http://informahealthcare.

com/ada
ISSN: 0095-2990 (print), 1097-9891 (electronic)

Am J Drug Alcohol Abuse, 2013; 39(5): 291–297

! 2013 Informa Healthcare USA, Inc. DOI: 10.3109/00952990.2013.811513

REGULAR ARTICLE

A proposal to evaluate mechanistic efficacy of hallucinogens

in addiction treatment
Brittany Vasae Burdick, BA1 and Bryon Adinoff, MD1,2
1
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA and 2VA North Texas Health Care System,
Am J Drug Alcohol Abuse Downloaded from informahealthcare.com by University of Hawaii on 08/24/13

Dallas VA Medical Center, Dallas, TX 75216, USA

Abstract Keywords
Current treatments for addiction are frequently ineffective. Hallucinogenic therapy has been Addiction, drug abuse, hallucinogens, review,
indicated as helpful for a range of substance use disorders, yet this approach remains psilocybin
understudied and publicly unavailable. It is nonetheless a promising treatment, which has
significant, long-term beneficial effects with single doses and a profile characterized by general History
safety, low toxicity, and non-addictiveness. However, pharmacological interventions, such as
hallucinogens, should not be offered if the same effects (e.g. psychological insights/mystical Received 29 March 2013
experiences) and outcomes (e.g. decreased drug use) could be achieved absent pharmaco- Accepted 29 May 2013
logical intervention. To date, there have been no clinical comparisons of drug-induced altered Published online 14 August 2013
states with non-drug-induced states for addiction treatment. We propose and then outline a
For personal use only.

clinical trial to address this gap in knowledge. The proposed design would evaluate abstinence
outcomes in a population of prescription opioid abusers after exposure to one of three
conditions: a drug-induced altered state using psilocybin, a non-drug-induced altered state via
hyperventilation (Holotropic Breathwork), and an active placebo with niacin. The outcomes of
such a study would reveal important differences in therapeutic potential by discriminating
hallucinogen-dependent effects from those psychological effects resulting from altered states.

Introduction as hallucinogens are generally safe, of low toxicity, not

physiologically addictive (17,19–25), and appear to have
Substance use disorders are chronic conditions that are difficult
significant, long-term effects with single doses (5,6,10,11,26).
to treat. One study of 1300 participants in treatment found a
However, no studies to date have specifically examined
median use of 27 years (1). Additionally, they found the median
mechanistic contributions of hallucinogens versus non-
time period between first treatment episode and last use to be 9
drug-induced ASC. This evaluation is essential for determin-
years. A similar study of 10 000 patients and their treatment
ing the direction of future research. It will, for example,
outcomes reported an average of 3.5 treatment episodes (2).
dictate whether developing specific ligands should be
Unfortunately, this evidence suggests present therapies regu-
prioritized over evaluating the best combination of dosage
larly fail in relieving many patients of their drug addiction.
Treatment of this complex, chronic disease may include
and psychotherapy. Additionally, hallucinogenic research is 13
20
fraught with obstacles. If similar mechanisms may be
induction of altered states of consciousness (ASCs) (3).
addressed through other means, it may be prudent to choose
Hallucinogenic therapy offers a possible method to induce
the less tortuous route.
ASC. Previous studies have demonstrated hallucinogens, as a
This article proposes a study design to assess such concerns.
class of substances, are effective in improving several types of
First, it presents the sociolegal concerns inherent in the subject
addictions (4–17). Lysergic acid diethylamide (LSD), for
matter, followed by a discussion of the proposed therapeutic
example, appears to reduce alcohol misuse. A recent meta-
biological and psychological mechanisms of hallucinogens.
analysis of six trials involving 536 participants supported this
We then offer a detailed proposal to evaluate efficacy claims
beneficial relationship (p50.0005) (6). This data is congruent
by comparing abstinence outcomes after exposure to active
with hallucinogen-users self-reports of improved substance
placebo, drug-induced ASC, or non-drug-induced ASC. This
abuse symptoms (18). The approach is particularly promising
proposal will also aim to correlate abstinence with the strength
of psychological mechanisms in ASCs.
Address correspondence to Bryon Adinoff, MD, Department of
Psychiatry, University of Texas Southwestern Medical Center, 5323 Sociolegal issues of hallucinogenic research
Harry Hines Boulevard, Dallas, TX 75208-8564, USA. Tel: +214-645-
6975. Mobile: +817-371-9798. Fax: +214-645-6976. E-mail: bryon. As mentioned, this area of research is promising, yet
adinoff@utsouthwestern.edu made difficult by social, legal and political concerns.
 292 B. V. Burdick & B. Adinoff
Historically, the study of hallucinogens ceased after the 1960s,
when their association with the counterculture led to their
illegalization and ensuing disappearance from the literature
(27,28). Nearly all of these substances are still currently
classified as Schedule I drugs in USA. Consequently, any study
wishing to clinically evaluate these substances must not
only obtain Food and Drug Administration (FDA) approval
for the use of an Investigational New Drug (IND) but also
a drug-specific, Drug Enforcement Administration (DEA)
Schedule I permit. Due to both strict regulations and decreased
availability, two earlier studies reported delays from 1.5 to
3 years in obtaining their supplies (29,30).
Presently, no ongoing trials involving peyote, mescaline,
ayahuasca, dimethyltryptamine (DMT) or ibogaine are
reported by governmental agencies at ClinicalTrials.gov,
despite prior favorable findings (7–9,16,26,31). A single
Am J Drug Alcohol Abuse Downloaded from informahealthcare.com by University of Hawaii on 08/24/13
LSD study on illness-related anxiety is listed, while five
studies on psilocybin are concurrent. These latter studies
examine psilocybin’s biological phenomena as well as its
therapeutic effects on illness-related anxiety, spirituality and
addiction. Twenty clinical studies on 3,4-methylenedioxy-
methamphetamine (MDMA) are in various stages of comple-
tion, over half of which focus solely on biological events.
Interestingly, ketamine, which has a similar psychological
profile to psilocybin and DMT (32,33), has over 200
investigations. These trends are congruent with the majority
of recent publications, suggesting certain drugs have momen-
For personal use only.
tum or greater supply availability. Indeed, several current
psilocybin studies are supplied with the same batch manu-
factured for earlier research in 2001, while ketamine is
Schedule III and routinely used as an anesthetic (34).
Funding presents an additional hurdle for projects.
Theoretically, it may come from publicly sourced grants, but
current trends show private, special interest groups as the pri-
mary financial backers. Examples include the Heffter Research
Institute and Multidisciplinary Association for Psychedelic
Studies (MAPS). Federal agencies, such as the National
Institute of Mental Health (NIMH), National Institute on
Drug Abuse (NIDA), National Institute on Alcohol Abuse and
Alcoholism (NIAAA) and the National Science Foundation
(NSF), have rarely provided funding and only to projects
involving non-classical hallucinogens, such as ketamine and
MDMA. Studies investigating ketamine’s effects on depres-
sion, schizophrenia and post-traumatic stress disorder (PTSD)
are funded by the NIMH, Department of Defense and
pharmaceutical companies. The lack of support is remarkable,
given classical hallucinogens’ relative safety and their ability to
potentially improve a wide range of public health concerns.
Specifically, they have been indicated in treatment for addic-
tion (4–17), depression (17), death-related anxiety (35), PTSD
(36) and obsessive–compulsive disorder (OCD) (22).
Therapeutic effects of hallucinogens in addiction
treatment
The therapeutic mechanisms of action in hallucinogens are
proposed to be both biological and psychological in nature.
Bogenschutz and Pommy (4) proposed a hierarchical model of
acute and persisting effects, followed by final change mech-
anisms. Acute effects were separated into biological and
Am J Drug Alcohol Abuse, 2013; 39(5): 291–297
psychological categories, while persisting effects included
favorable changes in mood, anxiety, personality, cognition and
neuroplasticity. Long-term changes were proposed to result in
improved self-efficacy and decreased craving. While these
elements are clearly interrelated, we will discuss them
independently.
Biological components
Hallucinogens are chemically divided into three classes: the
phenethylamines, such as mescaline, the tryptamines, such as
psilocybin and DMT, and the semi-synthetic ergolines, such
as LSD. These substances are thought to primarily function by
agonist action of 5-HT2A receptors (32). Supporting this
conclusion are studies evidencing ketanserin, a 5-HT2A
antagonist, blocks the subjective effects of psilocybin in
humans (37,38). However, while phenylethylamines are
highly selective for 5-HT2 receptors versus 5-HT1 sites, the
indoleamines (which include tryptamines and ergolines) are
relatively non-selective, displaying affinity for both 5-HT1
and 5-HT2 subtypes (39).
The stimulation of postsynaptic 5-HT2A receptors results
in glutamate release by pyramidal cells in the deep layers of
the prefrontal cortex, and subsequent activation of a-amino-3-
hydroxy-5-methyl-4-isoxazole propionate (AMPA) and
N-methyl-D-aspartate (NMDA) glutamate receptors (32).
This complex interaction between serotonergic and glutama-
tergic systems in the prefrontal cortex appears to cause the
perceptual and mood-altering effects characteristic of the
hallucinogenic experience (40). One study on dextromethor-
phan, an NMDA antagonist, details subjective experiences
comparable to psilocybin, which may indicate glutamic
involvement to a higher degree (41). Some substances, such
as the empathogen, MDMA, and the dissociative anesthetic,
ketamine, have substantially different mechanisms and
effects, making them ‘‘non-classical’’ examples of hallucino-
gens (19).
Psychological components
Despite their chemical diversity, hallucinogens are markedly
similar in their clinical efficacy and subjective effects.
Typically, the experience is characterized by changes in
perception (e.g. visual geometric patterning, hallucinations,
synesthesia), body sensation (e.g. headache, nausea, tingling),
cognition (e.g. distance from reality, metaphysical thinking,
ideas of reference, impaired volition, ineffability) and mood
(e.g. euphoria, lability). Psychological components can
largely be divided into two constructs: psychological insight
and mystical experience. Therapeutic uses of hallucinogens,
explored prior to their criminalization, focused on these
constructs independently (27).
Psychological insight
Psychedelic therapy utilizes high dosages with the intent of
eliciting a peak, or mystical, experience. This is in contrast to
psycholytic therapy, which employs small doses over many
sessions and is based on psychoanalytic principles: uncon-
scious forces of the psyche are responsible for functional
deficits, and insight into these forces reduces their disruptive
power. Indeed, hallucinogens may accelerate and assist the
 DOI: 10.3109/00952990.2013.811513
psycholytic therapeutic process by enhancing recollection.
A functional magnetic resonance imaging (fMRI) study, for
example, showed visual and other sensory cortical activations
from memory cues were present following psilocybin but not
placebo (42). Memory vividness was also rated higher after
psilocybin.
The trauma model reveals another perspective on psycho-
logical insight. Specifically, this model suggests impairment
following a trauma is derived from inadequate processing of
the event. For this reason, exposure therapy for PTSD focuses
on having the patient revisit the traumatic event, while
maintaining the appropriate level of emotional involvement
and sympathetic activation (43). In particular, MDMA
has helped with this treatment aim, due to its success in
decreasing fear while maintaining high cognitive processing
(36). Regardless of the underlying model, the goal is the
Am J Drug Alcohol Abuse Downloaded from informahealthcare.com by University of Hawaii on 08/24/13
same: the resolution of psychological conflicts.
Mystical experience
The construct ‘‘mystical experience’’ is difficult to define.
The dictionary describes the nebulous realm of spirituality as
‘‘of, relating to, consisting of, or affecting the spirit.’’ Cook
(44) attempts a more rigorous definition, identifying 13
relevant concepts through the analysis of 265 articles.
Of these, transcendence, meaningfulness and relatedness or
a sense of oneness were most frequently cited. Previous
psychedelic research has used a similar definition (45), and
For personal use only.
measured the construct through self-report. According to
recreational users, hallucinogens frequently induce spiritual
experiences (18). An additional recent study reported 72% of
18 participants had a mystical experience while on psilocybin
(46). Relatedly, another study on terminal cancer patients
assessed hallucinogens in the treatment of existential anxiety
(35). In this instance, 12 patients were given psilocybin and
had significant reductions in anxiety related to dying at 1 and
3 months post-treatment.
The relationship of hallucinogens and mystical experience
is significant in addiction treatment, where spirituality
appears to play a role. Religiosity is a protective factor in
drug habit formation (44). Arguably, this may not reflect a
causal relationship, but further support comes from the
literature on success factors in recovery. Matzger et al. (47)
surveyed 659 alcohol abusers and found three common
reasons for efforts in habit reduction: hitting rock bottom,
Figure 1. Study design. Patients will randomly be assigned to three conditions: psilocybin, HB or active placebo. Psilocybin represents a drug-induced
ASC, while HB represents a non-drug-induced ASC. The two primary endpoints are reduced drug use as measured by urine drug screen (UDS) and
TLFB through 12 weeks post-treatment. Secondary outcomes will be obtained for exploratory purposes.
Testing efficacy of hallucinogens 293
experiencing a traumatic event and undergoing a spiritual
awakening. While a spiritual connection is obvious in the last
motive, it may also be suggested that the first two reasons
are related to the meaningfulness component within spiritu-
ality. If addiction is conceived of as a state absent truth,
rock bottom and traumatic events may be conceptualized as
periods when truth can no longer be denied (48). Finally,
an active emphasis on spirituality in recovery has been shown
to improve the length of abstinence (49–57).
Proposal to evaluate mechanisms
Although the literature noted above suggests hallucinogens to
be efficacious in addiction treatment, the strength of specific
mechanisms of action has yet to be correlated with clinical
outcomes. As well, no studies have compared the effects
of or outcomes with drug-induced versus non-drug-induced
ASCs. Analysis of the differences between these approaches
would better distinguish biological and psychological phe-
nomena. We assume drug-induced ASCs better represent
a biological condition, while non-drug-induced ASCs better
exemplify psychological aspects. Such work is essential in
justifying hallucinogens as a pharmacological intervention, as
it evaluates the plausibility of alternate treatments. We outline
a study proposal to address these gaps in knowledge, which are
critical in defining the focus of this re-emerging field.
Study conditions
We propose a randomized trial of three treatment conditions,
with two experimental groups and one active placebo
(Figure 1). The two experimental groups would consist of
drug-induced (psilocybin) and non-drug-induced (Holotropic
Breathwork) ASCs.
Primary hypotheses
We hypothesize the psilocybin group will have significantly
better clinical outcomes, as measured by opioid use over
12 weeks, than either the Holotropic Breathwork (HB) or
placebo group. Additionally, we expect the HB group to use
less opioids compared to the placebo group.
Active placebo
A placebo reveals the efficacy of ACS treatment by providing
a baseline for comparison. It also separates effects due to
 294 B. V. Burdick & B. Adinoff
expectation versus treatment. Active placebo is preferred over
inactive to further remove bias in subjects and monitors
alike. Similar studies have used niacin (35), methylphenidate
(58), or a low, non-hallucinogenic dose of the drug under
investigation (11). We recommend niacin, as it has a mild
physiological impact that does not alter the psychological
condition (35).
ACS groups
The proposed experimental conditions involve induction of
an ASC by pharmacological or non-pharmacological means.
By comparing the outcomes of these groups, the therapeutic
role of hallucinogen-dependent effects may be distinguishable
from psychological effects resulting from ASCs.
In choosing a non-drug-induced altered state, methods
Am J Drug Alcohol Abuse Downloaded from informahealthcare.com by University of Hawaii on 08/24/13
of induction (59) should be ethical, simple and preferably,
evidence-based. Therefore, those methods which are unethic-
ally rigorous, such as extreme environment, exercise or diet, or
overly difficult, such as advanced meditation, must be
excluded. Evaluation for clinical practicality excludes sensory
deprivation and shamanic practices, such as sweat lodges,
as these require specialized settings. Of the remaining options,
respiratory techniques leading to hyperventilation appear most
clinically viable. We recommend the HB technique. It was
developed by S. Grof in the 1970s (60), and utilizes rapid, deep
breathing, music, elective touch (i.e. focused pressure to
For personal use only.
relieve muscle tension), and artistic exercises, to elicit an ASC
in participants.
HB has been reported to improve abstinence, existential
anxiety, self-esteem and psychiatric symptomatology (60–62).
Several long-term outcome studies, ranging from 12 weeks to
6 months, showed HB participants had reduced psychiatric
symptoms at follow-up, as compared to controls or their status
pre-intervention (62). Other studies have shown hyperventi-
lation reliably produces hallucinations in 60% of patients (63).
Evidence, however, is modest; the technique needs to be
subjected to more sophisticated assessments before it is
considered a validated treatment, and support for HB treating
addiction comes from four case reports (60). The biological
basis of this ASC is found in hypocapnia, a decrease in the
partial pressure of CO2 in the brain, and respiratory alkalosis
(62). Due to this evidence of potential efficacy and ASC
production, we feel HB adequately addresses the proposal’s
need for non-pharmacological induction of ASC.
In selecting the drug-induced ASC experimental condition,
availability should play a prudent role. For this reason, we
consider primarily psilocybin and ketamine as options. Both
have similar altered state profiles (32), but ketamine, while
more accessible, has greater dependency issues and health
concerns than classical hallucinogens (64). Animals reliably
self-administer ketamine, but not classical hallucinogens
(65–67). Also, health concerns associated with chronic use
of ketamine include cognitive deficits and organ damage
(68,69). These issues are not associated with the use of
classical hallucinogens (19). As well, ketamine’s ratio of fatal
dose to effective dose is 38:1, while psilocybin’s is 1000:1
(70). With respect to the population, we suggest psilocybin
as a better long-term solution for substance abusers.
However, for future studies, a longer hallucinogenic
Am J Drug Alcohol Abuse, 2013; 39(5): 291–297
experience may increase the likelihood of reaching a peak
state, or increase the yield of usable psychodynamic material.
Thus, LSD or ibogaine may be preferable to shorter-acting
hallucinogens in future studies.
Population
The population to be evaluated should be accessible, indi-
cated for treatment, and hallucinogen-naı̈ve. Hallucinogens
have been shown to improve various substance abuse
disorders (4–17), suggesting any drug addiction may be
improved by this method. No meta-analyses have been
performed to indicate which hallucinogens are most effective
for particular conditions. Thus, the population cannot be
determined by evidence of efficacy. Regarding accessibility,
there is an emerging epidemic of prescription opioid abuse
in USA. In recent years, these drugs were involved in more
overdose deaths than cocaine and heroin combined (71),
while there were 2 million new, non-medical users annually
(72). We suggest this population as it is understudied (73),
rapidly increasing, and presumably, available for recruitment.
As well, we assume this group will have experimented with
novel drugs less than other substance abusers, and conse-
quently, they are more likely to be hallucinogen-naı̈ve.
Naivety is preferred to decrease bias and to avoid triggering
craving in patients who may have used concurrently. Patients
should be recruited from residential treatment, where care is
more likely to be standardized.
In terms of criteria, participants should meet Diagnostic
and Statistical Manual of Mental Disorders, Fourth Edition
(DSM-IV) criteria for current dependence of prescription
opioids. They should be non-medical users, as classical
hallucinogens have been reported to decrease pain and the
need for narcotic medication, which could impact outcomes
(35). Further psychiatric screening is necessary to exclude
those vulnerable to rare, long-term complications from
psychotic reactions. Thus, patients with a current or past
history of psychotic, dissociative or Bipolar-I disorder should
be excluded. Additionally, those who are taking medications
that affect serotonergic function, such as tricyclic antidepres-
sants, serotonin reuptake inhibitors, monoamine oxidase
inhibitors or lithium should be omitted, as it may alter
psilocybin’s effects (19). Women should not be pregnant or
nursing, and if they are of child-bearing potential, should
practice effective birth control. Hypertensive patients should
be excluded, as classical hallucinogens can moderately
increase blood pressure (19).
Treatment
We will briefly discuss design concerns, although they
have been more exhaustively covered elsewhere (17,19).
Hallucinogens are unique as substances in that their risks are
primarily psychological, rather than physiological. Treatment
should be designed and administered with patient safety as the
foremost concern.
Subjects should participate in four introductory meetings,
one experimental session and biweekly follow-ups for 12
weeks. Several introductory sessions are necessary to properly
prepare the patient as to the nature of the possible unusual
experiences they may experience (19). This education is
 DOI: 10.3109/00952990.2013.811513
essential for obtaining informed consent and reducing nega-
tive reactions during administration. Additionally, this step
develops the necessary rapport between patients and session
monitors. Strong interpersonal support has been shown to
help minimize adverse psychological reactions, and adminis-
tration should not occur before a relationship of trust has been
established (19). The Composite International Diagnostic
Interview (CIDI) will be administered initially to diagnose
opioid dependence and psychiatric disorders (73).
The environment of the study should be as comfortable and
safe as possible. The setting should resemble a living space,
more than a sterile, high-tech, inpatient unit. Music, head-
phones and eyeshades should be available for patient comfort,
and medication for hypertension and acute distress should be
readily accessible in case of emergency. Session length should
be matched across groups according to the longest duration
Am J Drug Alcohol Abuse Downloaded from informahealthcare.com by University of Hawaii on 08/24/13
of effects among conditions, which in this case is 8 h (the
active time of psilocybin) (22). Quiet leisure materials, such
as magazines and writing materials, will be provided to all
participants to use at their discretion, as niacin and HB
activity will be notably shorter.
During the next day follow-up, the patient should be
encouraged to discuss the events of the session, allowing for
greater reflection about, and integration of, their experience.
Also at this time, continuing perceptual distortions should
be probed for, and their psychological stability assessed.
At subsequent follow-ups, further outcome measures will be
For personal use only.
obtained.
Outcome measures
Outcome measures are modeled on previous prescription
opiate addiction studies and hallucinogenic investigations.
Follow-up sessions will take place the day after administra-
tion, biweekly for 12 weeks (73), and at 6, 12, 18 and 24
months (11), at which time abstinence will be measured by
urine analysis and confirmed by self-report through timeline
followback (TLFB) (74). As utilized by Weiss et al. (73), our
two primary endpoints will be the absence of two consecutive,
opioid-positive urine screens and no self-reported opioid use
44 days per month through Week 12. Participants with more
than one missed follow-up will be counted as relapsing. We
feel this definition of a successful outcome is appropriate
and reasonable, as a meta-analysis of LSD and alcohol abuse
shows significant effects at 12 weeks (6). Follow-up measures
taken after this period will be for exploratory purposes.
Secondary outcomes will additionally be measured by the
Visual Analog Scale of Craving (VASC) and Locus of Control
Scale (LCS) (11). ASC effects should be measured during
administration by physiological measures and directly after
the drug or ASC’s active time by the OAV scale, a Monitor
Rating Questionnaire, and the Mysticism Scale (46,75). The
OAV scale is a revised version of Dittrich’s Abnormal Mental
States (APZ) survey.
Conclusion
Hallucinogens have been shown to be relatively safe to
administer to carefully selected participants in supervised
and supportive settings. In the future, hallucinogens may be
validated as a potent psychiatric tool in the treatment of a
Testing efficacy of hallucinogens 295
variety of disorders, and evidence is growing regarding their
clinically relevancy in improving addiction (4–17), depression
(17), death-related anxiety (35), PTSD (36), and obsessive–
compulsive disorder (OCD) (22). However, further investiga-
tion into these chemical’s mechanistic efficacy is critical to
their successful application as therapeutic agents. There must
be a demonstrated improvement on known pharmacological
and non-pharmacological interventions. The study we have
proposed aims to address these concerns by seeking new
insights in this promising, re-emerging field.
Declaration of interest
Authors report no conflicts of interest. Authors alone are
responsible for the content and writing of this article.
References
1. Dennis ML, Scott CK, Funk R, Foss MA. The duration and
correlates of addiction and treatment careers. J Subst Abuse Treat
2005;28:S51–S62.
2. Anglin MD, Hser YI, Grella CE. Drug addiction and treatment
careers among clients in the Drug Abuse Treatment Outcome Study
(DATOS). Psychol Addict Behav 1997;11:308–323.
3. McPeake JD, Kennedy BP, Gordon SM. Altered states of
consciousness therapy: a missing component in alcohol and drug
rehabilitation treatment. J Subst Abuse Treat 1991;8:75–82.
4. Bogenschutz MP, Pommy JM. Therapeutic mechanisms of classic
hallucinogens in the treatment of addictions: from indirect evidence
to testable hypotheses. Drug Test Anal 2012;4:543–555.
5. Savage C, McCabe OL. Residential psychedelic (LSD) therapy for
the narcotic addict. A controlled study. Arch Gen Psychiatry 1973;
28:808–814.
6. Krebs TS, Johansen PO. Lysergic acid diethylamide (LSD) for
alcoholism: meta-analysis of randomized controlled trials.
J Psychopharmacol 2012;26:994–1002.
7. Fábregas JM, González D, Fondevila S, Cutchet M, Fernández X,
Barbosa PCR, Alcázar-Córcoles MT, et al. Assessment of addiction
severity among ritual users of ayahuasca. Drug Alcohol Depend
2010;111:257–261.
8. Grob CS, McKenna DJ, Callaway JC, Brito GS, Neves ES,
Oberlaender G, Saide OL, et al. Human psychopharmacology of
hoasca, a plant hallucinogen used in ritual context in Brazil. J Nerv
Ment Dis 1996;184:86–94.
9. Halpern JH, Sherwood AR, Passie T, Blackwell KC, Ruttenber AJ.
Evidence of health and safety in American members of a religion
who use a hallucinogenic sacrament. Med Sci Monit 2008;14:
SR15–SR22.
10. Krupitsky EM, Grinenko AY. Ketamine-assisted psychotherapy
(KPT) of alcoholism. Alcologia 1996;8:161–176.
11. Krupitsky E, Burakov A, Romanova T, Dunaevsky I, Strassman R,
Grinenko A. Ketamine psychotherapy for heroin addiction: imme-
diate effects and two-year follow-up. J Subst Abuse Treat 2002;23:
273–283.
12. Krupitsky EM, Burakov AM, Dunaevsky IV, Romanova TN,
Slavina TY, Grinenko AY. Single versus repeated sessions of
ketamine-assisted psychotherapy for people with heroin depend-
ence. J Psychoactive Drugs 2007;39:13–19.
13. Soskin RA. Personality and attitude change after two alcohol-
ism treatment programs. Comparative contributions of
lysergide and Human Relations Training. Q J Stud Alcohol 1970;
31:920–931.
14. Pahnke WN, Kurland AA, Unger S, Savage C, Grof S. The
experimental use of psychedelic (LSD) psychotherapy. JAMA
1970;212:1856–1863.
15. Johnson FG. LSD in the treatment of alcoholism. Am J Psychiatry
1969;126:481–487.
16. Blum K, Futterman SL, Pascarosa P. Peyote, a potential
ethnopharmacologic agent for alcoholism and other drug depen-
dencies: possible biochemical rationale. Clin Toxicol 1977;11:
459–472.
 296 B. V. Burdick & B. Adinoff
17. Strassman RJ. Hallucinogenic drugs in psychiatric research and
treatment. J Nerv Ment Dis 1995;183:127–138.
18. Carhart-Harris RL, Nutt DJ. User perceptions of the benefits and
harms of hallucinogenic drug use: a web-based questionnaire study.
J Subst Use 2010;15:283–300.
19. Johnson MW, Richards WA, Griffiths RR. Human hallucinogen
research: guidelines for safety. J Psychopharmacol 2008;22:
603–620.
20. Frecska E, Luna LE. The adverse effects of hallucinogens from
intramural perspective. Neuropsychopharmacol Hung 2006;8:
189–200.
21. Carhart-Harris RL, Williams TM, Sessa B, Tyacke RJ, Rich AS,
Feilding A, Nutt DJ. The administration of psilocybin to
healthy, hallucinogen-experienced volunteers in a mock-functional
magnetic resonance imaging environment: a preliminary
investigation of tolerability. J Psychopharmacol 2011;25:
1562–1567.
22. Moreno FA, Wiegand CB, Taitano EK, Delgado PL. Safety,
tolerability, and efficacy of psilocybin in 9 patients with obsessive-
compulsive disorder. J Clin Psychiatry 2006;67:1735–1740.
Am J Drug Alcohol Abuse Downloaded from informahealthcare.com by University of Hawaii on 08/24/13
23. Passie T, Halpern JH, Stichtenoth DO, Emrich HM, Hintzen A.
The pharmacology of lysergic acid diethylamide: a review. CNS
Neurosci Ther 2008;14:295–314.
24. Passie T, Seifert J, Schneider U, Emrich HM. The pharmacology of
psilocybin. Addict Biol 2002;7:357–364.
25. Studerus E, Kometer M, Hasler F, Vollenweider FX. Acute,
subacute and long-term subjective effects of psilocybin in
healthy humans: a pooled analysis of experimental studies.
J Psychopharmacol 2011;25:1434–1452.
26. Alper KR, Lotsof HS, Frenken GMN, Luciano DJ, Bastiaans J.
Treatment of acute opioid withdrawal with ibogaine. Am J Addict
1999;8:234–242.
27. Grinspoon L, Doblin R. Psychedelics as catalysts of insight-
oriented psychotherapy. Soc Res 2001;68:676–695.
For personal use only.
28. Dyck E. ‘Hitting highs at rock bottom’: LSD treatment for
alcoholism, 1950-1970. Soc Hist Med 2006;19:313–329.
29. Strassman R. DMT: the spirit molecule: a doctor’s revolutionary
research into the biology of near-death and mystical experience.
Rochester (VT): Park Street Press; 2001.
30. Moreno FA. Progress report: the psilocybin/obsessive-compulsive
disorder (OCD) study obtains final FDA approval. MAPS Bull
2001;11:1–2.
31. MačiIulaitis R, Kontrimavičiute V, Bressolle FMM, Briedis V.
Ibogaine, an anti-addictive drug: pharmacology and time to go
further in development. A narrative review. Hum Exp Toxicol
2008;27:181–194.
32. Vollenweider FX, Kometer M. The neurobiology of psychedelic
drugs: implications for the treatment of mood disorders. Nat Rev
Neurosci 2010;11:642–651.
33. Gouzoulis-Mayfrank E, Heekeren K, Neukirch A, Stoll M, Stock C,
Obradovic M, Kovar KA. Psychological effects of (S)-ketamine
and N,N-dimethyltryptamine (DMT): a double-blind, cross-
over study in healthy volunteers. Pharmacopsychiatry 2005;38:
301–311.
34. Kumar S. Clinical study protocol: psilocybin-assisted psychother-
apy in the management of anxiety associated with stage IV
melanoma. MAPS 2007; final version, IND[79,321].
35. Grob CS, Danforth AL, Chopra GS, Hagerty M, McKay CR,
Halberstad AL, Greer GR. Pilot study of psilocybin treatment for
anxiety in patients with advanced-stage cancer. Arch Gen
Psychiatry 2011;68:71–78.
36. Mithoefer MC, Wagner MT, Mithoefer AT, Jerome L, Doblin R.
The safety and efficacy of 3,4-methylenedioxymethamphetamine-
assisted psychotherapy in subjects with chronic, treatment-resistant
posttraumatic stress disorder: the first randomized controlled pilot
study. J Psychopharmacol 2011;25:439–452.
37. Vollenweider FX, Vollenweider-Scherpenhuyzen MFI, Bäbler A,
Vogel H, Hell D. Psilocybin induces schizophrenia-like psychosis
in humans via a serotonin-2 agonist action. NeuroReport 1998;9:
3897–3902.
38. Kometer M, Schmidt A, Bachmann R, Studerus E, Seifritz E,
Vollenweider FX. Psilocybin biases facial recognition, goal-
directed behavior, and mood state toward positive relative to
negative emotions through different serotonergic subreceptors.
Biol Psychiatry 2012;72:898–906.
Am J Drug Alcohol Abuse, 2013; 39(5): 291–297
39. Halberstadt AL, Geyer MA. Multiple receptors contribute
to the behavioral effects of indoleamine hallucinogens.
Neuropharmacology 2011;61:364–381.
40. Moreno JL, Holloway T, Albizu L, Sealfon SC, González-Maeso J.
Metabotropic glutamate mGlu2 receptor is necessary for the
pharmacological and behavioral effects induced by hallucinogenic
5-HT2A receptor agonists. Neurosci Lett 2011;493:76–79.
41. Reissig CJ, Carter LP, Johnson MW, Mintzer MZ, Klinedinst MA,
Griffiths RR. High doses of dextromethorphan, an NMDA antag-
onist, produce effects similar to classic hallucinogens.
Psychopharmacology 2012;223:1–15.
42. Carhart-Harris RL, Leech R, Williams TM, Erritzoe D, Abbasi N,
Bargiotas T, Hobden P, et al. Implications for psychedelic-assisted
psychotherapy: functional magnetic resonance imaging study with
psilocybin. Br J Psychiatry 2012;200:238–244.
43. Foa EB, Keane TM, Friedman MJ, et al. Effective treatments for
PTSD: practice guidelines from the International Society for
Traumatic Stress Studies. 2nd ed. New York (NY): Guilford
Press; 2009.
44. Cook CCH. Addiction and spirituality. Addiction 2004;99:539–551.
45. Pahnke WN. Psychedelic drugs and mystical experience. Int
Psychiatry Clin 1969;5:149–162.
46. Griffiths RR, Johnson MW, Richards WA, Richards BD,
McCann U, Jesse R. Psilocybin occasioned mystical-type
experiences: immediate and persisting dose-related effects.
Psychopharmacology 2011;218:649–665.
47. Matzger H, Kaskutas LA, Weisner C. Reasons for drinking less and
their relationship to sustained remission from problem drinking.
Addiction 2005;100:1637–1646.
48. Kemp R. Relating to the other: truth and untruth in addiction.
Eur J Psychother Counsell Health 2009;11:355–368.
49. Bliss DL. Severity of alcohol dependence: impact on spirituality in
early treatment process. Alcohol Treat Q 2009;27:66–81.
50. Kelly JF, Hoeppner B, Stout RL, Pagano M. Determining the
relative importance of the mechanisms of behavior change within
alcoholics anonymous: a multiple mediator analysis. Addiction
2012;107:289–299.
51. Zemore SE. A role for spiritual change in the benefits of 12-step
involvement. Alcohol Clin Exp Res 2007;31:76s–79s.
52. Carter TM. The effects of spiritual practices on recovery
from substance abuse. J Psychiatr Ment Health Nurs 1998;5:
409–413.
53. Dawson DA, Goldstein RB, Ruan WJ, Grant BF. Correlates of
recovery from alcohol dependence: a prospective study over a
3-year follow-up interval. Alcohol Clin Exp Res 2012;36:
1268–1277.
54. Galanter M, Dermatis H, Bunt G, Williams C, Trujillo M,
Steinke P. Assessment of spirituality and its relevance to addiction
treatment. J Subst Abuse Treat 2007;33:257–264.
55. Green LL, Fullilove MT, Fullilove RE. Stories of spiritual
awakening: the nature of spirituality in recovery. J Subst Abuse
Treat 1998;15:325–331.
56. Kelly JF, Stout RL, Magill M, Tonigan JS, Pagano ME. Spirituality
in recovery: a lagged mediational analysis of alcoholics anonym-
ous’ principal theoretical mechanism of behavior change. Alcohol
Clin Exp Res 2011;35:454–463.
57. Pardini DA, Plante TG, Sherman A, Stump JE. Religious faith and
spirituality in substance abuse recovery: determining the mental
health benefits. J Subst Abuse Treat 2000;19:347–354.
58. Griffiths RR, Richards WA, McCann U, Jesse R. Psilocybin
can occasion mystical-type experiences having substantial and
sustained personal meaning and spiritual significance.
Psychopharmacology 2006;187:268–283.
59. Vaitl D, Gruzelier J, Jamieson GA, Lehmann D, Ott U, Sammer G,
Strehl U, et al. Psychobiology of altered states of consciousness.
Psychol Bull 2005;131:98–127.
60. Brewerton TD, Eyerman JE, Cappetta P, Mithoefer MC. Long-term
abstinence following Holotropic Breathwork as adjunctive treat-
ment of substance use disorders and related psychiatric comorbid-
ity. Int J Ment Health Addict 2012;10:453–459.
61. Holmes SW, Morris R, Clance PR, Putney RT. Holotropic
Breathwork: an experiential approach to psychotherapy.
Psychotherapy 1996;33:114–120.
62. Rhinewine JP, Williams OJ. Holotropic Breathwork: the potential
role of a prolonged, voluntary hyperventilation procedure as an
 DOI: 10.3109/00952990.2013.811513
adjunct to psychotherapy. J Altern Complement Med 2007;13:
771–776.
63. Lempert T, Bauer M, Schmidt D. Syncope: a videometric analysis
of 56 episodes of transient cerebral hypoxia. Ann Neurol 1994;36:
233–237.
64. Morgan CJA, Curran HV. Ketamine use: a review. Addiction 2012;
107:27–38.
65. Johanson CE, Balster RL. A summary of the results of a drug
self-administation study using substitution procedures in rhesus
monkeys. Bull Narc 1978;30:43–54.
66. Fantegrossi WE, Woods JH, Winger G. Transient reinforcing effects
of phenylisopropylamine and indolealkylamine hallucinogens in
rhesus monkeys. Behav Pharmacol 2004;15:149–157.
67. Poling A, Bryceland J. Voluntary drug self-administration by
nonhumans: a review. J Psychedelic Drugs 1979;11:185–190.
68. Morgan CJA, Muetzelfeldt L, Curran HV. Consequences of chronic
ketamine self-administration upon neurocognitive function and
psychological wellbeing: a 1-year longitudinal study. Addiction
2010;105:121–133.
69. Wai MSM, Chan WM, Zhang AQ, Wu Y, Yew DT. Long-term
Am J Drug Alcohol Abuse Downloaded from informahealthcare.com by University of Hawaii on 08/24/13
ketamine and ketamine plus alcohol treatments produced damages
in liver and kidney. Hum Exp Toxicol 2012;31:877–886.
For personal use only.
Testing efficacy of hallucinogens 297
70. Gable RS. The toxicity of recreational drugs. Am Scientist 2006;
94:206.
71. CDC. Vital signs: overdoses of prescription opioid pain relievers-
United States, 1999-2008. MMWR 2011;60:1–6.
72. Substance Abuse and Mental Health Services, US Department
of Health and Human Services. Results from the 2010
national survey on drug use and health: summary of national
findings. NSDUH Series H-41, HHS Publication No. (SMA)
11-4658. Rockville (MD): Substance Abuse and Mental Health
Services Administration; 2011.
73. Weiss RD, Potter JS, Fiellin DA, Byrne M, Connery HS, Dickinson
W, Gardin J. Adjunctive counseling during brief and extended
buprenorphine-naloxone treatment for prescription opioid depend-
ence: a 2-phase randomized controlled trial. Arch Gen Psychiatry
2011;68:1238–1246.
74. Hjorthøj CR, Hjorthøj AR, Nordentoft M. Validity of timeline
follow-back for self-reported use of cannabis and other illicit
substances – systematic review and meta-analysis. Addict Behav
2012;37:225–233.
75. Studerus E, Gamma A, Vollenweider FX. Psychometric evaluation
of the altered states of consciousness rating scale (OAV). PLoS One
2010;5:e12412g.