2013

http://informahealthcare.com/adaISSN: 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 hallucinogensin addiction treatment

Brittany Vasae Burdick, BA1 and Bryon Adinoff, MD

1,2

1Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA and 2VA North Texas Health Care System,

Dallas VA Medical Center, Dallas, TX 75216, USA

Abstract

Current treatments for addiction are frequently ineffective. Hallucinogenic therapy has beenindicated as helpful for a range of substance use disorders, yet this approach remainsunderstudied and publicly unavailable. It is nonetheless a promising treatment, which hassignificant, long-term beneficial effects with single doses and a profile characterized by generalsafety, low toxicity, and non-addictiveness. However, pharmacological interventions, such ashallucinogens, should not be offered if the same effects (e.g. psychological insights/mysticalexperiences) and outcomes (e.g. decreased drug use) could be achieved absent pharmaco-logical intervention. To date, there have been no clinical comparisons of drug-induced alteredstates with non-drug-induced states for addiction treatment. We propose and then outline aclinical trial to address this gap in knowledge. The proposed design would evaluate abstinenceoutcomes in a population of prescription opioid abusers after exposure to one of threeconditions: a drug-induced altered state using psilocybin, a non-drug-induced altered state viahyperventilation (Holotropic Breathwork), and an active placebo with niacin. The outcomes ofsuch a study would reveal important differences in therapeutic potential by discriminatinghallucinogen-dependent effects from those psychological effects resulting from altered states.

Keywords

Addiction, drug abuse, hallucinogens, review,psilocybin

History

Received 29 March 2013Accepted 29 May 2013Published online 14 August 2013

Introduction

Substance use disorders are chronic conditions that are difficult

to treat. One study of 1300 participants in treatment found a

median use of 27 years (1). Additionally, they found the median

time period between first treatment episode and last use to be 9

years. A similar study of 10 000 patients and their treatment

outcomes reported an average of 3.5 treatment episodes (2).

Unfortunately, this evidence suggests present therapies regu-

larly fail in relieving many patients of their drug addiction.

Treatment of this complex, chronic disease may include

induction of altered states of consciousness (ASCs) (3).

Hallucinogenic therapy offers a possible method to induce

ASC. Previous studies have demonstrated hallucinogens, as a

class of substances, are effective in improving several types of

addictions (4–17). Lysergic acid diethylamide (LSD), for

example, appears to reduce alcohol misuse. A recent meta-

analysis of six trials involving 536 participants supported this

beneficial relationship (p50.0005) (6). This data is congruent

with hallucinogen-users self-reports of improved substance

abuse symptoms (18). The approach is particularly promising

as hallucinogens are generally safe, of low toxicity, not

physiologically addictive (17,19–25), and appear to have

significant, long-term effects with single doses (5,6,10,11,26).

However, no studies to date have specifically examined

mechanistic contributions of hallucinogens versus non-

drug-induced ASC. This evaluation is essential for determin-

ing the direction of future research. It will, for example,

dictate whether developing specific ligands should be

prioritized over evaluating the best combination of dosage

and psychotherapy. Additionally, hallucinogenic research is

fraught with obstacles. If similar mechanisms may be

addressed through other means, it may be prudent to choose

the less tortuous route.

This article proposes a study design to assess such concerns.

First, it presents the sociolegal concerns inherent in the subject

matter, followed by a discussion of the proposed therapeutic

biological and psychological mechanisms of hallucinogens.

We then offer a detailed proposal to evaluate efficacy claims

by comparing abstinence outcomes after exposure to active

placebo, drug-induced ASC, or non-drug-induced ASC. This

proposal will also aim to correlate abstinence with the strength

of psychological mechanisms in ASCs.

Sociolegal issues of hallucinogenic research

As mentioned, this area of research is promising, yet

made difficult by social, legal and political concerns.

Address correspondence to Bryon Adinoff, MD, Department ofPsychiatry, University of Texas Southwestern Medical Center, 5323Harry Hines Boulevard, Dallas, TX 75208-8564, USA. Tel: +214-645-6975. Mobile: +817-371-9798. Fax: +214-645-6976. E-mail: bryon.adinoff@utsouthwestern.edu

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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

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-

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 addictiontreatment

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

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

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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

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

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,

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

Figure 1. Study design. Patients will randomly be assigned to three conditions: psilocybin, HB or active placebo. Psilocybin represents a drug-inducedASC, while HB represents a non-drug-induced ASC. The two primary endpoints are reduced drug use as measured by urine drug screen (UDS) andTLFB through 12 weeks post-treatment. Secondary outcomes will be obtained for exploratory purposes.

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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

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

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

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-naıve. 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-naıve.

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

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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

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

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

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.

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