Secondary Logo

Journal Logo

Hallucinogens and Their Therapeutic Use

A Literature Review

BEGOLA, MATTHEW J. DO; SCHILLERSTROM, JASON E. MD

Journal of Psychiatric Practice®: September 2019 - Volume 25 - Issue 5 - p 334–346
doi: 10.1097/PRA.0000000000000409
Articles
Free

The exploration of possible therapeutic benefits of hallucinogenic substances has undergone a revitalization in the past decade. This literature review investigated the published literature regarding the psychotherapeutic uses of hallucinogens in psychiatric disorders. The results showed that a variety of substances have been evaluated in the treatment of psychiatric disorders, including ayahuasca, ibogaine, ketamine, lysergic acid diethylamide, 3,4-methylenedioxymethamphetamine, and psilocybin. The conditions treated ranged from depression to autism, with the largest volume of research dedicated to substance use disorders. The majority of studies that were reviewed demonstrated significant associations with improvement in the conditions investigated. However, it was difficult to draw definitive conclusions as most studies suffered from small sample sizes, inconsistent measures, and poor study design. To properly assess the risks and potential benefits of hallucinogens in psychiatric treatment, there is a need for well designed, standardized studies that demonstrate the impact of hallucinogenic substances on psychiatric conditions.

BEGOLA, SCHILLERSTROM: Department of Psychiatry, UT Health San Antonio, San Antonio, TX

The authors declare no conflicts of interest.

Please send correspondence to: Matthew J. Begola, DO, Psychiatry Resident, UT Health San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229 (e-mail: begolam@gmail.com).

Online date: September 6, 2019

Hallucinogens are classified by the fifth edition of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-5) as a diverse group of substances that, despite having different chemical structures and possibly involving different molecular mechanisms, produce similar alterations of perception, mood, and cognition in users.1 Multiple substances comprise this category ranging from naturally occurring plants to synthetically produced compounds. Examples include ayahuasca, ibogaine, ketamine, lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA), and psilocybin (the active ingredient in “magic mushrooms”).

Although hallucinogens have been used in spiritual rituals among multiple cultures for nearly 2500 years, they were largely unknown to western society until the discovery of LSD’s mind altering effects in 1943.2 In 1947, the first clinical paper published about LSD discussed possible applications in the field of psychiatry.2 Subsequently, LSD was sold under the name Delysid. The first indication listed in its information packet was “analytical psychotherapy, to elicit release of repressed material and provide mental relaxation, particularly in anxiety states and obsessional neuroses.”2 Although now disproven, the second indication encouraged self-experimentation to perform studies on the nature of psychoses, advising “by taking Delysid himself, the psychiatrist is able to gain an insight into the world of ideas and sensations of mental patients.”2 Research with psychedelics occurred for 2 decades until widespread misuse, political pressures, stigmatization, and eventual illegalization ended the investigations. However, these same adverse factors that stopped academic research have not curtailed illicit exploration and abuse.

The 2015 National Survey on Drug Use and Health estimates that >40 million people (15.3% of the US population) have used hallucinogens at least once in their lifetime.3 Given increasingly lax substance control laws, the increasing availability of hallucinogenic substances on the Internet, and travel to experience ritualistic hallucinogenic use becoming more frequent,4 the number of hallucinogenic users is predicted to increase. These factors make psychiatrists’ knowledge about hallucinogens more than a matter of academic curiosity, but rather valuable in daily patient management.

After decades of obscurity, the field of psychedelic research is reemerging. In 2012, the University of Pennsylvania hosted “Psychedemia,” a weekend event attended by researchers, clinicians, and other scientists to discuss the impact of hallucinogens in a variety of fields.5 In April 2017, the largest reported gathering of professionals to discuss hallucinogenic research took place in California, boasting an attendance of 3000.6 Most recently, in September 2017, the United States Food and Drug Administration (FDA) approved a phase 3 trial for MDMA-assisted psychotherapy for patients with posttraumatic stress disorder (PTSD).7 Despite increasing awareness of and revitalized interest in hallucinogens, their safety and usefulness have been debated and challenged in the medical literature.8–10

While the use of hallucinogens remains controversial, investigation of clinical applications of illicit substances is not a novel idea. Many illicit substances are classified by the FDA to allow their use in specific clinical scenarios. Examples include the use of cocaine for nose bleeds and anesthetic eye drops, opioids for pain, and cannabinoids for pain, glaucoma, and appetite stimulation. Hallucinogens are unique, however, as their therapeutic use is believed to go beyond their physiological actions, many of which are just beginning to be discovered. Rather, the therapeutic value of hallucinogens is attributed to their distinct ability to alter consciousness and invoke new insights, thereby creating fundamental changes in mental schema.11,12 While some argue that one experience cannot produce life changing effects, research has shown at 14 months after receiving a psychedelic dose of psilocybin, 50% of subjects rated the experience as “the most personally meaningful and spiritually significant of their lives,” with 64% reporting “increased well-being or life satisfaction.”13

Back to Top | Article Outline

SUBSTANCES AND ASSOCIATED PROPERTIES

This review includes ayahuasca, dipropyltryptamine (DPT), diethyltryptamine (DET), ibogaine, ketamine, LSD, MDMA, and psilocybin. All of these substances possess hallucinogenic properties, but their mechanisms of action and proposed therapeutic attributes vary.

Back to Top | Article Outline

LSD

LSD is theorized to enable access to thoughts, associations, feelings, and inner processes that are usually excluded from consciousness.14 When patients compare the effects of LSD-assisted psychotherapy with those of traditional psychotherapy, they mention facilitated access to emotions, important insights, faster progress, and accessing feelings of safety and facilitation of “letting go” as the most prominent differences.15 It seems that the core of these deeply affecting experiences is a tension-free state of well-being or a positive experience of “pure existence in the here and now” accompanied by a relative freedom from concerns about the past as well as from guilt, depression, and anxiety. The biological effects are secondary to primary affinity for 5-HT2A receptors, as well as significant modulation of 5-HT2C and 5-HT1A receptors, which may lead to cascades creating excess neuronal excitability in key areas of the brain including the prefrontal cortex and ventral tegmental nucleus.15

Amid investigations into the therapeutic potential of hallucinogens in the 1960s and 1970s, researchers hoped to find substances that could produce similar effects, but would possess a shorter duration of effect and allow for a more abrupt return to baseline consciousness than LSD, the most commonly researched hallucinogen at the time.14 Three tryptamine derivatives were found to have hallucinogenic properties: dimethyltryptamine (DMT), DET, and DPT.14 Similar to LSD, these compounds act upon 5HT1A/2A receptors.16

Back to Top | Article Outline

Ketamine

Ketamine is a prescription medication that when administered in subanesthetic dosages produces hallucinations and dissociative effects.12 Because of its established legal status, classification, safety profile, and availability, ketamine has been at the forefront of experimental study designs over the past several years. Ketamine also has a significant advantage over other hallucinogens because of its significantly shorter duration of effect of 45 to 60 minutes when administered intramuscularly.17 Ketamine has been studied for the treatment of addiction and mood disorders. Ketamine exerts its anticraving effects by acting on N-methyl-D-aspartate (NMDA) ligands, similar to acamprosate and ibogaine.17 The antidepressant effects of ketamine may be secondary to increased serotonin or glutamate in the prefrontal cortex caused by the diversion of glutamate signaling to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors as a result of ketamine’s antagonistic activity at NMDA receptors.18

Back to Top | Article Outline

Psilocybin

Psilocybin is a naturally occurring hallucinogen found in various types of “magic mushrooms.” Psilocybin’s effects are similar to those of LSD, but they are considered to be more strongly visual, more euphoric, and less emotionally intense with fewer related panic and paranoid reactions.19 Once digested, psilocybin is metabolized to psilocin, a potent 5-HT1A/2A/2C receptor agonist.20 In clinical trials, psilocybin is often used to target anxiety-related disorders and depression. Therapeutically, psilocybin increases the vividness of memories and promotes an overall feeling of well-being.21 Imaging studies have also shown that psilocybin reduces amygdala reactivity to negative and neutral stimuli. Amygdala hyperactivity in response to negative stimuli has been consistently demonstrated in depressed patients.22

Back to Top | Article Outline

Ayahuasca

Ayahuasca is an Amazonian botanical hallucinogenic brew containing DMT and B-carboline alkaloids including harmine.23 Harmine produces peripheral reversible monoamine oxidase A (MAO-A) inhibition, while DMT is a 5HT1A/2A/2C receptor agonist.24 The MAO-A inhibition and global elevation of serotonin may give the substance antidepressant properties. It is also theorized that the alkaloids, which are unique to ayahuasca, balance dopamine levels in the mesolimbic dopamine pathway through both direct and indirect actions.25 This unique action may contribute to ayahuasca’s potential to alleviate addiction feedback loops.25

Back to Top | Article Outline

Ibogaine

Ibogaine is an alkaloid extracted from plants that is often classified as a hallucinogen given its strong psychoactive properties when consumed in certain quantities. It acts as an agonist at 5HT2 and 5HT3 receptors, as well as other receptors including glutamate NMDA and acetylcholine muscarinic receptors.25 Ibogaine may also inhibit adenylyl cyclase; an effect opposite to the activation of adenylyl cyclase that is classically associated with opioid withdrawal.26 This corresponds with reports suggesting that illicit ibogaine users most frequently obtain the substance for relief from opioid withdrawal.26

Back to Top | Article Outline

MDMA

In contrast to other hallucinogens, MDMA is believed to have a distinct ability to affect the emotional sphere without altering visual perception or sense of self.27 MDMA, also known as “ecstasy,” inhibits the reuptake of serotonin and stimulates the release of dopamine and norepinephrine.28 By reducing anxiety and fear and enhancing empathy, MDMA is postulated to strengthen the therapeutic alliance while allowing patients to process troubling or disturbing memories.29 It is hypothesized that these properties may augment PTSD treatment by enhancing the patient’s ability to share traumatic experiences with the therapist that will hasten and facilitate recovery.

Back to Top | Article Outline

OBJECTIVE

Theories abound about the potential therapeutic utility of hallucinogens for treating patients with mental illness. The purpose of this review was to critique actual clinical trials measuring the value of hallucinogens in psychiatric practice. We identified clinical studies investigating the psychotherapeutic use of hallucinogens, classified those studies using established levels of an evidence grading system, and critiqued the reported clinical efficacy and safety.

Back to Top | Article Outline

METHODS

We identified relevant articles published between 1946 and September 2017 using OVID MEDLINE. We used the search term hallucinogens, which was then limited to the subheading “therapeutic use.” We selected only articles that investigated the use of hallucinogens in human subjects as treatment for psychiatric diagnoses. We excluded duplicate articles and articles that were not available in English. We excluded reports on cannabinoids as these are distinguished from hallucinogens in DSM-5.

Each author reviewed and classified the selected articles in accordance with the levels of evidence grading system above (Table 1).30 Differences between the authors’ ratings were resolved through discussion. Only class I, II, and III studies were eligible for inclusion. Table 2 documents the study design, hallucinogen administered, exposure parameters, detailed outcome measures, and summary of significant findings. All outcomes documented in Table 2 were statistically significant unless otherwise stated. Funding sources, if present, were primarily nonprofit agencies or research grants, and no trial was funded by a pharmaceutical company or private entity.

TABLE 1

TABLE 1

TABLE 2

TABLE 2

TABLE 2

TABLE 2

TABLE 2

TABLE 2

Back to Top | Article Outline

RESULTS

Sixteen of 214 abstracts met criteria for review. We identified class I (n=3), class II (n=6), and class III (n=7) studies. Fifteen of the 16 studies found that the therapeutic use of hallucinogens led to reduction in symptomatology. Substance use disorders were the most commonly studied conditions. No long-term adverse outcomes were reported, and the hallucinogens were generally well tolerated with acute increases in blood pressure and vomiting being the most common side effects.

Back to Top | Article Outline

Ayahuasca

Our review identified 1 class II and 1 class III study. Both studies were small, open-label, crossover trials with subjects serving as their own controls. They investigated the antidepressant effects of ayahuasca on patients diagnosed with recurrent major depressive disorder (MDD), mild to severe. In the class II study,23 after completing a 2-week washout of medications, patients with MDD unresponsive to standard medications (N=17) took a single dose of ayahuasca. Reductions in depression were reported from 80 minutes up to 21 days after consumption on all 3 depression rating scales used, with a mean reduction of 61% recorded between baseline and day 21.23 In a similar, class III study24 (N=6) performed by the same investigators, patients reported an average 62% reduction in depression on day 1, and ∼72% reduction on days 7 and 21.24 Ayahuasca was generally well tolerated with the exception of vomiting which was reported by 50% of participants.23,24

Back to Top | Article Outline

DET and DPT

Our review identified 1 class II and 1 class III study investigating the effects of tryptamine derivatives on alcohol use disorder. In a class II, open-label, nonrandomized, pilot study, using subjects as their own controls, patients with alcohol use disorder (N=51) were administered a high dose of DPT during a multiweek course of psychotherapy in an inpatient setting.14 Subjects were in treatment for an average of 8 weeks and participated in an average of 1.86 unguided DPT sessions that were both preceded and followed by drug-free therapy sessions. Nearly all patients reported profound esthetic experiences, including the reliving of emotionally salient memories with abreaction or catharsis, and experiences that were religious or mystical in nature. Immediate posttesting demonstrated significant improvement on multiple rating scales, including depression, self-regard, and insight. At 6-month follow-up, 47 patients were contacted and 46.8% reported reductions in alcohol use, and improvements in occupational functioning and interpersonal relations (t=8.02, P=0.001), occupational adjustment (t=3.05, P=0.01), and interpersonal functioning (t=4.14, P=0.001); 38.2% were totally abstinent and 53.2% reported minimal departure from total abstinence. A brief psychotic episode was experienced by 1 subject 3 weeks after the last DPT session.14

In a smaller, class III, placebo-controlled study, subjects with alcohol use disorder (N=12) were randomly treated with mild, moderate, or high dosages of tryptamine derivatives DPT, DET, or the nonhallucinogenic derivative 6-fluoro-DET.31 Five weekly experimental sessions took place after 2 weeks of psychotherapy. At 1- and 2-year follow-up, only 3 of 12 subjects showed improvement in drinking behavior and social adjustment. One subject denied that the hallucinogens had any impact on his recovery, while the remaining 2 were actively engaged in therapy and Alcoholics Anonymous. The success of these last 2 patients was attributed to the ability of the hallucinogens to bring awareness to personal problems, which in combination with continued treatment, allowed them to find new meaning in life and remain sober. Side effects were not reported in this study.

Back to Top | Article Outline

Ibogaine

Our review identified 1 class III study investigating ibogaine. Investigators retrospectively studied the abstinence rates of subjects (N=75) with alcohol, cannabis, and cocaine use disorders (72% polysubstance users) treated with ibogaine during dialectical behavioral therapy.32 The treatments ranged from 1 (44% subjects) to 9 (1% subjects) unguided, 10-hour ibogaine sessions. The authors reported that 61% of the sample were abstinent for a median of 5.5 months for those treated with 1 session and for a median of 8.4 months for those treated with multiple sessions. Most subjects attributed abstinence to ibogaine but acknowledged the possible contribution of therapy. Abstinence rates in the ibogaine treatment group (56%) were markedly greater compared with rates in those who received psychotherapy alone (26%).32 Side effects frequently included nausea, ataxia, headaches, mental confusion, tremors, and vomiting during intoxication.

Back to Top | Article Outline

Ketamine

Our review identified 2 class I studies and 1 class II study investigating ketamine. In a class I, randomized, active-placebo controlled, double-blind study, detoxified subjects with opioid use disorder (N=70) underwent ketamine-assisted psychotherapy.17 Thirty-five subjects received 1 hallucinogenic dose and 35 subjects received a comparison nonhallucinogenic lower dose of ketamine. While both dosages reduced cravings, the reduction in craving was markedly greater in the group who received the hallucinogenic dose at 1-month (74% vs. 44%) and 3-month (82% vs. 22%) follow-up. In addition, the hallucinogenic dose group’s reduction in craving was significant at 24 months, versus only the first month in the low dose group. The difference in both abstinence and relapse rates also favored the hallucinogenic dose group in all months of follow-up, reaching clinical significance in 22 of 24 months. When comparing subjects’ responses at the conclusion of the study, those who received the psychedelic dose reported greater positive change in emotional attitudes. No long-term adverse outcomes, including psychosis, flashbacks, or addiction, were found. An acute 20% to 30% elevation in blood pressure was noted in all subjects.

In a class I double-blind, placebo-controlled, crossover trial, subjects with MDD (N=30) received 1 ketamine and 1 placebo session in randomized order.18 All subjects continued their established antidepressant medication regimen throughout the trial. The statistical analyses included only subjects who completed both arms of the trial (n=27). One session of ketamine was associated with ∼30% reduction of core depressive symptoms versus placebo. These responses persisted at days 1, 4, and 7. Five subjects reported depressive symptom reductions of 50% or greater at all 3 follow-ups after receiving ketamine compared with none in the placebo group. Ketamine serum levels did not correlate with depressive symptom reduction. Rather, reduction correlated with the intensity of the ketamine experience. This relationship was maintained and most pronounced 7 days after treatment (r=−0.40, P=0.04). Side effects were limited to those associated with subanesthetic dosages of ketamine, including perceptual disturbances, confusion, mild elevation of blood pressure, and emotional blunting. The majority of side effects lasted ∼30 minutes with none lasting beyond 60 minutes.

In a class II, open-label, nonrandomized, controlled trial performed over the course of 10 years, researchers investigated the incorporation of ketamine psychotherapy into a standard 3-month treatment course for patients with alcohol use disorder (N=211).12 Subjects were divided into 2 groups, those who consented to receive an experimental ketamine treatment and those who did not consent to ketamine, but underwent the same 3-month psychotherapy course. Seventy-three of 111 (65.8%) subjects in the ketamine group obtained total abstinence for >1 year compared with 24 of 100 (24%) in the nonketamine group. Personality rating scales of subjects who underwent ketamine psychotherapy demonstrated significant improvement in multiple areas including decrease in regression defense mechanism, internal locus of control with increased confidence to manage difficult situations, self-perception, spiritual contentment, appreciation of the importance of achieving life goals, and a deeper understanding of the meaning of life. The authors reported treating over 1000 patients with ketamine psychotherapy without any reports of prolonged psychosis, flashbacks, agitation, or ketamine abuse.

Back to Top | Article Outline

LSD

Our review identified 4 articles investigating LSD: class I (n=1), class II (n=2), and class III (n=1). A class I meta-analysis was performed on 6 randomized controlled trials using LSD as a treatment for alcohol use disorder (N=536).33 A single dose of LSD showed greater benefit and a lower number needed to treat to maintain abstinence (NNT=7) than daily use of naltrexone (NNT=33), acamprosate (NNT=9), or disulfiram (NNT=9).33 Common reports of improvement in patients included increased insight into their problems, a sense of having “a new lease on life,” and building a stronger resolution to discontinue drinking. The benefit of a single dose of LSD was reported up to 6 months after treatment, but the effect was no longer significant by 12 months. Two of 3 trials that reported employment data found higher rates of employment in those receiving LSD. Acute adverse reactions included “acting bizarrely” (n=2), agitation (n=1), unspecified adverse reaction (n=2), and a seizure by a patient with a history of alcohol withdrawal seizures and recent abstinence (n=1). In the days after the session, transient moderate confusion (n=1) and a transient “adverse reaction” (n=1) were recorded. One study reported acute side effects of nausea, vomiting, and “moderate agitation” relieved by support in a small number of subjects. Another study reported episodes of “vivid perceptual thoughts or feelings clearly related to the LSD experience” in approximately one third of 18 subjects. These effects were commonly experienced in the context of alcohol consumption. In a different study, similar experiences were specifically denied by subjects (n=13) at 6-month follow-up.

The first class II nonrandomized, crossover controlled trial we identified incorporated a single LSD-guided session into a structured 3-week psychotherapy regimen for subjects with alcohol use disorder (N=69).34 Subjects received 12 to 15 hours of therapy over the 2-week period preceding the LSD session. Depression, social inversion, and severe personality disturbances improved. Tests of intellectual functioning before and after sessions trended toward enhancement. At 6-month follow-up, 33% of subjects maintained abstinence. Adverse outcomes were not reported in this study. There were no significant electroencephalogram (EEG) changes in 20 randomly selected subjects.

The second class II, nonrandomized, crossover controlled trial (N=10), incorporated 2 LSD sessions within 8 psychotherapy sessions over the course of 3 months for the treatment of anxiety.15 Anxiety decreased by 27% at the end of the study and this decrease was maintained at 12-month follow-up. Seventy-eight percent (n=7/9 subjects) reported reduction in anxiety and less fear of death, and 67% (n=6/9 subjects) reported an improved quality of life. Personality changes such as increased openness and deepened awareness were subjectively reported.

The class III, open-label, nonrandomized, pilot study examined the benefits of LSD for subjects with schizophrenia (N=17) who were administered 4 to 15 increasing dosages of LSD or Ditran (a hallucinogen chosen for its ability to desynchronize EEGs) at 1 to 2 week intervals.35 After evidencing EEG changes or after being nonresponsive after 3 months, the agents were discontinued. Subjects were then re-started on psychotropic medications for 2 to 12 months. Twelve subjects completed the study, 6 of whom received LSD and 6 of whom received Ditran. Upon conclusion of the study, all subjects had improved from baseline according to a 7-point global functioning rating scale. Three of 6 subjects treated with LSD and 4 of 6 subjects treated with Ditran met criteria for discharge. The most significant improvements were found in areas of attention and concentration, comprehension, insight and judgment, aggressive behavior, and uncooperativeness in the LSD group after starting the second antipsychotic. The authors concluded that subjects demonstrating marked EEG changes after hallucinogenic drugs responded better to subsequent conventional treatment. All 12 subjects demonstrated worsening of symptoms during the experimental drug phase, with subjects receiving LSD experiencing increased depersonalization, perceptual disturbances, and disturbed motor behavior.

Back to Top | Article Outline

N-Methyl-3,4-Methylenedioxy-Amphetamine (MDMA)

Our review identified 1 class III study investigating MDMA. In a small (N=6) double-blind, randomized, placebo-controlled study, women with chronic PTSD from sexual trauma were assigned to 3 groups; 1 receiving 75 mg MDMA, 3 receiving 50 mg MDMA, and 2 receiving placebo.29 Each subject underwent 3 therapy sessions before and after the therapist-guided experimental session. Immediate posttreatment rating scales measuring the severity of PTSD symptoms demonstrated a mean reduction of 24% with MDMA versus 10% with placebo. At 1-month follow-up this reduction improved to 33%. The reduction in PTSD symptoms seemed to correlate with dosage, with the subject receiving 75 mg reporting the greatest reductions in symptoms; 35% at 1 month follow-up, and 42% at 3-month follow-up. Neither the 75 or 50 mg dose increased symptomatology. All of the subjects, except 1 who was receiving placebo, reported an improved therapeutic alliance. At 24-hour follow-up, side effects including headache, palpitations, photosensitivity, and sedation, were scored as mild by 2 subjects receiving MDMA.

Back to Top | Article Outline

Psilocybin

Our review identified 3 studies investigating psilocybin: class II (n=1) and class III (n=2). In a double-blind, placebo-controlled, crossover study, subjects with varying cancers and a comorbid anxiety-related diagnosis (N=12) received a moderate dose (0.2 mg/kg) of psilocybin and were assessed monthly for 6 months for improvement in anxiety.19 Subjects did not receive counseling before, during, or after the experimental session. Although improvements in anxiety and depression were reported 1 month after the session, reductions only reached clinical significance at remote time frames during the 6-month follow-up. Depression symptoms decreased by 30% at 1-month follow-up and reached statistically significant improvement at 6-month follow-up (t=2.71, P=0.03) when symptoms were reduced by 55% from baseline. Administration of psilocybin was associated with statistically significant peak increases in heart rate (mean increase of 11.1 beats per minute), systolic blood pressure (mean increase of 21.9 mm Hg), and diastolic blood pressure (mean increase of 6.3 mmHg ). These elevations all returned to baseline after 6 hours and did not produce long term sequelae. Heart monitoring demonstrated no sustained tachyarrythmias or heart block.

In a class III, modified double-blind, nonrandomized, active-placebo crossover trial, subjects with obsessive-compulsive disorder (OCD) (N=9) participated in up to 4 individual nonguided psilocybin sessions with dosages ranging from very low (25 µg/kg), low (100 µg/kg), medium (200 µg/kg), and high (300 µg/kg).20 Subjects must have failed to respond to at least one trial of standard treatment for OCD and tolerated at least one prior hallucinogenic experience. OCD symptoms decreased by 45% for all dosages at 24 hours postingestion. While not prospectively followed, 1 subject who completed all 4 dosage sessions reported sustained remission of symptoms at 6-month follow-up. One subject experienced transient hypertension 24 hours after ingestion, and 2 subjects dropped out due to discomfort with the hospital setting.

In the second class III trial, a secondary analysis of an open-label, crossover, uncontrolled trial, researchers studied the relationship between psilocybin and smoking cessation. In the original trial, patients with tobacco use disorder (N=15) were treated with 2 or 3 psilocybin sessions during a 15-week course of cognitive-behavioral therapy, mindfulness practices, and imagery exercises.11 Subjects then received weekly follow-up to reinforce treatment techniques. At 6-month follow-up, 12 of 15 (80%) subjects demonstrated laboratory confirmed abstinence. Those in remission reported significantly higher ratings of meaningfulness, spiritual significance, and impact on well-being of the psilocybin experience compared to those unable to quit smoking. Significant correlations were also identified between the personal meaning of the experience and both confidence to abstain (r=0.68, P=0.005) and reduced temptation to smoke (r=−0.70, P=0.004). Ratings of intensity of the psilocybin session were not significantly different between the 2 groups. No lasting significant adverse events were reported, but 40% of subjects experienced at least 1 psilocybin session characterized by transient fear and feelings of being trapped that resolved by end of session.

Back to Top | Article Outline

DISCUSSION

This literature review identified 16 studies examining the potential benefits of 7 different hallucinogens for augmenting the treatment of 8 different psychiatry diagnoses: MDD, anxiety, PTSD, OCD, schizophrenia, alcohol use disorder, nicotine use disorder, and opioid use disorder. This broad, but thin, yield coupled with quality design issues (only 7 studies had a placebo or comparison group) and low power (only 6 studies had 50 or more participants) make it difficult to draw significant inferences. However, we can conclude that this body of pilot literature suggests the possibility of therapeutic benefit that could outweigh adverse events and warrants more rigorous, definitive investigation.

In 15 of the 16 studies, it was reported that hallucinogen monotherapy or augmentation therapy produced clinically significant reduction in symptomatology. Many of these improvements occurred in subjects who had previously failed to respond to traditional treatments. Furthermore, many studies demonstrated improvement in less time than commonly observed with traditional psychopharmacology or therapy. For example, psilocybin was reported to have reduced OCD symptoms by 45% within 24 hours of ingestion and 1 patient maintained remission at 6-month follow-up.20 By comparison, serotonin reuptake inhibitors reduce OCD symptoms by 30% in 40% to 60% of patients.36 In another study, 12 of 15 smokers treated with psilocybin achieved 6-month cessation compared with typical cessation rates of 35% for those treated with traditional medications.11

Ironically, 8 of the 16 studies, including a meta-analysis, examined the benefit of hallucinogens for substance use disorders and all but one reported significant benefits.11,12,14,17,31–34 Ketamine’s effectiveness in the treatment of alcohol use disorder was particularly noteworthy given the extensive history of drinking in the selected subjects.12 The investigators attributed ketamine’s success to its ability to improve unconscious emotional attitudes. However, another contributing factor may be that it reduced depression and anxiety independent of sobriety. LSD was theorized to help subjects obtain abstinence by alleviating rumination and preoccupation with negative thought content.34 Regardless of cause, these pilot trials support investigators’ advocacy for more studies to examine the potential benefit of hallucinogens and determine the mechanism of action that facilitates the restoration of sobriety.

Despite feared side effects, most subjects tolerated the treatments. The most notable adverse effects were that ayahuasca caused vomiting in half of those ingesting it and LSD exacerbated psychotic symptoms in subjects with schizophrenia.35 Contemporary clinical trials of hallucinogens now exclude subjects with psychosis as treatment through symptom provocation is no longer practiced.

The known common side effects of hallucinogens include transient paranoia, mood changes, anxiety, sleep disturbances, headaches, and memory deficits.1,37 In the studies discussed in this review, the most common side effects reported were acute increases in blood pressure and vomiting. Although a few instances of mood irritability did occur, these were able to be resolved by the treatment team. Reports of long-term side effects of hallucinogens also vary in the literature.38,39 For example, MDMA is associated with persistent depression, anxiety, low self-esteem, as well as neuroendocrine impairments, and memory deficits.10 No studies reviewed in this study reported long-term adverse outcomes, including the DSM-5 condition of hallucinogen-persisting perception disorder. This may suggest that factors beyond the hallucinogen itself, such as genetics, comorbid substance abuse, additives, and setting contribute to adverse outcomes. Regardless, this finding also supports the need for longer term studies before these substances could ever be recommended or approved for therapeutic use.

In addition to the small sample sizes, multiple other limitations must be addressed in future studies. Many trials lacked quality, parallel control groups, making it impossible to determine to what extent the hallucinogen led to improvement versus the extensive time spent in therapy and the therapeutic treatment settings. Compounding this limitation was lack of feedback from subjects in some studies regarding the impact the hallucinogen had on their improvement. Comprehensive side effect rating scales were also not included in some studies, which may have led to an underrepresentation of side effects experienced. The side effects may have also been affected by selection bias, as some studies selected only subjects who had previously used hallucinogens. Individual studies also suffered from poor control, with subjects predicting which substance they were receiving, while the retrospective nature of other studies made causal relationships indeterminate.

The number of hallucinogenic sessions was not always standardized, and data correlating number of sessions with improvement was not documented. One ketamine trial also utilized 3 compounds in addition to ketamine.12 These were bemegride to enhance emotional experience and visions, aethimizol to enhance storage of experiences in long-term memory, and nimodipine to improve memory of the psychedelic experience. The impact of these additives on the success of the trial is uncertain.

While the successes reported in the studies reviewed here are intriguing, they should not be misinterpreted as an endorsement for the use of hallucinogens to medicate any of the above conditions. This review was inherently biased by the selection criteria, and dangers of hallucinogenic drug use were not the focus of this review. This should not, however, distract from the potential benefits described. The improvements reported warrant further investigation into the mechanisms of action, duration of effects, and frequency of treatments needed to bring about improvement, as well as into the detailed side effect profiles of these agents. The impact of cultural stigma of a substance may also be of interest in determining if the results reported with native substances such as ayahuasca are reproducible across multiple cultures.

Future clinical trials must use parallel treatment groups as well as placebo-controlled comparison groups to draw meaningful conclusions despite the inherent challenge of finding a “blinded” placebo. Larger sample sizes will improve statistical power for detecting benefits and adverse events, and comparing subjects naive to hallucinogen use with those who have had previous hallucinogen experience may delineate efficacy and acute side effect profiles.

Despite promising findings in therapeutic hallucinogen trials, current factors, including funding, laws, and stigma, continue to impose limitations on further research. Schedule 1 classification makes study development difficult, costly, and prolonged. Funding by both government and pharmaceutical companies is nonexistent. The field does receive support from foundations such as the Heffter Institute and the Multidisciplinary Association for Psychedelic Studies, but these organizations rely on public donations. At some point, the field must overcome these barriers if we are to advance our knowledge about the impact of hallucinogenic agents on the treatment of serious mental conditions.

Back to Top | Article Outline

REFERENCES

1. American Psychiatric Association (APA). Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Arlington, VA: APA; 2013.
2. Hofmann A. LSD: My Problem Child. Saline, MI: McNaughton & Gunn; 2009.
3. Center for Behavioral Health Statistics and Quality. National Survey on Drug Use and Health: Detailed Tables, 2015. Available at: www.samhsa.gov/data/sites/default/files/NSDUH-DetTabs-2015/NSDUH-DetTabs-2015/NSDUH-DetTabs-2015.pdf. Accessed August 21, 2017.
4. Hill D. Peru’s ayahuasca industry booms as westerners search for alternative healing, 2016. Available at: www.theguardian.com/travel/2016/jun/07/peru-ayahuasca-drink-boom-amazon-spirituality-healing. Accessed October 2, 2017.
5. Psychedemia. Academic conference hosted at the University of Pennsylvania from September 27–30, 2012. Available at: http://psychedemia.org. Accessed November 10, 2017.
6. Multidisciplinary Association for Psychedelic Studies. Psychedelic Sciences, 2017, conference held April 19–24, 2017 in Oakland, CA. Available at: www.maps.org/news/bulletin/articles/426-bulletin-summer-2017/6842-psychedelic-science-2017-bulletin-summer-2017. Accessed December 12, 2017.
7. United States National Library of Medicine, Clinical Trials. A multi-site phase 3 study for MDMA-assisted psychotherapy for PTSD, 2018. Available at: www.clinicaltrials.gov/ct2/show/NCT03537014?term=Phase+III&cond=PTSD&rank=2. Accessed June 23, 2018.
8. Parrott AC. MDMA is certainly damaging after 25 years of empirical research: a reply and refutation of Doblin et al. Hum Psychopharmacol. 2014;29:109–119.
9. Parrott AC. The potential dangers of using MDMA for psychotherapy. J Psychoactive Drugs. 2014;46:37–43.
10. Verheyden SL, Maidment R, Curran HV. Quitting ecstasy: an investigation of why people stop taking the drug and their subsequent mental health. J Psychopharmacol. 2003;17:371–378.
11. Garcia-Romeu A, Griffiths RR, Johnson MW. Psilocybin-occasioned mystical experiences in the treatment of tobacco addiction. Curr Drug Abuse Rev. 2015;7:157–164.
12. Krupitsky EM, Grinenko AY. Ketamine psychedelic therapy (KPT): a review of the results of ten years of research. J Psychoactive Drugs. 1997;29:165–183.
13. Majic T, Schmidt TT, Galliant J. Peak experiences and the afterglow phenomenon: when and how do therapeutic effects of hallucinogens depend on psychedelic experiences. J Psychopharmacol. 2015;29:241–253.
14. Grof S, Soskin RA, Richards WA, et al. DPT as an adjunct in psychotherapy of alcoholics. Int Pharmacopsychiatry. 1973;8:104–115.
15. Gasser P, Kirchner K, Passie T. LSD-assisted psychotherapy for anxiety associated with a life-threatening disease: a qualitative study of acute and sustained subjective effects. J Psychopharmacol. 2015;29:57–68.
16. Fantegrossi WE, Reissig EB, Katz HL, et al. Hallucinogen-like effects of N, N-dipropyltryptamine (DPT): possible mediation by serotonin 5-HTA1A and 5-HT2A receptors in rodents. Pharmacol Biochem Behav. 2008;88:358–365.
17. Krupitsky E, Burakov A, Romanova T, et al. Ketamine psychotherapy for heroin addiction: immediate effects and two-year follow-up. J Subst Abuse Treat. 2002;23:273–283.
18. Sos P, Klirova M, Novak T, et al. Relationship of ketamine’s antidepressant and psychotomimetic effects in unipolar depression. Neuro Endocrinol Lett. 2013;34:287–293.
19. Grob CS, Danforth AL, Chopra GS, et al. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiatry. 2011;68:71–78.
20. Moreno FA, Wiegand CB, Taitano EK. Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder. J Clin Psychiatry. 2006;67:1735–1740.
21. Carhart-Harris RL, Leech R, Williams TM, et al. Implications for psychedelic-assisted psychotherapy: functional magnetic resonance imaging study with psilocybin. Br J Psychiatry. 2012;200:238–244.
22. Kraehenmann R, Preller KH, Scheidegger M, et al. Psilocybin-induced decrease in amygdala reactivity correlates with enhanced positive mood in healthy volunteers. Biol Psychiatry. 2015;78:572–581.
23. Sanches RF, Osorio F, dos Santos RG, et al. Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a SPECT study. J Clin Psychopharmacol. 2016;36:77–81.
24. Osório F, Sanches RF, Macedo LR, et al. Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report. Braz J Psychiatry. 2015;37:13–20.
25. Winkelman M. Psychedelics as medicine for substance abuse rehabilitation: evaluating treatments with LSD, peyote, ibogaine, and ayahuasca. Curr Drug Abuse Rev. 2014;7:101–116.
26. Alper KR, Lotsof HS, Kaplan CD. The ibogaine medical subculture. J Ethnopharmacol. 2007;115:9–24.
27. Grob CSGrob CS. Deconstructing ecstasy: the politics of MDMA research. Hallucinogens: A Reader. New York, NY: Jeremy R. Tarcher/Putnam; 2002:217–262.
28. Kalant H. The pharmacology and toxicology of “ecstasy” (MDMA) and related drugs. CMAJ. 2001;165:917–928.
29. Bouso JC, Doblin R, Farré M, et al. MDMA-assisted psychotherapy using low doses in a small sample of women with chronic posttraumatic stress disorder. J Psychoactive Drugs. 2008;40:225–236.
30. Ishii LE. Thoughtful methods to increase evidence and analyze nonparametric data. JAMA Facial Plast Surg. 2015;17:307–308.
31. Faillace LA, Vourlekis A, Szara S. Hallucinogen drugs in the treatment of alcoholism: two-year follow-up. Compr Psychiatry. 1970;11:51–56.
32. Schenberg EE, Comis MA, Chavez BR, et al. Treating drug dependence with the aid of ibogaine: a retrospective study. J Psychopharmacol. 2014;28:993–100.
33. Krebs TS, Johansen P. Lysergic acid diethylamide (LSD) for alcoholism: meta-analysis of randomized controlled trials. J Psychopharmacol. 2012;26:994–1002.
34. Kurland AA, Unger S, Shaffer J, et al. Psychedelic therapy utilizing LSD in the treatment of the alcoholic patient: a preliminary study. Am J Psychiatry. 1967;123:1202–1209.
35. Itil TM, Keskiner A, Holden JMC. The use of LSD and ditran in the treatment of therapy resistant schizophrenics (symptom provocation approach). Dis Nerv Syst. 1969;30 (suppl):93–103.
36. Dougherty DD, Wilhelm S, Jenike MAHales RE, Yudofsky SC, Roberts LW. Obsessive-compulsive and related disorders. Textbook of Psychiatry, 6th ed. Alexandria, VA: American Psychiatric Publishing; 2014:431–454.
37. Kosten TR, Newton TF, De La Garza R II, et alHales RE, Yudofsky SC, Roberts LW. Substance-related and addictive disorders. Textbook of Psychiatry, 6th ed. Alexandria, VA: American Psychiatric Publishing; 2014:735–813.
38. Halpern JH, Sherwood AR, Hudson JI, et al. Psychological and cognitive effects of long-term peyote use among Native Americans. Biol Psychiatry. 2005;58:624–631.
39. Loizaga-Velder A, Verres R. Therapeutic effects of ritual ayahuasca use in the treatment of substance dependence—qualitative results. J Psychoactive Drugs. 2014;46:63–72.
Keywords:

hallucinogens; hallucinogenic drugs; psychedelics; psychiatry; lysergic acid diethylamide (LSD); psilocybin; ibogaine; ayahuasca; 3,4-methylenedioxymethamphetamine (MDMA); ketamine

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.