This case report SPECT imaging study explored the sequential administration of ibogaine and 5-MeO-DMT in the treatment of alcohol use disorder (AUD). It reported that the patient felt improvement in mood, cessation of alcohol use, and decreased cravings at 5 days post-treatment, but the patient returned partially to mild alcohol use at 2 months. Also, higher perfusion in multiple brain regions broadly associated with AUD and known pharmacology of both compounds was reported.

Abstract

“Ibogaine is a plant-derived alkaloid and dissociative psychedelic that demonstrates anti-addictive properties with several substances of abuse, including alcohol. 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a naturally occurring psychedelic known to occasion potent mystical-type experiences and also demonstrates anti-addictive properties. The potential therapeutic effects of both compounds in treating alcohol use disorder require further investigation and there are no published human neuroimaging findings of either treatment to date. We present the case of a 31-year-old male military veteran with moderate alcohol use disorder who sought treatment at an inpatient clinic in Mexico that utilized a sequential protocol with ibogaine hydrochloride (1550 mg, 17.9 mg/kg) on day 1, followed by vaporized 5-MeO-DMT (bufotoxin source 50 mg, estimated 5-MeO-DMT content, 5–7 mg) on day 3. The patient received SPECT neuroimaging that included a resting-state protocol before, and 3 days after completion of the program. During the patient’s ibogaine treatment, he experienced dream-like visions that included content pertaining to his alcohol use and resolution of past developmental traumas. He described his treatment with 5-MeO-DMT as a peak transformational and spiritual breakthrough. On post-treatment SPECT neuroimaging, increases in brain perfusion were noted in bilateral caudate nuclei, left putamen, right insula, as well as temporal, occipital, and cerebellar regions compared to the patient’s baseline scan. The patient reported improvement in mood, cessation of alcohol use, and reduced cravings at 5 days post-treatment, effects which were sustained at 1 month, with a partial return to mild alcohol use at 2 months. In this case, serial administration of ibogaine and 5-MeO-DMT resulted in increased perfusion in multiple brain regions broadly associated with alcohol use disorders and known pharmacology of both compounds, which coincided with a short-term therapeutic outcome. We present theoretical considerations regarding the potential of both psychedelic medicines in treating alcohol use disorders in the context of these isolated findings, and areas for future investigation.”

Authors: Joseph P. Barsuglia, Martin Polanco, Robert Palmer, Benjamin J. Malcolm, Benjamin Kelmendi & Tanya Calvey

Summary

A 31-year-old male military veteran with moderate alcohol use disorder received SPECT imaging after receiving ibogaine hydrochloride (1550mg, 17.9mg/kg) and 5-MeO-DMT (bufotoxin source 50mg, estimated 5-MeO-DMT content, 5 – 7mg).

1 INTRODUCTION

Multiple psychedelic compounds have demonstrated initial evidence of anti-addictive properties in the treatment of alcohol abuse, which is a top preventable leading cause of death in the United States. Ibogaine is a plant-derived psychedelic dissociative compound that demonstrates addiction-interrupting properties with alcohol. Ayahuasca, psilocybin, and 5-methoxy-N,N-dimethyltryptamine are hallucinogenic Amazonian plant mixtures that have been shown to reduce alcohol use in ritual users and animal models. The following investigation includes a rationale for administering both compounds in the context of alcohol addiction treatment.

1.1 IBOGAINE BACKGROUND AND POTENTIAL AS A TREATMENT FOR ALCOHOL USE DISORDER

Ibogaine is an alkaloid present in the root bark of the Tabernanthe iboga plant, which has an ancient history of ceremonial use in Central Africa. It has shown promising results in treating opioid dependence, but no formal studies have examined its use for treating alcohol use disorders.

Ibogaine is an alkaloid that demonstrates complex, broad, and novel pharmacological mechanisms of action to consider in the potential treatment of alcohol use disorders. It is hepatically metabolized to an active metabolite, noribogaine, which has a longer duration of action.

Ibogaine reduces alcohol intake in alcohol-preferring rats through upregulation of GDNF in the ventral tegmental area (VTA), which is a major region implicated in reward neurocircuitry. Ibogaine also increases serotonin and dopamine release in mesolimbic pathways, including the nucleus accumbens, striatum, and the prefrontal cortex. Ibogaine binds to , , and opiate receptors, and has been shown to reverse opioid tolerance. It is also an NMDA antagonist, and may be implicated broadly in its “addiction-interrupting” effects with other substances such as alcohol.

Ibogaine induces potent dissociative and waking dream-like (oneiric) states that engender transformative psychological insights. These insights include heightened memory retrieval specifically related to drug abuse, the perception of one’s own future with or without drug use, and visions.

Ibogaine has been found to have multiple potential pharmacological and psychological properties for treating alcohol use disorders, including the evocation of repressed traumatic memories, improvement in mood and anxiety symptoms, and insight into the cause of addiction.

5-MeO-DMT is a relatively less researched organic short-acting psychoactive indolealkylamine that is found naturally in the bufotoxin of the Colorado River toad and various plant species. It causes potent visionary and auditory changes as well as alterations in time perception.

In a recent epidemiological study, over 500 individuals who utilized different forms of 5-MeO-DMT in uncontrolled settings reported therapeutic effects attributed to their use. Most reported consuming 5-MeO-DMT infrequently (once/year) for the purpose of spiritual exploration.

5-MeO-DMT is a structural analog of serotonin and melatonin and has been shown to be neuroprotective, anti-inflammatory, influence morphogenesis of human brain cells, modulate immune responses, and have anti-depressant properties. It was shown to produce a temporary reversible reconfiguration of brain network dynamics.

5-MeO-DMT has been shown to have anti-addictive properties due to its ability to downregulate metabotropic glutamate receptor 5, and classic psychedelics with similar serotonergic effects have consistently demonstrated therapeutic potential in treating alcohol use disorders.

5-MeO-DMT occasions mystical-type experiences similar to psilocybin, which are a key predictor of positive outcomes in human studies with other serotonergic hallucinogens in the treatment of addictive disorders. Therefore, 5-MeO-DMT may possess similar or potentially greater efficacy in treating alcohol use disorders than psilocybin.

1.3 RATIONALE FOR SEQUENTIAL TREATMENT PROTOCOL AND STUDY

Ibogaine and 5-MeO-DMT demonstrate preliminary pre-clinical and observational evidence as potential agents for treating alcohol use disorder, and utilizing both compounds in sequence may have additive effects. Ibogaine catalyzes close-eyed dream-like visions and insight, but does not occasion mystical-type experiences to the extent or type as classic psychedelics. 5-MeO-DMT was implemented in a sequenced psychedelic treatment program with ibogaine because of its therapeutic mystical-type experiences and anti-addictive and antidepressant properties. 5-MeO-DMT lacks documentation of its clinical effects in humans with addiction. We documented these effects via single-photon emission computed tomography.

2 CASE REPORT

A 31-year-old male, right-handed, biracial (Native American, African American) military Air Force veteran presented for treatment of alcohol use disorder. He reported inability to cut down or stop drinking, and his alcohol use exacerbated his PTSD and interfered with his ability to build his startup business.

The veteran had issues with physical altercations with other active duty military personnel, and developed nightmares about people chasing him with guns. He received group therapy and weekly psychotherapy for alcohol use and PTSD, but denied prior medication treatment for his alcohol use. A man with remote neuropsychiatric history of ADHD was evaluated. He discontinued using mixed amphetamine salts one to two times per week, and had a significant family medical history of alcohol abuse and depression.

3.1 TREATMENT COURSE

A patient was treated in a 4-day program that included administration of ibogaine HCl and 5-MeO-DMT at a treatment facility in Mexico. The program utilized the Global Ibogaine Therapy Alliance (GITA) consensus clinical treatment guidelines as part of screening criteria and risk management.

The patient was administered 1550mg of ibogaine HCl in four doses, with the fourth dose given 3h after the prior dose. He was monitored by five clinical staff members, including a paramedic, nurse, two physicians, and a program counselor.

The patient experienced ataxia, vomiting, and acute panic during ibogaine treatment.

During his counseling session, he described contents of the psychedelic/visionary aspects of his experience, including floating through the universe, being surrounded by the stars, and asking himself questions. He noted being visually transported to new realms, where he saw symbols representing the answers to his questions. When he became nauseated, the beings told him not to vomit, but he physically vomited and was given rocket boots by the creator of the matrix to enter the light.

The patient was administered 5-MeO-DMT in the form of inhaled vaporized bufotoxin from the Colorado River toad on day 3 of treatment. He received education and preparation regarding the nature of the substance, its origins, possible therapeutic benefits, potential risks, and techniques for navigating transcendental psychedelic states.

The patient’s 5-MeO-DMT session lasted 45min with acute effects, and within 60min from administration he demonstrated a full return to baseline orientation and mental status. He reported a deeply spiritual and healing experience, and described his experience as the single-most peak transformational experience of his life.

3.2 SPECT PROCEDURES

SPECT images were reformatted into three-dimensional images using Picker Prism Odyssey Rendering Software, and clinical readings were performed at Amen Clinics.

4.1.1 Baseline

A patient’s baseline pre-treatment resting-state SPECT revealed moderately decreased activity bilaterally of the inferior orbitofrontal cortices and temporal lobes, as well as mildly decreased activity of the occipital lobes and the medial cerebellum.

4.1.2 Post-treatment

The patient’s post-treatment scan showed an improvement in the decreased activity in the temporal lobes, occipital lobes, and internal cerebellar activity, but continued moderately decreased activity bilaterally of the inferior orbitofrontal cortex.

4.2 SUBJECTIVE POST-TREATMENT REPORT

The patient reported feeling calmer, with improved mental focus/concentration, clarity, mood, and a comforting absence of thought, 110h post-ibogaine administration. He noted his 5-MeO-DMT experience helped him to forgive and accept himself for his perceived shortcomings. At 1-month follow-up, the patient reported minimal cravings, no alcohol consumption, and a sense of peace, mental clarity, increased energy, and emotional stability that persisted for 3 months. He expressed interest in returning to do another ibogaine treatment in the future.

5 DISCUSSION 5.1 REVIEW OF CASE

A 31-year-old individual who sought treatment with ibogaine and 5-MeO-DMT for alcohol use disorder and PTSD reported acute remission of alcohol use, reduced cravings for alcohol, and improvements in cognition, mood, and interpersonal functioning. Baseline SPECT imaging revealed reduced perfusion in multiple regions of interest associated with alcohol abuse. Post-treatment, the patient demonstrated increased perfusion in bilateral caudate nuclei, left putamen as well as in temporal, occipital and cerebellar regions.

5.2 CASE FINDINGS AND THEORETICAL ASSOCIATIONS WITH IBOGAINE IN TREATING ALCOHOL USE DISORDERS

Based on the reductions in alcohol use/cravings and changes in brain functioning in this case, and the known neuropharmacological properties of ibogaine, we present several speculative associations relevant for treating alcohol use disorders.

A patient with alcoholism demonstrated hypoperfusion of the cerebellum, which was improved by ibogaine treatment. The cerebellum is implicated in reward processing, motivational and cognitive control processing, and over-responsive recruitment of the cerebellum during task demands compared to normal subjects.

Ibogaine is toxic to Purkinje cells in the vermis and simplex lobules of the cerebellum in certain species, yet it is also neuroprotective in humans via NDMA antagonism and upregulation of GDNF.

The patient demonstrated increased blood flow in the basal nuclei, occipital lobe, and temporal lobes following treatment with ibogaine. This increase may be related to ibogaine’s noted effects on dopaminergic and cholinergic muscarinic receptors, which are expressed in the caudate and putamen and commonly demonstrate hypoperfusion in chronic alcohol use.

Ibogaine treatment increased perfusion in the anterior cingulate and the right insula, coupled with a decrease in left insular perfusion, in a patient with alcohol use disorder. This could be an indication that ibogaine is improving signaling in this region. The right insula is more dominant in interoceptive awareness and representation of aversive somatic markers, which are central processes in addiction. The right insula has a high density of opiate and dopamine receptors, which may be relevant in future studies of ibogaine.

The current case describes a patient who underwent ibogaine treatment for alcohol use disorders and post-traumatic stress disorder. The patient reported having visionary experiences during ibogaine treatment that were therapeutically meaningful for him.

The increase in cerebellar functioning after treatment may have relevance in the treatment of PTSD. The ability of ibogaine to stimulate cerebellar activity may be a focus of future therapeutic interest.

The patient reported temporary improvements in mood and cognition following his treatment with ibogaine, and a greater ability to manage and control his anger. These improvements were helpful in improving his global functioning and ability to have a clinically meaningful period of abstinence from alcohol use. Ibogaine may be beneficial in treating comorbidities in alcohol use disorders, such as depression and anger issues. However, multiple versus single ibogaine treatments are associated with better outcomes in substance users.

Ibogaine may act on several mechanisms, including SERT, DAT, sigma, NMDA, nAChR, opioid receptors, and GDNF production, which are important for the treatment of depression and cognitive enhancement. Ibogaine has been shown to have anti-addictive effects and to have potential for treating co-morbid pathologies associated with alcohol use disorders including PTSD, depression and cognitive dysfunction.

5.3 CASE FINDINGS AND THEORETICAL ASSOCIATIONS WITH 5-MeO-DMT IN TREATING ALCOHOL USE DISORDERS

In this case, 5-MeO-DMT was used 2 days after ibogaine and 3 days prior to the follow-up scan. Although the effects of 5-MeO-DMT on human brain functioning have not been investigated to date, there may be persisting neuroadaptational effects that impact cerebral blood flow 3 days post-administration.

5-MeO-DMT demonstrates prominent affinity for multiple serotonin receptors, including 5HT1A and 5HT7 subtypes, and is also expressed in the ventral tegmental area (associated with reward and addiction) and the striatum (i.e. caudate putamen).

A patient reported that 5-MeO-DMT occasioned a mystical experience and helped him to release longheld emotional trauma associated with his alcohol addiction. This outcome is similar to outcomes of observational studies of 5-MeO-DMT users and studies of the effects of other pharmacologically related psychoactive tryptamines. Studies with ayahuasca have shown that individuals are able to process traumatic memories, in part through the anti-amnesic effects of ayahuasca, which activates 1 receptors.

5-MeO-DMT demonstrates anti-depressant properties in vivo on human cerebral organoid cells, which may help treat mood-related comorbidities in alcohol use disorders. Further investigation of the use of 5-MeO-DMT in the treatment of alcohol addiction and PTSD, as well as mood-related comorbidities, would be advantageous.

5.4 LIMITATIONS

The patient’s history clouds the etiological picture, and the patient’s post-treatment account of his substance use could be questionable. It is not feasible to draw any causal or mechanistic conclusions given the small sample size and sequential administration of two psychedelic compounds.

5.5 POTENTIAL SYNERGISTIC EFFECTS OF THE SEQUENTIAL PSYCHEDELIC THERAPY PROTOCOL

Ibogaine and 5-MeO-DMT may have synergistic effects when administered sequentially, as ibogaine inhibits the serotonin transporter and 5-MeO-DMT demonstrates affinity for multiple serotonergic pathways. This could lead to longer lasting effects and a more effective treatment for alcohol-related neuropathology.

Ibogaine and 5-MeO-DMT have multiple potential neurotherapeutic properties relevant to the treatment of addiction, including affinity for 1 receptors and stimulation of GDNF and possibly BDNF. These properties could work together to minimize the potential neurotoxic effects of increased glutamate.

5-MeO-DMT, a 5HT1A and 1 receptor agonist, may stimulate production of brain-derived neurotropic factor (BDNF), which is crucial for neuronal plasticity and regulates alcohol-drinking behaviors. Ibogaine and 5-MeO-DMT may have similar potential given their respective pharmacological profiles.

Combination psychedelic therapy requires clinicians to exercise extreme caution during the administration and interpretation of the necessary cardiac, psychiatric and general health screening protocol as well as during the treatment itself.

6 CONCLUSION

Ibogaine and 5-MeO-DMT demonstrate initial behavioral and pharmacological evidence as potential treatments for alcohol use disorder. Further studies are necessary to examine the neurological effects of both compounds independently in larger samples, document the in vivo effects during treatment, and correlate outcomes with phenomenology of psychedelic states.