the relationship between psychedelic drugs and the mystical consciousness. Ph.D. Thesis, Harvard University.
  69. Pahnke WN (1969) Psychedelic drugs and mystical experience. Int Psychiatry Clin 5: 149-162.
  70. Pahnke WN, Kurland AA, Goodman LE, et al. (1969) LSD-assisted psychotherapy with terminal cancer patients. Curr Psychiatr Ther 9: 144-152.
  71. Pahnke WN, Kurland AA, Unger S, et al. (1970) The experimental use of psychedelic (LSD) psychotherapy. JAMA 212: 1856-1863.
  72. Piedmont RL (1999) Does spirituality represent the sixth factor of personality? Spiritual transcendence and the Five-Factor Model. J Person 67: 985-1013.
  73. Ray TS (2010) Psychedelics and the human receptorome. PLoS ONE 5: e9019.
  74. Richards WA (1975) Counseling, peak experiences and the human encounter with death: An empirical study of the efficacy of DPT-assisted counseling in enhancing the quality of life of persons with terminal cancer and their closest family members. Ph.D. Thesis, Catholic University of America, Washington, DC.
  75. Richards WA, Rhead JC, Dileo FB, et al. (1977) The peak experience variable in DPT-assisted psychotherapy with cancer patients. J Psychedelic Drugs 9: 1-10.
  76. Rosell DR, Thompson JL, Slifstein M, et al. (2010) Increased serotonin 2a receptor availability in the orbitofrontal cortex of physically aggressive personality disordered patients. Biol Psychiatry 67: 1154-1162.
  77. Ross S (2012) Serotonergic hallucinogens and emerging targets for addiction pharmacotherapies. Psychiatric Clin N Am 35: 357-374.
  78. Schwartz SH (1992) Universals in the content and structure of values: Theory and empirical tests in 20 countries. In: Zanna M (ed) Advances in Experimental Social Psychology, Vol. 25. New York: Academic Press, pp. 1-65.
  79. Schwartz SH (2006) Les valeurs de base de la personne: Theorie, mesures et applications [Basic human values: Theory, measurement, and applications]. Revue française de sociologie 42: 249-288.
  80. Shelton RC, Sanders-Bush E, Manier DH, Schwartz SH (2009) Elevated 5-HT2a receptors in postmortem prefrontal cortex in major depression is associated with reduced activity of protein kinase A. Neuroscience 158: 1406-1415.
  81. Sherwood JN, Stolaroff MJ and Harman WW (1962) The psychedelic experience - a new concept in psychotherapy. J Neuropsychiatr 4: 69-80.
  82. Smart RG, Storm T, Baker EF, Schwartz SH (1966) A controlled study of lysergide in the treatment of alcoholism. 1. The effects on drinking behavior. Q J Stud Alcohol 27: 469-482.
  83. Sobell LC and Sobell MB (1992) Timeline follow-back: A technique for assessing self-reported alcohol consumption. In: Litten RA and Allen JP (eds) Measuring Alcohol Consumption: Psychosocial and Biological Methods. Totowa, NJ: Humana Press, pp. 41-72.
  84. Sobell LC and Sobell MB (1995) Alcohol Timeline Followback Users' Manual. Toronto, Canada: Addiction Research Foundation.
  85. Soloff PH, Price JC, Meltzer CC, et al. (2007) 5-HT2a receptor binding is increased in borderline personality disorder. Biol Psychiatry 62: 580-587.
  86. Strassman RJ (1984) Adverse reactions to psychedelic drugs. A review of the literature. J Nerv Ment Dis 172: 577-595.
  87. Strassman RJ, Qualls CR, Uhlenhuth EH, et al. (1994) Dose-response study of N,N-dimethyltryptamine in humans. II. Subjective effects and preliminary results of a new rating scale. Arch Gen Psychiatry 51: 98-108.
  88. Sullivan JT, Sykora K, Schneiderman J, et al. (1989) Assessment of alcohol withdrawal: The Revised Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-AR). Br J Addict 84: 1353-1357.
  89. Thompson PM, Cruz DA, Olukotun DY, et al. (2012) Serotonin receptor, Sert mRNA and correlations with symptoms in males with alcohol dependence and suicide. Acta Psychiatr Scand 126: 165-174.
  90. Tomsovic M and Edwards RV (1970) Lysergide treatment of schizophrenic and nonschizophrenic alcoholics: A controlled evaluation. Q J Stud Alcohol 31: 932-949.
  91. Tsuchioka M, Takebayashi M, Hisaoka K, et al. (2008) Serotonin (5-HT) induces glial cell line-derived neurotrophic factor (GDNF) mRNA expression via the transactivation of fibroblast growth factor receptor 2 (FGFR2) in rat C6 glioma cells. J Neurochem 106: 244-257.
  92. Turek IS, Soskin RA and Kurland AA (1974) Methylenedioxyamphetamine (MDA) subjective effects. J Psychedelic Drugs 6: 7-14.
  93. Underwood MD, Mann JJ, Huang YY, et al. (2008) Family history of alcoholism is associated with lower 5-HT2A receptor binding in the prefrontal cortex. Alcohol Clin Exp Res 32: 593-599.
  94. Vaidya VA, Marek GJ, Aghajanian GK, et al. (1997) 5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. J Neurosci 17: 2785-2795.
  95. Vollenweider FX and Kometer M (2010) The neurobiology of psychedelic drugs: Implications for the treatment of mood disorders. Nat Rev Neurosci 11: 642-651.
  96. Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Babler A, et al. (1998) Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport 9: 3897-3902.
  97. Wiesbeck GA, Weijers HG, Chick J, et al. (1999) Ritanserin in relapse prevention in abstinent alcoholics: Results from a placebo-controlled double-blind international multicenter trial. Ritanserin in Alcoholism Work Group. Alcohol Clin Exp Res 23: 230-235.



search on psilosophy:  
 

TutorialS ]   [ ForuM ]   [ SpecieS ]   [ GalerY (pl) ]   [ TripograM ]   [ PsilosOpediuM ]  

© psilosophy 2001-2020