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A case report SPECT study and theoretical rationale for the sequential administration of ibogaine and 5-MeO-DMT in the treatment of alcohol use disorder

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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.

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... In summary, a total of 18 articles were included in the systematic review. Of the 18 selected articles, 15 were case reports or case series (Breuer et al. 2015;Marta et al. 2015;O'Connell et al. 2015;Cloutier-Gill et al. 2016;Hildyard et al. 2016;Meisner et al. 2016;Henstra et al. 2017;Wilkins et al. 2017;Knuijver et al. 2018;Mash et al. 2018;Steinberg and Deyell, 2018;Barsuglia et al. 2018;Grogan et al. 2019;Matamoros-Castillo et al. 2019;Wilson et al. 2021). There were also two randomized, double-blind clinical trials (Glue et al. 2016(Glue et al. , 2015, and one observational study (Brown and Alper, 2018). ...
... Regarding adverse events, the results obtained after analyzing the articles were divided between acute (< 24 h) and long-lasting effects (> 24 ho). Almost half of the citations (8 in 18) reported absence of effects after the first 24 h (Glue et al. 2016;O'Connell et al. 2015;Wilkins et al. 2017;Mash et al. 2018;Barsuglia et al. 2018;Wilson et al. 2021;Glue et al. 2015;Brown and Alper, 2018). In the case reports, most cases required hospital intervention, some of them being admitted to intensive care units (Breuer et al. 2015;Steinberg and Deyell 2018;Grogan et al. 2019). ...
... Only in five out of 15 case reports the presence of ibogaine could be determined (O'Connell et al. 2015;Henstra et al. 2017;Wilkins et al. 2017;Mash et al. 2018;Grogan et al. 2019), and in only one both the presence and the quantity of ibogaine were measured (O'Connell et al. 2015). Iboga root bark was supposedly used in three cases (Breuer et al. 2015;Grogan et al. 2019;Wilson et al. 2021), while the other ones supposedly used ibogaine HCl (O'Connell et al. 2015;Cloutier-Gill et al. 2016;Hildyard et al. 2016;Meisner et al. 2016;Henstra et al. 2017;Wilkins et al. 2017;Mash et al. 2018;Steinberg and Deyell, 2018;Barsuglia et al. 2018;Brown and Alper, 2018), or it was unknown (Marta et al. 2015;Matamoros-Castillo et al. 2019). The clinical trials used ibogaine HCl (Knuijver et al. 2018;Glue et al. 2015) or noribogaine HCl (Glue et al. 2016). ...
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Context Ibogaine is the main alkaloid of the African shrub Tabernanthe iboga. It produces hallucinogenic and psychostimulant effects, but it is currently known for the anti-addictive properties. Despite the potential therapeutic effects, several cases of fatalities and serious adverse events related to ibogaine/noribogaine use can be found in the literature. Most studies consist in case reports or were conducted under non-controlled settings, so causation cannot be clearly established. Objectives To update (2015–2020) the literature on the adverse events and fatalities associated with ibogaine/noribogaine administration. Methods Systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Results Eighteen studies were included in the final selection. Highly heterogeneous results were found in terms of kind of product used or the known dosages. The adverse events were classified in acute effects (< 24 h), mainly cardiac (the most common was QTc prolongation), gastrointestinal, neurological, and clinical alterations, and long-lasting effects (> 24 h), mainly persistent cardiac alterations, psychiatric, and neurological signs. Conclusions There is a high need of phase I clinical trials that can describe the safety of different dosages of ibogaine with standardized products. Further research should perform clinical profiling of vulnerable populations, and design effective screening methods and clinical procedures.
... 25 Ibogaine treatment is reported to alleviate a spectrum of mood and anxiety symptoms [25][26][27][28] and is associated with self-reported improvements in cognitive functioning in individuals with substance use disorders. [29][30][31] During treatment, ibogaine allows the evocation and reprocessing of traumatic memories and occasions therapeutic and meaningful visions of spiritual and autobiographical content, 26,29,30,32 which are of central relevance in addressing PTSD-related psychological content. The benefits of ibogaine may be associated with its effects on serotonin and dopamine transporters, sigma, N-methyl-d-aspartate, nicotinic acetylcholine, and opioid receptors, 29,33,34 and the production of glial-derived neurotrophic factors 35 and brain-derived neurotropic factor 36 which are identified sites of interest in the treatment of cognitive impairment in neuropsychiatric disorders. ...
... 25 Ibogaine treatment is reported to alleviate a spectrum of mood and anxiety symptoms [25][26][27][28] and is associated with self-reported improvements in cognitive functioning in individuals with substance use disorders. [29][30][31] During treatment, ibogaine allows the evocation and reprocessing of traumatic memories and occasions therapeutic and meaningful visions of spiritual and autobiographical content, 26,29,30,32 which are of central relevance in addressing PTSD-related psychological content. The benefits of ibogaine may be associated with its effects on serotonin and dopamine transporters, sigma, N-methyl-d-aspartate, nicotinic acetylcholine, and opioid receptors, 29,33,34 and the production of glial-derived neurotrophic factors 35 and brain-derived neurotropic factor 36 which are identified sites of interest in the treatment of cognitive impairment in neuropsychiatric disorders. ...
... [29][30][31] During treatment, ibogaine allows the evocation and reprocessing of traumatic memories and occasions therapeutic and meaningful visions of spiritual and autobiographical content, 26,29,30,32 which are of central relevance in addressing PTSD-related psychological content. The benefits of ibogaine may be associated with its effects on serotonin and dopamine transporters, sigma, N-methyl-d-aspartate, nicotinic acetylcholine, and opioid receptors, 29,33,34 and the production of glial-derived neurotrophic factors 35 and brain-derived neurotropic factor 36 which are identified sites of interest in the treatment of cognitive impairment in neuropsychiatric disorders. [37][38][39][40][41][42] The primary adverse effects of ibogaine include cardiovascular effects (e.g., Q-wave/Twave interval prolongation, bradycardia, arrythmias, and in rare cases, sudden cardiac death), 43 ataxia, nausea, and vomiting, 44 and psychological effects (e.g., auditory and visual hallucinations, re-experiencing traumatic memories, acute fear, distress, or guilt). ...
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Background U.S. Special Operations Forces Veterans are at increased risk for a variety of mental health problems and cognitive impairment associated with military service. Current treatments are lacking in effectiveness and adherence. Therefore, this study examined psychedelic treatment with ibogaine and 5-methoxy-N,N-dimethyltryptamine for trauma-related psychological and cognitive impairment among U.S. Special Operations Forces Veterans. Method We conducted a survey of Veterans who completed a specific psychedelic clinical program in Mexico between 2017 and 2019. Questions probed retrospective reports of mental health and cognitive functioning during the 30 days before and 30 days after treatment. A total of 65 people completed treatment during this time frame and were eligible for contact. Of these, 51 (78%) completed the survey and were included in data analyses (mean age = 40; male = 96%; married = 55%; Caucasian/White = 92%; Operation Enduring Freedom/Operation Iraqi Freedom Service = 96%). Results Results indicated significant and very large reductions in retrospective report of suicidal ideation (p < .001; d = −1.9), cognitive impairment (p < .001; d = −2.8), and symptoms of posttraumatic stress disorder (p < .001; d = −3.6), depression (p < .001; d = −3.7), and anxiety (p < .001; d = −3.1). Results also showed a significant and large increase in retrospective report of psychological flexibility (p < .001; d = 2.9) from before-to-after the psychedelic treatment. Increases in the retrospective report of psychological flexibility were strongly associated with retrospective report of reductions in cognitive impairment, and symptoms of posttraumatic stress disorder, depression, and anxiety (rs range −0.61 to −0.75; p < .001). Additionally, most participants rated the psychedelic experiences as one of the top five personally meaningful (84%), spiritually significant (88%), and psychologically insightful (86%) experiences of their lives. Limitations: Several limitations should be considered including the retrospective, self-report, survey design of the study, and the lack of randomization and blinding, thus making these finding preliminary. Conclusion U.S. Special Operations Forces Veterans may have unique treatment needs because of the sequela of problems associated with repeated trauma exposure and the nature of the exposure. Psychedelic-assisted therapy with these under-researched psychedelics may hold unique promise for this population. However, controlled studies are needed to determine whether this treatment is efficacious in relieving mental health and cognitive impairment among U.S. Special Operations Forces Veterans.
... The patient maintained opioid abstinence for two years. Barsuglia et al. (2018) published a case report of a 31-year-old male military veteran with moderate alcohol use disorder (AUD) who was treated with ibogaine (17.9 mg/kg) on day 1, followed by inhaled, vaporized 5-MeO-DMT (5-7 mg) on day 3. The patient reported mood improvement, cessation of alcohol use, and reduced alcohol cravings for a month. ...
Article
Background Iboga and its primary alkaloids, ibogaine and noribogaine, have been of interest to researchers and practitioners, mainly due to their putative efficacy in treating substance use disorders (SUDs). For many SUDs, still no effective pharmacotherapies exist. Distinct psychoactive and somatic effects of the iboga alkaloids set them apart from classic hallucinogens like LSD, mescaline, and psilocybin. Aims The study team performed this systematic review focusing on clinical data and therapeutic interventions involving ibogaine and noribogaine. Methods The team conducted a search for all publications up to December 7, 2020, using PubMed and Embase following PRISMA guidelines. Results In total, we identified 743 records. In this review, we consider 24 studies, which included 705 individuals receiving ibogaine or noribogaine. This review includes two randomized, double-blind, controlled clinical trials, one double-blind controlled clinical trial, 17 open-label studies or case series (including observational or retrospective studies), three case reports, and one retrospective survey. The published data suggest that ibogaine is an effective therapeutic intervention within the context of SUDs, reducing withdrawal symptoms and craving. Data also point toward a beneficial impact on depressive and trauma-related psychological symptoms. However, studies have reported severe medical complications and deaths, which seem to be associated with neuro- and cardiotoxic effects of ibogaine. Two of these fatalities were described in the 24 studies included in this review. Conclusion Treatment of SUDs and persisting comorbidities requires innovative treatment approaches. Rapid-onset therapies such as the application of ibogaine may offer novel treatment opportunities for specific individuals. Rigorous study designs within medical settings are necessary to warrant safe application, monitoring, and, possibly, medical intervention.
... In this growing field of research there have been multiple forms of therapy utilizing classical psychedelics as alternative forms of treatment often with positive results (Barsuglia et al., 2018). ...
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Draft for examining DMT and 5 MeO as alternative approaches for treating addiction.
... In a case study using SPECT, a patient suffering from alcohol dependence underwent a trial treatment with ibogaine hydrochloride (17 HCl, 1.5 g) followed two days later with vaporized 5-MeO-DMT (15, 5-7 mg) [143]. The patient experience insightful visions during the ibogaine (17) treatment, and later reported a decline in alcohol consumption. ...
Article
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Hallucinogens are a loosely defined group of compounds including LSD, N,N-dimethyltryptamines, mescaline, psilocybin/psilocin, and 2,5-dimethoxy-4-methamphetamine (DOM), which can evoke intense visual and emotional experiences. We are witnessing a renaissance of research interest in hallucinogens, driven by increasing awareness of their psychotherapeutic potential. As such, we now present a narrative review of the literature on hallucinogen binding in vitro and ex vivo, and the various molecular imaging studies with positron emission tomography (PET) or single photon emission computer tomography (SPECT). In general, molecular imaging can depict the uptake and binding distribution of labelled hallucinogenic compounds or their congeners in the brain, as was shown in an early PET study with N1-([11C]-methyl)-2-bromo-LSD ([11C]-MBL); displacement with the non-radioactive competitor ketanserin confirmed that the majority of [11C]-MBL specific binding was to serotonin 5-HT2A receptors. However, interactions at serotonin 5HT1A and other classes of receptors and pleotropic effects on second messenger pathways may contribute to the particular experiential phenomenologies of LSD and other hallucinogenic compounds. Other salient aspects of hallucinogen action include permeability to the blood–brain barrier, the rates of metabolism and elimination, and the formation of active metabolites. Despite the maturation of radiochemistry and molecular imaging in recent years, there has been only a handful of PET or SPECT studies of radiolabeled hallucinogens, most recently using the 5-HT2A/2C agonist N-(2[11CH3O]-methoxybenzyl)-2,5-dimethoxy- 4-bromophenethylamine ([11C]Cimbi-36). In addition to PET studies of target engagement at neuroreceptors and transporters, there is a small number of studies on the effects of hallucinogenic compounds on cerebral perfusion ([15O]-water) or metabolism ([18F]-fluorodeoxyglucose/FDG). There remains considerable scope for basic imaging research on the sites of interaction of hallucinogens and their cerebrometabolic effects; we expect that hybrid imaging with PET in conjunction with functional magnetic resonance imaging (fMRI) should provide especially useful for the next phase of this research.
... Evidence also suggests that mystical experiences occasioned by vaporized 5-MeO-DMT in a psychologically supported environment are similar in intensity to moderately high doses of oral psilocybin administered in the laboratory (Barsuglia, Polanco, et al., 2018), and are associated with naturalistic improvement in depression and anxiety after 5-MeO-DMT use . However, some have argued for differing routes of 5-MeO-DMT administration (e.g., intramuscular injection, insufflation) in order to capitalize on a more gradual onset and sustained plateau of acute effects (HumbleVoyager, 2017;Metzner, 2013;Uthaug et al., 2020). ...
Chapter
Research has shown the promise of psychedelics used as an adjunct to psychotherapy in the treatment of various mental health disorders, including post-traumatic stress disorder (PTSD), treatment-resistant depression, and anxiety-related disorders (Barone et al., 2019; Carhart-Harris et al., 2018; Garcia-Romeu, Kersgaard, & Addy, 2016; Griffiths et al., 2016; Ot’alora et al., 2018; Ross et al., 2016). Psychedelics such as O-phosphoryl-4-hydroxy-N,N-dimethyltryptamine (4-PODMT; commonly known as psilocybin), and psychedelic like drugs such as 3,4-methylenedioxymethamphetamine (MDMA) may be approved for medical use by the U.S. Food and Drug Administration and the European Medicines Agency in the coming years. However, their long duration of psychoactive effects (4–6 hours for psilocybin, approximately 4 hours for MDMA) increases the clinical and infrastructure resources needed for daylong treatment sessions, thus likely to result in high costs associated with these treatments. Such high costs could limit the accessibility of psilocybin- and MDMA-assisted psychotherapy to many people who could benefit from this type of treatment, especially those from vulnerable populations such as people of color, sexual and gender minorities, and military veterans. In order to decrease the fiscal burden of these treatments, psychedelics such as N,Ndimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), and N,N-dipropyltryptamine (DPT), used as an adjunct to psychotherapy, may provide a more cost-effective alternative due to their quick onset and short duration of acute effects. Although all three of these substituted tryptamines have similar molecular structures, each has slightly different profiles of acute effects that could show promise for clinical indications. In this chapter, we review the current literature on the history, basic pharmacology, and acute phenomenology of DMT, 5-MeO-DMT, and DPT, and explain the therapeutic potential by presenting evidence of their potential to alleviate symptoms associated with various mental health conditions.
... 5-MeO-DMT induces a diversity of subjective effects, including auditory, visual, and time perception distortions, emotional experiences, and memory impairment that vary depending on the dose and route of administration (Ott 2001;Shulgin and Shulgin 1997). In fact, low doses of 5-MeO-DMT (bufotoxin source 50 mg, estimated 5-MeO-DMT content 5-7 mg) appear to occasion mystical experiences of similar intensity to high-dose psilocybin ( Barsuglia et al. 2018), but with a much shorter duration of action. ...
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Rationale 5-methoxy-N,N-dimethyltryptamine is a psychotropic substance found in various plant and animal species and is synthetically produced. 5-methoxy-N,N-dimethyltryptamine is used in naturalistic settings for spiritual exploration, recreation, or to address negative affect and mood problems. However, scientific knowledge on the effects of 5-methoxy-N,N-dimethyltryptamine in humans is scarce. Objectives The first objective was to assess the effects of inhalation of vaporized synthetic 5-methoxy-N,N-dimethyltryptamine on neuroendocrine markers. The second objective was to assess effects of the substance on affect and mindfulness. In addition, we assessed whether ratings of subjective measures were associated with changes in stress biomarkers (i.e., cortisol) and immune response (i.e., IL-6, CRP, IL-1β), as well as the acute psychedelic experience. Methods Assessments (baseline, immediately post-session, and 7-day follow-up) were made in 11 participants. Salivary samples were collected at baseline and post-session and analyzed by high-sensitivity enzyme-linked immunosorbent assay (ELISA). Results 5-methoxy-N,N-dimethyltryptamine significantly increased cortisol levels and decreased IL-6 concentrations in saliva immediately post-session. These changes were not correlated to ratings of mental health or the psychedelic experience. Relative to baseline, ratings of non-judgment significantly increased, and ratings of depression decreased immediately post-session and at follow-up. Ratings of anxiety and stress decreased from baseline to 7-day follow-up. Participant ratings of the psychedelic experience correlated negatively with ratings of affect and positively with ratings of non-judgment. Conclusion Inhalation of vaporized synthetic 5-methoxy-N,N-dimethyltryptamine produced significant changes in inflammatory markers, improved affect, and non-judgment in volunteers. Future research should examine the effect of 5-methoxy-N,N-dimethyltryptamineamine with healthy volunteers in a controlled laboratory setting.
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If mental health has become a reactionary concept, much like the notion of public health in the age of the Covid‐19 pandemic, then how can critical theory best elaborate a concern for well‐being which includes both a psychic and social dimension? This article proposes the concept of existential health to grasp the salubrious zest for life that has been extinguished from social life since March 2020, due to rolling lockdowns and the rise of totalitarian impulses within the medical‐industrial complex. It draws on the relational art practice of Lygia Clark along with developments in the psychedelic treatment of addiction to articulate a vision of existential health in an age of mental illness that is irreducible to the specialised domain of psychologists signified by the ‘mental’ in mental health.
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Background & aims Special Operations Forces Veterans (SOFV) have unique treatment needs stemming from multiple repeated forms of combat exposure resulting in a complex sequela of problems including alcohol misuse and post-traumatic stress symptoms. Current approved pharmacologic treatments for alcohol misuse and PTSD are lacking in adherence and efficacy, warranting novel treatment development. The current study examined the correlations between psychedelic treatment and changes in alcohol misuse among trauma exposed United States SOFV. Method An anonymous internet-based survey was conducted among SOFV who completed a specific psychedelic clinical program in Mexico. Retrospective questions probed alcohol use and post-traumatic stress symptoms during the 30-days before and 30-days after the psychedelic treatment. A total of 65 SOFV completed treatment and were eligible for contact. Of these, 51 (78%) completed the survey, and 27 (42%) reported alcohol misuse (≥4 on the AUDIT-C) in the 30 days prior to treatment and were included in analyses (Mean Age = 40; male = 96%; Caucasian/White = 96%). Results There were significant and very large reductions in retrospective reports of alcohol use ( P < 0.001; d = –2.4) and post-traumatic stress symptoms ( P < 0.001; d = –2.8) and a significant and large increase in psychological flexibility ( P < 0.001; d = –1.8), from before-to-after the psychedelic treatment. In the 30 days after treatment, 85% reduced their alcohol consumption to non-risky levels (33% abstinent; 52% non-risky drinking). Increases in psychological flexibility were strongly associated with reductions in alcohol use and post-traumatic stress symptoms (rs range 0.38–0.90; ps < 0.05). Conclusion Rigorous longitudinal studies should be conducted to determine whether psychedelic-assisted therapy holds promise as an intervention in this population.
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Background: 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a naturally occurring, short-acting psychedelic tryptamine, produced by a variety of plant and animal species. Plants containing 5-MeO-DMT have been used throughout history for ritual and spiritual purposes. The aim of this article is to review the available literature about 5-MeO-DMT and inform subsequent clinical development. Methods: We searched PubMed database for articles about 5-MeO-DMT. Search results were cross-checked against earlier reviews and reference lists were hand searched. Findings were synthesised using a narrative synthesis approach. This review covers the pharmacology, chemistry and metabolism of 5-MeO-DMT, as well epidemiological studies, and reported adverse and beneficial effects. Results: 5-MeO-DMT is serotonergic agonist, with highest affinity for 5-HT1A receptors. It was studied in a variety of animal models, but clinical studies with humans are lacking. Epidemiological studies indicate that, like other psychedelics, 5-MeO-DMT induces profound alterations in consciousness (including mystical experiences), with potential beneficial long-term effects on mental health and well-being. Conclusion: 5-MeO-DMT is a potentially useful addition to the psychedelic pharmacopoeia because of its short duration of action, relative lack of visual effects and putatively higher rates of ego-dissolution and mystical experiences. We conclude that further clinical exploration is warranted, using similar precautions as with other classic psychedelics.
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Opioid use disorder (OUD) is currently an epidemic in the United States (US) and ibogaine is reported to have the ability to interrupt opioid addiction by simultaneously mitigating withdrawal and craving symptoms. This study examined opioid withdrawal and drug craving scores in 50 participants with OUD undergoing a week-long detoxification treatment protocol with ibogaine. The Addiction Severity Index (ASI) was used for baseline characterization of participants' OUD. Clinical Opioid Withdrawal Scale (COWS), Subjective Opioid Withdrawal Scale (SOWS), and Brief Substance Craving Scale (BSCS) scores were collected at 48 and 24 hours prior to ibogaine administration, as well as 24 and 48 hours after ibogaine administration. At 48 hours following ibogaine administration, withdrawal and craving scores were significantly lowered in comparison to baseline: 78% of patients did not exhibit objective clinical signs of opioid withdrawal, 79% reported minimal cravings for opioids, and 68% reported subjective withdrawal symptoms in the mild range. Ibogaine appears to facilitate opioid detoxification by reducing opioid withdrawal and craving in participants with OUD. These results warrant further research using rigorous controlled trials.
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In spite of tremendous development in central nervous system research, current treatment is suboptimal, especially in severe mental disorders. In medicine, there are two main methods of improving the health care provided: seeking new treatment procedures and perfecting (optimizing) the existing ones. Optimization of treatment includes not only practical tools such as therapeutic drug monitoring but also implementation of general trends in the clinical practice. New pharmacological options include new more sophisticated forms of monoaminergic drugs, old drugs rediscovered on the base of a better understanding of pathophysiology of mental illnesses, and drugs aimed at new treatment targets. In depression, treatment resistance to antidepressive pharmacotherapy represents one of the most important clinical challenges. Switching to monotherapy with new multimodal/multifunctional antidepressants and augmentation with new atypical antipsychotics (aripiprazole and brexpiprazole) may be promising options. Further, current evidence supports utility and safety of adjunctive treatment of nutraceuticals. Novel approaches being studied include ketamine and opioids. Recent advances in technology and emerging knowledge about dysfunctional brain circuits and neuroplasticity have led to the development of different new neuromodulation techniques usually used as add-on therapy. Antipsychotics are still the cornerstone of the current treatment of schizophrenia. Two new partial dopamine agonists, brexpiprazole and cariprazine, are now available in addition to aripiprazole. Although the mechanisms of action are similar, the two agents differ in terms of their pharmacodynamic profiles. Further, two new formulations of long-acting injections of second-generation antipsychotics (aripiprazole lauroxil and 3-month paliperidone palmitate) were introduced into clinical practice. New treatment options not yet available include cannabidiol, glutamate modulators, and nicotine receptors agonists.
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Research on the clinical applications of psychedelic-assisted psychotherapy has demonstrated promising early results for treatment of alcohol dependence. Detailed description of the content and methods of psychedelic-assisted psychotherapy, as it is conducted in clinical settings, is scarce. Methods: An open-label pilot (proof-of-concept) study of psilocybin-assisted treatment of alcohol dependence (NCT01534494) was conducted to generate data for a phase 2 RCT (NCT02061293) of a similar treatment in a larger population. The present paper presents a qualitative content analysis of the 17 debriefing sessions conducted in the pilot study, which occurred the day after corresponding psilocybin medication sessions. Results: Participants articulated a series of key phenomena related to change in drinking outcomes and acute subjective effects of psilocybin. Discussion: The data illuminate change processes in patients' own words during clinical sessions, shedding light on potential therapeutic mechanisms of change and how participants express effects of psilocybin. This study is unique in analyzing actual clinical sessions, as opposed to interviews of patients conducted separately from treatment.
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Treatment for opioid use disorder in the United States evolved in response to changing federal policy and advances in science. Inpatient care began in 1935 with the US Public Health Service Hospitals in Lexington, Kentucky, and Fort Worth, Texas. Outpatient clinics emerged in the 1960s to provide aftercare. Research advances led to opioid agonist and opioid antagonist therapies. When patients complete opioid withdrawal, return to use is often rapid and frequently deadly. US and international authorities recommend opioid agonist therapy (i.e., methadone or buprenorphine). Opioid antagonist therapy (i.e., extended-release naltrexone) may also inhibit return to use. Prevention efforts emphasize public and prescriber education, use of prescription drug monitoring programs, and safe medication disposal options. Overdose education and naloxone distribution promote access to rescue medication and reduce opioid overdose fatalities. Opioid use disorder prevention and treatment must embrace evidence-based care and integrate with physical and mental health care. Expected final online publication date for the Annual Review of Public Health Volume 39 is April 1, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Rationale: Recent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy. Objectives: Here, we report on safety and efficacy outcomes for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression. Methods: Twenty patients (six females) with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. Depressive symptoms were assessed from 1 week to 6 months post-treatment, with the self-rated QIDS-SR16 as the primary outcome measure. Results: Treatment was generally well tolerated. Relative to baseline, marked reductions in depressive symptoms were observed for the first 5 weeks post-treatment (Cohen's d = 2.2 at week 1 and 2.3 at week 5, both p < 0.001); nine and four patients met the criteria for response and remission at week 5. Results remained positive at 3 and 6 months (Cohen's d = 1.5 and 1.4, respectively, both p < 0.001). No patients sought conventional antidepressant treatment within 5 weeks of psilocybin. Reductions in depressive symptoms at 5 weeks were predicted by the quality of the acute psychedelic experience. Conclusions: Although limited conclusions can be drawn about treatment efficacy from open-label trials, tolerability was good, effect sizes large and symptom improvements appeared rapidly after just two psilocybin treatment sessions and remained significant 6 months post-treatment in a treatment-resistant cohort. Psilocybin represents a promising paradigm for unresponsive depression that warrants further research in double-blind randomised control trials.
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Background This study examined how alcohol use disorder (AUD) patients with post-traumatic stress disorder (PTSD) differed from those without PTSD in terms of demography, drinking patterns and C-reactive protein, inflammatory cytokines, tryptophan metabolism parameters, and brain-derived neurotrophic factor (BDNF). Methods A consecutive sample (N = 187) of treatment-receiving AUD individuals were recruited from Nepalese facilities. They underwent fully structured psychiatric interviews. Serum levels of inflammatory cytokines [interleukin (IL)-6, IL-1 Receptor antagonist (IL-1Ra), IL-10, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ)] were determined by a multiplex assay, kynurenine and tryptophan levels by high-performance liquid chromatography, and BDNF by enzyme-linked immunosorbent assay (ELISA). Results The prevalence of exposure to severe trauma and PTSD was 74% and 17%, respectively. PTSD comorbidity was not associated with age, gender, or socioeconomic status, but with co-occurring major depression, history of attempted suicide, earlier peak of drinking problems, higher drinking quantity and withdrawal symptoms, experiencing alcoholic blackouts, and drinking problems among parents. None of the assessed neuroimmune parameters was related to comorbid PTSD. Conclusions The findings support routine trauma screening in AUD treatment samples and screening for risky drinking in trauma populations to help guide interventions. The expected aberrations in neuroimmune functioning may not be found when examined in a sample with multiple psychiatric morbidities.
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Background: Ibogaine is a monoterpene indole alkaloid used in medical and nonmedical settings for the treatment of opioid use disorder. Its mechanism of action is apparently novel. There are no published prospective studies of drug use outcomes with ibogaine. Objectives: To study outcomes following opioid detoxification with ibogaine. Methods: In this observational study, 30 subjects with DSM-IV Opioid Dependence (25 males, 5 females) received a mean total dose of 1,540 ± 920 mg ibogaine HCl. Subjects used oxycodone (n = 21; 70%) and/or heroin (n = 18; 60%) in respective amounts of 250 ± 180 mg/day and 1.3 ± 0.94 g/day, and averaged 3.1 ± 2.6 previous episodes of treatment for opioid dependence. Detoxification and follow-up outcomes at 1, 3, 6, 9, and 12 months were evaluated utilizing the Subjective Opioid Withdrawal Scale (SOWS) and Addiction Severity Index Composite (ASIC) scores, respectively. Results: SOWS scores decreased from 31.0 ± 11.6 pretreatment to 14.0 ± 9.8 at 76.5 ± 30 hours posttreatment (t = 7.07, df = 26, p < 0.001). At 1-month posttreatment follow-up, 15 subjects (50%) reported no opioid use during the previous 30 days. ASIC Drug Use and Legal and Family/Social Status scores were improved relative to pretreatment baseline at all posttreatment time points (p < .001). Improvement in Drug Use scores was maximal at 1 month, and subsequently sustained from 3 to 12 months at levels that did not reach equivalence to the effect at 1 month. Conclusion: Ibogaine was associated with substantive effects on opioid withdrawal symptoms and drug use in subjects for whom other treatments had been unsuccessful, and may provide a useful prototype for discovery and development of innovative pharmacotherapy of addiction.
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Background: Ayahuasca is a plant tea containing the psychedelic 5-HT2A agonist N,N-dimethyltryptamine (DMT) and harmala monoamine-oxidase inhibitors. Acute administration leads to neurophysiological modifications in brain regions of the default mode network (DMN), purportedly through a glutamatergic mechanism. Post-acutely, ayahuasca potentiates mindfulness capacities in volunteers, and induces rapid and sustained antidepressant effects in treatment-resistant patients. However, the mechanisms underlying these fast and maintained effects are poorly understood. Here we investigated in an open-label uncontrolled study in sixteen healthy volunteers ayahuasca-induced post-acute neurometabolic and connectivity modifications, and their association with mindfulness measures. Methods: Using 1H-magnetic resonance spectroscopy (MRS) and functional connectivity, we compared baseline and post-acute neurometabolites and seed-to-voxel connectivity in the posterior (PCC) and anterior (ACC) cingulate cortex after a single ayahuasca dose. Results: MRS showed post-acute reductions in Glx (glutamate+glutamine), creatine and NAA-NAAG (N-acetylaspartate+N-acetylaspartylglutamate) in the PCC. Connectivity was increased between the PCC and the ACC, and between the ACC and limbic structures in the right medial temporal lobe (MTL). Glx reductions correlated with increases in the "Non-Judging" subscale of the Five Facets Mindfulness Questionnaire. Increased ACC-MTL connectivity correlated with increased scores on the Self-Compassion questionnaire. Post-acute neural changes predicted sustained elevations in "Non-Judging" two months later. Conclusions: These results support the involvement of glutamate neurotransmission in the effects of psychedelics in humans. They further suggest that neurometabolic changes in the PCC, a key region within the DMN, and increased connectivity between the ACC and MTL structures involved in emotion and memory, potentially underlie the post-acute psychological effects of ayahuasca.
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Recent brain imaging studies in Psychedelic Brain Science are breaking new ground in our understanding of neurological substrate of biological consciousness in humans. The emerging field of inner experience and neuroscience is particularly well suited to the reexamination of the actions of psychedelics on subjective conscious experience. This approach is best understood as neurophenomenology. My work over the last few years has focused on the EEG correlates of the visionary tryptamine DMT action. I believe the researcher must also have the drug experience as part of the experimental protocol, in order to fully understand the richness of the phenomenon. The objective of this exploratory research was to examine the QEEG correlates of the psychoactive smoked inhalation of exogenous DMT action. Known as a potent visionary tryptamine, DMT is ubiquitous in nature and has also been localized in the brain and peripheral tissues of mammals, including humans. The exact function of this endogenous DMT is the subject of ongoing neuropharmacological research. Three sources of DMT were tested: high purity synthetic 5-MeO-DMT, Bufo 5-MeO-DMT (an extract from the Sonoran desert toad venom, Bufo alvarius), and N,N-DMT from a natural extract of the Acacia tree Mimosa hostilis root bark. The DMT was delivered by smoked inhalation (vaporization). The rapid onset (10-20 sec), short acting (5-15 min.), and reversible nature of the effects made such a QEEG study feasible. DMT dosage was adjusted to elicit an effective psychedelic experience (ca. 20-30 mg for N,N-DMT; 2-5 mg for synthetic 5-MeO-DMT, and 30-40 mg for the Bufo 5-MeO-DMT material). Healthy volunteers (age 25-60; N=15 men, N=8 women) were tested. The protocol consisted of: 5-10 min. baseline control (resting eyes closed) was first acquired, followed by the DMT test condition, usually lasting 5-15 min. When subjects recovered from the DMT induced altered state, a report of their subjective experience was recorded on video and a post recovery EEG reading was made typically at 15-30 min. A statistical comparison (paired t-tests, correlated samples) of absolute power values for all EEG bands between baseline vs. DMT tests and post recovery conditions was carried out for all subjects. The DMT-induced profound alterations in consciousness were tracked with the shifts in the QEEG metrics analysed. The time course and intensity of the subjective experience correlated with the magnitude of the observed EEG effects. www.cosmosandhistory.org 115
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Background The aim of this study was to systematically summarize knowledge on the association between exposure to interpersonal trauma and addictive behaviors. Extant reviews on this association focused on a restricted range of substance-related addictions, and/or used a narrative instead of a systematic approach. Methods Systematic searches of 8 databases yielded 29,841 studies, of which 3054 studies were included and subsequently classified in relation to study design (scoping review). A subset of observational studies (N = 181) prospectively investigating the relationship between exposure to interpersonal traumata and subsequent behavioral or substance-related addiction problems were characterized. Heterogeneity in study methodologies and types of addictive behaviors and traumatic experiences assessed precluded meta-analysis. Instead, the proportions of associations tested in this literature that revealed positive, negative, or null relationships between trauma exposure and subsequent addictive behaviors were recorded, along with other methodological features. Results Of 3054 included studies, 70.7% (n = 2160) used a cross-sectional design. In the 181 prospective observational studies (407,041 participants, 98.8% recruited from developed countries), 35.1% of the tested associations between trauma exposure and later addictive behaviors was positive, 1.3% was negative, and 63.6% was non-significant. These results were primarily obtained among non-treatment seeking samples (80.7% of studies; n = 146), using single and multi-item measures of addictive behaviors of unknown psychometric quality (46.4% of studies). Positive associations were more frequently observed in studies examining childhood versus adult traumatization (39.7% vs. 29.7%). Conclusions Longitudinal research in this area emphasizes alcohol abuse, and almost no research has examined behavioral addictions. Results provide some support for a positive association between exposure to interpersonal trauma and subsequent addictive behaviors but this relationship was not consistently reported. Longitudinal studies typically assessed trauma exposure retrospectively, often after addictive behavior onset, thus precluding robust inferences about whether traumatization affects initial onset of addictive behaviors. Electronic supplementary material The online version of this article (doi:10.1186/s12888-017-1323-1) contains supplementary material, which is available to authorized users.
Poster
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Background : 5-MeO-DMT is a potent tryptamine found in high concentrations in the venom of the Colorado River Toad. Practical experience suggests that vaporized 5-MeO-DMT may induce mystical experiences that are relatively brief, yet have comparable or greater intensity than those induced by psilocybin. Quantitative evaluations of 5-MeO-DMT induced mystical experiences have not yet been published. Methods : Study participants were patients (n = 44, 61% male, M age = 34.6 yrs.) from a clinic in Mexico that utilizes 5-MeO-DMT as part of addiction and psychospiritual clinical treatment protocols. All patients received vaporized organic/toadsource 5-MeO-DMT at the median effective dose (50mg raw weight, estimated 5-MeO-DMT content = 57mg, Metzner, 2013). All patients completed the States of Consciousness Questionnaire (SOCQ) 24 hours following treatment. The SOCQ contains all items of the Mystical Experience Questionnaire (MEQ30) (Barrett et al., 2015; Griffiths et al., 2006). Results : The mean endorsement on the MEQ30 following 5-MeO-DMT was 75.5 percent (sd = 16.5) of the maximum possible total score, suggestive of mysticaltype experiences in the sample. A majority of patients (61.4%) had “a complete mystical experience” ( > 60% of the maximum possible score on all MEQ30 subscales: mystical, positive mood, space/time, ineffability). Overall, the MEQ30 exhibited excellent internal consistency (α = .96). Several SOCQ items not contained in the MEQ30 were also endorsed as “strong” or “extreme” by twothirds or more of the sample and included: experiencing overflowing energy and radiant/golden light, and feeling universal or infinite love, closeness with guides, and a hyperreal sense of consciousness (7566% of sample). Significance: The mystical experience occasioned by the 5-MeO-DMT containing toad venom was consistent with MEQ30 ratings with moderate to high psilocybin doses (2030mg/ 70kg) administered in prior research (Barrett, Johnson, & Griffiths, 2015). The short duration of action of 5MeODMT may be advantageous for clinical and psychospiritual interventions.
Poster
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Human studies on the efficacy of ibogaine in interrupting substance use disorders are limited, and studies on the long-term outcomes are even fewer. Therefore, we designed the current retrospective study to evaluate the subjective effectiveness of ibogaine treatment on problematic opioid consumption, and the long-term associations of treatment with psychological functioning. Using an online data collection procedure, 88 patients who had completed ibogaine treatment at Crossroads Treatment Center between 2011 and 2015 completed our survey. The majority of the sample (72%) had used opioids for four years or more, and 69% had used 30/30 days in the month leading up to treatment. Most participants (80%) indicated that ibogaine treatment eliminated or drastically reduced their withdrawal symptoms, and 50% indicated that ibogaine reduced their craving, for at least one week, and 25% of these participants indicated that it lasted for three months or more. In terms of opioid use following treatment, 30% reported that they never returned to using opioids, 54% of these abstainers had maintained abstinence for at least one year, and 31% of them for at least two years following ibogaine treatment. Additionally, 48% reported that, although they returned to using opioids after treatment, their use had decreased from pre-treatment consumption levels. Treatment response was negatively correlated with depression and anxiety symptoms, and positively correlated with subjective well-being at the time of survey. Specifically, those who never used opioids again statistically had the lowest rates of depressive, anxious, and stress symptoms and the highest levels of subjective well-being at the time of the survey. Taken together, these results suggest that ibogaine is effective at reducing and ameliorating problematic opioid consumption and has long-term positive psychological outcomes in a meaningful proportion of opioid users. Future research should investigate the efficacy of ibogaine treatment using rigorous longitudinal and controlled treatment designs.
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Plant-based psychedelics such as psilocybin have an ancient history of medicinal use. After the first English-language report on LSD in 1950, psychedelics enjoyed a short-lived relationship with psychology and psychiatry. Used most notably as aides to psychotherapy for the treatment of mood disorders and alcohol dependence, drugs such as LSD showed initial therapeutic promise before prohibitive legislature in the mid-1960s effectively ended all major psychedelic research programmes. Since the early 1990s, there has been a steady revival of human psychedelic research: last year saw reports on the first modern brain imaging study with LSD and 3 separate clinical trials of psilocybin for depressive symptoms. In this Circumspective piece, Robin Carhart-Harris and Guy Goodwin share their opinions on the promises and pitfalls of renewed psychedelic research, with a focus on the development of psilocybin as a treatment for depression.Neuropsychopharmacology accepted article preview online, 26 April 2017. doi:10.1038/npp.2017.84.
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Background: The psychoactive indole alkaloid ibogaine has been associated with encouraging treatment outcomes for opioid dependence. The legal status of ibogaine in New Zealand provides a unique opportunity to evaluate durability of treatment outcomes. Objective: To examine longitudinal treatment effects over a 12-month period among individuals receiving legal ibogaine treatment for opioid dependence. Method: This observational study measured addiction severity as the primary outcome in 14 participants (50% female) over 12 months post-treatment using the Addiction Severity Index-Lite (ASI-Lite) following a single ibogaine treatment by either of two treatment providers. Secondary effects on depression were assessed via the Beck Depression Inventory-II (BDI-II). The Subjective Opioid Withdrawal Scale (SOWS) was collected before and immediately after treatment to measure opioid withdrawal symptoms. Results: Nonparametric comparisons via Friedman Test between baseline and 12-month follow-up for participants completing all interviews (n = 8) showed a significant reduction for the ASI-Lite drug use (p = 0.002) composite score. Reductions in BDI-II scores from baseline to 12-month follow-up were also significant (p < 0.001). Significant reductions in SOWS scores for all participants (n = 14) were also observed acutely after treatment (p = 0.015). Patients with partial data (n = 4) also showed reductions in ASI-Lite drug use scores and family/social status problems. One patient enrolled in the study died during treatment. Conclusion: A single ibogaine treatment reduced opioid withdrawal symptoms and achieved opioid cessation or sustained reduced use in dependent individuals as measured over 12 months. Ibogaine’s legal availability in New Zealand may offer improved outcomes where legislation supports treatment providers to work closely with other health professionals.
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Background Worldwide, alcohol abuse is a burgeoning problem. Abstinence is key to allow recovery of physical and mental health as well as quality of life, but treatment for alcohol dependence is associated with high relapse rates. Preliminary data have suggested that a combined repeated ketamine and psychological therapy programme may be effective in reducing relapse in severe alcohol use disorder. This non-commercial proof-of-concept trial is aimed at making a preliminary assessment of the effectiveness of this combined treatment in this patient group. Methods/designThis is a phase II, randomised, double-blind, placebo-controlled, parallel-group clinical trial taking place in two sites in the UK: the South West of England and London. Ninety-six recently detoxified alcoholics, with comorbid depressive symptoms, will be randomised to one of four treatment arms. Patients will receive either three sessions of ketamine (0.8 mg/kg administered intravenously (IV) over 40 minutes) or placebo (50 ml saline 0.9% IV over 40 minutes) plus either seven sessions of manualised psychological therapy or an alcohol education control. Patients will be assessed at 3 and 6 months on a range of psychological and biological variables. The primary endpoints are (1) relapse rates at 6 months and (2) percentage days abstinent at 6 months. Secondary endpoints include 3 and 6 month percentage days abstinence, tolerability (indicated by dropout), adverse events, depressive symptoms, craving and quality of life. DiscussionThis study will provide important information on a new combined psychological and pharmacological intervention aimed at reducing relapse rates in alcoholics. The findings would have broad application given the worldwide prevalence of alcoholism and its associated medical, psychological and social problems. Trial registrationClinicalTrials.gov, NCT02649231. Registered on 5 January 2016.
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Background: Substance use disorders are important contributors to the global burden of disease, but current treatments are not associated with high rates of recovery. The lack of approved and effective treatments is acutely problematic for psychostimulants like cocaine and crack cocaine. One promising alternative in the treatment of drug dependence in general and psychostimulants in particular is the use of the psychedelic alkaloid ibogaine combined with psychotherapy. This was recently shown to induce prolonged periods of abstinence in polydrug users, including psychostimulants. However, drug dependence treatments cannot be comprehensively evaluated with reductions in consumption alone, with current recommendations including secondary outcome measures like craving, family and social relationship, quality of life, and self-efficacy. Methods: We therefore employed a directed approach to qualitative content analysis to evaluate the outcomes of a treatment combining ibogaine with cognitive-behavioral therapy based on data gathered from patient’s reports obtained in semi-structured interviews. Main findings: The results revealed that patients benefited from the treatment in all the secondary outcomes, reporting decreases in craving and improvements in personal relationships, quality of life, and self-efficacy, thus supporting existing notions that treatments combining ibogaine and psychotherapy do have a therapeutic potential in the treatment of substance use disorders
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Alcohol dependence is a chronic relapsing illness. Alcohol and stress cues have consistently been shown to increase craving and relapse risk in recovering alcohol-dependent (AUD) patients. However, differences in functional connectivity in response to these cues have not been studied using data-driven approaches. Here, voxel-wise connectivity is used in a whole-brain investigation of functional connectivity differences associated with alcohol and stress cues and to examine whether these differences are related to subsequent relapse. In Study 1, 45, 4- to 8-week abstinent, recovering AUD patients underwent functional magnetic resonance imaging during individualized imagery of alcohol, stress, and neutral cues. Relapse measures were collected prospectively for 90days post-discharge from inpatient treatment. AUD patients showed blunted anterior (ACC), mid (MCC) and posterior cingulate cortex (PCC), voxel-wise connectivity responses to stress compared to neutral cues and blunted PCC response to alcohol compared to neutral cues. Using Cox proportional hazard regression, weaker connectivity in ACC and MCC during neutral exposure was associated with longer time to relapse (better recovery outcome). Similarly, greater connectivity in PCC during alcohol-cue compared to stress cue was associated with longer time to relapse. In Study 2, a sub-group of 30 AUD patients were demographically-matched to 30 healthy control (HC) participants for group comparisons. AUD compared to HC participants showed reduced cingulate connectivity during alcohol and stress cues. Using novel data-driven approaches, the cingulate cortex emerged as a key region in the disruption of functional connectivity during alcohol and stress-cue processing in AUD patients and as a marker of subsequent alcohol relapse.
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Previous studies suggest that serotonin (5-HT) might interact with brain-derived neurotrophic factor (BDNF) during the stress response. However, the relationship between 5-HT and BDNF expression under purely psychological stress is unclear. In this study, one hour before psychological stress exposure, the 5-HT1A receptor agonist 8-OH-DPAT or antagonist MDL73005, or the 5-HT2A receptor agonist DOI or antagonist ketanserin were administered to rats exposed to psychological stress. Immunohistochemistry and in situ hybridization revealed that after psychological stress, with the exception of the ventral tegmental area, BDNF protein and mRNA expression levels were higher in the 5-HT1A and the 5-HT2A receptor agonist groups compared with the solvent control no-stress or psychological stress group in the CA1 and CA3 of the hippocampus, prefrontal cortex, central amygdaloid nucleus, dorsomedial hypothalamic nucleus, dentate gyrus, shell of the nucleus accumbens and the midbrain periaqueductal gray. There was no significant difference between the two agonist groups. In contrast, after stress exposure, BDNF protein and mRNA expression levels were lower in the 5-HT1A and 5-HT2A receptor antagonist groups than in the solvent control non-stress group, with the exception of the ventral tegmental area. Our findings suggest that 5-HT regulates BDNF expression in a rat model of acute psychological stress.
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Little is known about how emotion dysregulation (ED) and trauma exposure differentially affect the relationship between abuse in childhood and adult substance use. We examined associations between child abuse, trauma exposure, ED, and current substance use in an already existing dataset. Participants (N = 2,014 adults, 90% African American) had been recruited from an urban hospital for a parent study. Analyses showed that drug and alcohol use was significantly positively correlated with child abuse (emotional, physical, and sexual), later trauma exposure, and ED (all ps < .001). Linear regression showed that exposure to abuse when older than a child was significantly associated with drug and alcohol use independent of child abuse and demographic variables (R2Δ = .08, p < .001; R2Δ = .04, p < .001). ED was significantly associated with drug and alcohol use independently of child abuse, nonabuse trauma, and demographic variables (R2Δ = .02, p < .001; R2Δ = .04, p < .001). Multiple mediation analyses showed that ED and later trauma exposure accounted for variance in the association between emotional abuse and substance use (p < .001). A better understanding of vulnerabilities to additional traumatization and emotion-regulation deficits in individuals who have been exposed to child abuse and in addition have comorbid substance use problems may inform treatments that lead to improved outcomes.
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Introduction: Evidence based treatment for Substance use disorders (SUD) includes psychotherapy and pharmacotherapy. However, these are only partially effective. Hallucinogens, such as psilocybin, may represent potential new treatment options for SUD. This review provides a summary of (human) studies on the putative therapeutic effects of psilocybin, and discusses the receptor systems, brain regions and cognitive and emotional processes mediating psilocybin's effects. Psilocybin's chemical structure is similar to that of serotonin. Dysregulations in the serotonin system are associated with alterations in stress hormones, such as cortisol, and mood disorders. After psilocybin administration cortisol levels spike and activate the executive control network, with subsequent increased control over emotional processes, and relief of negative thinking and persistent negative emotions. Preliminary data of ongoing alcohol and smoking addiction studies in humans shows promising effects of psilocybin administration on substance use. Importantly, psilocybin has a low risk of toxicity and dependence and can be used safely under controlled clinical conditions. Areas covered: This paper is a narrative review based on the search terms: psilocybin, substance use disorder, addiction, depression, serotonin. Literature on potential efficacy and mechanisms of action of psilocybin in SUD is discussed. Expert commentary: Recent positive findings with psilocybin need confirmation in well-designed placebo controlled randomized trials employing a large sample size.
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Over the past three decades, insights into the role of the cerebellum in emotional processing have substantially increased. Indeed, methodological refinements in cerebellar lesion studies and major technological advancements in the field of neuroscience are in particular responsible to an exponential growth of knowledge on the topic. It is timely to review the available data and to critically evaluate the current status of the role of the cerebellum in emotion and related domains. The main aim of this article is to present an overview of current facts and ongoing debates relating to clinical, neuroimaging, and neurophysiological findings on the role of the cerebellum in key aspects of emotion. Experts in the field of cerebellar research discuss the range of cerebellar contributions to emotion in nine topics. Topics include the role of the cerebellum in perception and recognition, forwarding and encoding of emotional information, and the experience and regulation of emotional states in relation to motor, cognitive, and social behaviors. In addition, perspectives including cerebellar involvement in emotional learning, pain, emotional aspects of speech, and neuropsychiatric aspects of the cerebellum in mood disorders are briefly discussed. Results of this consensus paper illustrate how theory and empirical research have converged to produce a composite picture of brain topography, physiology, and function that establishes the role of the cerebellum in many aspects of emotional processing.
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Alcohol addiction is a debilitating disorder producing maladaptive changes in the brain, leading drinkers to become more sensitive to stress and anxiety. These changes are key factors contributing to alcohol craving and maintaining a persistent vulnerability to relapse. Serotonin (5-Hydroxytryptamine, 5-HT) is a monoamine neurotransmitter widely expressed in the central nervous system where it plays an important role in the regulation of mood. The serotonin system has been extensively implicated in the regulation of stress and anxiety, as well as the reinforcing properties of all of the major classes of drugs of abuse, including alcohol. Dysregulation within the 5-HT system has been postulated to underlie the negative mood states associated with alcohol use disorders. This review will describe the serotonergic (5-HTergic) neuroplastic changes observed in animal models throughout the alcohol addiction cycle, from prenatal to adulthood exposure. The first section will focus on alcohol-induced 5-HTergic neuroadaptations in offspring prenatally exposed to alcohol and the consequences on the regulation of stress/anxiety. The second section will compare alterations in 5-HT signalling induced by acute or chronic alcohol exposure during adulthood and following alcohol withdrawal, highlighting the impact on the regulation of stress/anxiety signalling pathways. The third section will outline 5-HTergic neuroadaptations observed in various genetically-selected ethanol preferring rat lines. Finally, we will discuss the pharmacological manipulation of the 5-HTergic system on ethanol- and anxiety/stress-related behaviours demonstrated by clinical trials, with an emphasis on current and potential treatments.
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Substance use disorders (SUD) and posttraumatic stress disorder (PTSD) are chronic, debilitating conditions that frequently co-occur. Individuals with co-occurring SUD and PTSD suffer a more complicated course of treatment and less favorable treatment outcomes compared to individuals with either disorder alone. The development of effective psychosocial and pharmacological interventions for co-occurring SUD and PTSD is an active and critically important area of investigation. Several integrated psychosocial treatments for co-occurring SUD and PTSD have demonstrated promising outcomes. While recent studies examining medications to treat co-occurring SUD and PTSD have yielded encouraging findings, there remain substantial gaps in the evidence base regarding the treatment of co-occurring SUD and PTSD. This review will summarize the findings from clinical trials targeting a reduction in SUD and PTSD symptoms simultaneously. These results may improve our knowledge base and subsequently enhance our ability to develop effective interventions for this complex comorbid condition.
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Background: Psilocybin is a serotonin receptor agonist that occurs naturally in some mushroom species. Recent studies have assessed the therapeutic potential of psilocybin for various conditions, including end-of-life anxiety, obsessive-compulsive disorder, and smoking and alcohol dependence, with promising preliminary results. Here, we aimed to investigate the feasibility, safety, and efficacy of psilocybin in patients with unipolar treatment-resistant depression. Methods: In this open-label feasibility trial, 12 patients (six men, six women) with moderate-to-severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 mg and 25 mg, 7 days apart) in a supportive setting. There was no control group. Psychological support was provided before, during, and after each session. The primary outcome measure for feasibility was patient-reported intensity of psilocybin's effects. Patients were monitored for adverse reactions during the dosing sessions and subsequent clinic and remote follow-up. Depressive symptoms were assessed with standard assessments from 1 week to 3 months after treatment, with the 16-item Quick Inventory of Depressive Symptoms (QIDS) serving as the primary efficacy outcome. This trial is registered with ISRCTN, number ISRCTN14426797. Findings: Psilocybin's acute psychedelic effects typically became detectable 30-60 min after dosing, peaked 2-3 h after dosing, and subsided to negligible levels at least 6 h after dosing. Mean self-rated intensity (on a 0-1 scale) was 0·51 (SD 0·36) for the low-dose session and 0·75 (SD 0·27) for the high-dose session. Psilocybin was well tolerated by all of the patients, and no serious or unexpected adverse events occurred. The adverse reactions we noted were transient anxiety during drug onset (all patients), transient confusion or thought disorder (nine patients), mild and transient nausea (four patients), and transient headache (four patients). Relative to baseline, depressive symptoms were markedly reduced 1 week (mean QIDS difference -11·8, 95% CI -9·15 to -14·35, p=0·002, Hedges' g=3·1) and 3 months (-9·2, 95% CI -5·69 to -12·71, p=0·003, Hedges' g=2) after high-dose treatment. Marked and sustained improvements in anxiety and anhedonia were also noted. Interpretation: This study provides preliminary support for the safety and efficacy of psilocybin for treatment-resistant depression and motivates further trials, with more rigorous designs, to better examine the therapeutic potential of this approach. Funding: Medical Research Council.
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Sigma receptors are usually classified as a separate class of intracellular receptors. Among them the sigma-1 receptor has been the most studied regarding its pharmacological applications. This receptor with average or high affinity binds a wide range of chemical compounds of very different structural classes and a variety of therapeutic and pharmacological properties. The sigma-1 receptor is a trans-membrane protein placed in the endoplasmic reticulum (ER), which regulates the function of inositol-3-phosphate receptor, stabilizing the calcium signaling between ER and mitochondria. There are studies that the sigma-1 receptor is involved in the formation of many neurological and psychiatric conditions. It is assumed that the sigma-1 receptor acts as a sensor of normal calcium operation. The studies over the recent years have shown the role of the violation in calcium signaling in the pathogenesis of Alzheimer's and Huntington's diseases. In particular, changes in calcium homeostasis of the endoplasmic reticulum lead to the break of synaptic connections in the neurons. Thus, the sigma-1 receptor holds promise in application as a potential therapeutic target for the treatment of neuropathological diseases.
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Recent open label trials show that psychedelics, such as ayahuasca, hold promise as fast-onset antidepressants in treatment-resistant depression. In order to further test the antidepressant effects of ayahuasca, we conducted a parallel-arm, double-blind randomized placebo-controlled trial in 29 patients with treatment-resistant depression. Patients received a single dose of either ayahuasca or placebo. Changes in depression severity were assessed with the Montgomery–Åsberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating scale (HAM-D). Assessments were made at baseline, and at one (D1), two (D2) and seven (D7) days after dosing. We observed significant antidepressant effects of ayahuasca when compared to placebo at all timepoints. MADRS scores were significantly lower in the ayahuasca group compared to placebo (at D1 and D2: p=0.04; and at D7: p<0.0001). Between-group effect sizes increased from D1 to D7 (D1: Cohen’ s d=0.84; D2: Cohen’ s d=0.84; D7: Cohen’ s d=1.49). Response rates were high for both groups at D1 and D2, and significantly higher in the ayahuasca group at D7 (64% vs. 27%; p=0.04), while remission rate was marginally significant at D7 (36% vs. 7%, p=0.054). To our knowledge, this is the first controlled trial to test a psychedelic substance in treatment-resistant depression. Overall, this study brings new evidence supporting the safety and therapeutic value of ayahuasca, dosed within an appropriate setting, to help treat depression.
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We examined persisting effects, self-perceived challenges, and potential benefits associated with positive outcomes following ibogaine detoxification using data collected as part of a larger online retrospective study of patients (n=73) who received treatment for chronic opioid use in Mexico between 2012 and 2015. A mixed-methods design was used comparing treatment responders versus non-responders, as well as content coding of themes from open-ended questions. Most participants reported positive persisting effects of ibogaine detoxification (e.g., enhanced personal sense of gratitude and authenticity, and meaning and appreciation for life). Compared to non-responders, treatment responders endorsed greater persisting changes in their ability to tolerate difficult/painful feelings, capacity for coping with stress, and reduced unhealthy anger. Treatment responders reported greater change in subjective levels of inner peace, joy, feelings of love/openheartedness, and experiences of sacredness in life. Qualitative analyses revealed that treatment responders reported a heightened sense of spiritual awareness and greater connection to their intra/inter-personal relationships after ibogaine detoxification. Notable challenges of ibogaine detoxification included psychological and health-related difficulties during treatment and challenges with post-treatment integration. Findings highlight the persisting effects associated with positive response to ibogaine detoxification and possible post-treatment needs (i.e., more integration/aftercare resources). Future research using rigorous experimental designs is needed.
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Background/aim: 5-Methoxy- N,N-dimethyltryptamine (5-MeO-DMT) is a psychoactive compound found in several plants and in high concentrations in Bufo alvarius toad venom. Synthetic, toad, and plant-sourced 5-MeO-DMT are used for spiritual and recreational purposes and may have psychotherapeutic effects. However, the use of 5-MeO-DMT is not well understood. Therefore, we examined patterns of use, motivations for consumption, subjective effects, and potential benefits and consequences associated with 5-MeO-DMT use. Methods: Using internet-based advertisements, 515 respondents ( Mage=35.4. SD=11.7; male=79%; White/Caucasian=86%; United States resident=42%) completed a web-based survey. Results: Most respondents consumed 5-MeO-DMT infrequently (<once/year), for spiritual exploration, and had used less than four times in their lifetime. The majority (average of 90%) reported moderate-to-strong mystical-type experiences ( Mintensity=3.64, SD=1.11; range 0-5; e.g., ineffability, timelessness, awe/amazement, experience of pure being/awareness), and relatively fewer (average of 37%) experienced very slight challenging experiences ( Mintensity=0.95, SD=0.91; range 0-5; e.g., anxiousness, fear). Less than half (39%) reported repeated consumption during the same session, and very few reported drug craving/desire (8%), or legal (1%), medical (1%), or psychiatric (1%) problems related to use. Furthermore, of those who reported being diagnosed with psychiatric disorders, the majority reported improvements in symptoms following 5-MeO-DMT use, including improvements related to post-traumatic stress disorder (79%), depression (77%), anxiety (69%), and alcoholism (66%) or drug use disorder (60%). Conclusion: Findings suggest that 5-MeO-DMT is used infrequently, predominantly for spiritual exploration, has low potential for addiction, and might have psychotherapeutic effects. Future research should examine the safety and pharmacokinetics of 5-MeO-DMT administration in humans using rigorous experimental designs.
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The investigation of psychosocial factors in relation to opiate addiction is limited and typically uses binary measures to assess how incidences of childhood trauma correlate with addiction. There has also been a lack of enquiry into how experiences of noninterpersonal versus interpersonal trauma may impact drug use addiction. In this regard, the current study utilized a novel measurement of interpersonal versus noninterpersonal lifetime trauma and a scale assessing severity of childhood trauma to examine how these factors may impact patients with opioid addiction. The interaction between these factors and current perceived stress was also examined. Thirty-six opioid-dependent individuals (recruited from the Drug Health Services and Opioid Treatment Program at the Royal Prince Alfred Hospital in Sydney, Australia) and 33 healthy controls completed the Childhood Maltreatment Questionnaire, Lifetime Trauma Survey, and Perceived Levels of Stress Scale. The patient group reported significantly greater childhood trauma severity, more incidences of lifetime trauma, and higher perceived stress than controls. Logistic regression analyses indicated that the severity of childhood trauma was more strongly associated with addiction status than perceived stress. A greater number of lifetime trauma incidence was the best predictor of addiction. Contrary to expectations, noninterpersonal lifetime trauma was a better predictor of addiction status than was interpersonal lifetime trauma. Results suggest that lifetime trauma and childhood trauma may play an important factor in opioid addiction over what can be accounted for by stress.
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Growing evidence suggests that glutamate neurotransmission plays a critical role in alcohol addiction. Cue-induced change of glutamate has been observed in animal studies but never been investigated in humans. This work investigates cue-induced change in forebrain glutamate in individuals with alcohol use disorder (AUD). A total of 35 subjects (17 individuals with AUD and 18 healthy controls) participated in this study. The glutamate concentration was measured with single-voxel 1H-MR spectroscopy at the dorsal anterior cingulate. Two MRS sessions were performed in succession, the first to establish basal glutamate levels and the second to measure the change in response to alcohol cues. The changes in glutamate were quantified for both AUD subjects and controls. A mixed model ANOVA and t-tests were performed for statistical analysis. ANOVA revealed a main effect of cue-induced decrease of glutamate level in the anterior cingulate cortex (ACC). A significant interaction revealed that only AUD subjects showed significant decrease of glutamate in the ACC. There were no significant group differences in the level of basal glutamate. However, a negative correlation was found between the basal glutamate level and the number of drinking days in the past 2 weeks for the AUD subjects. Collectively, our results indicate that glutamate in key areas of the forebrain reward circuit is modulated by alcohol cues in early alcohol dependence.
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5-MeO-DMT is a natural hallucinogen acting as serotonin 5-HT1A/5-HT2A receptor agonist. Its ability to evoke hallucinations could be used to study the neurobiology of psychotic symptoms and to identify new treatment targets. Moreover, recent studies revealed the therapeutic potential of serotonin hallucinogens in treating mood and anxiety disorders. Our previous results in anesthetized animals show that 5-MeO-DMT alters cortical activity via 5-HT1A and 5-HT2A receptors. Here, we examined 5-MeO-DMT effects on oscillatory activity in prefrontal (PFC) and visual (V1) cortices, and in mediodorsal thalamus (MD) of freely-moving wild-type (WT) and 5-HT2A-R knockout (KO2A) mice. We performed local field potential multi-recordings evaluating the power at different frequency bands and coherence between areas. We also examined the prevention of 5-MeO-DMT effects by the 5-HT1A-R antagonist WAY-100635. 5-MeO-DMT affected oscillatory activity more in cortical than in thalamic areas. More marked effects were observed in delta power in V1 of KO2A mice. 5-MeO-DMT increased beta band coherence between all examined areas. In KO2A mice, WAY100635 prevented most of 5-MeO-DMT effects on oscillatory activity. The present results indicate that hallucinatory activity of 5-MeO-DMT is likely mediated by simultaneous alteration of prefrontal and visual activities. The prevention of these effects by WAY-100635 in KO2A mice supports the potential usefulness of 5-HT1A receptor antagonists to treat visual hallucinations. 5-MeO-DMT effects on PFC theta activity and cortico-thalamic coherence may be related to its antidepressant activity.
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Alcohol use disorder represents a serious clinical, social and personal burden on its sufferers and a significant financial strain on society. Current treatments, both psychological and pharmacological are poor, with high rates of relapse after medical detoxification and dedicated treatment programs. The earliest historical roots of psychedelic drug-assisted psychotherapy in the 1950s were associated with Lysergic acid diethylamide (LSD)-assisted psychotherapy to treat what was then called, alcoholism. But results were varied and psychedelic therapy with LSD and other 'classical' psychedelics fell out of favour in the wake of socio-political pressures and cultural changes. A current revisiting of psychedelic clinical research is now targeting substance use disorders - and particularly alcohol use disorder - again. 3,4-Methylenedioxymethamphetamine (MDMA)-assisted psychotherapy has never been formally explored as a treatment for any form of substance use disorder. But in recent years MDMA has risen in prominence as an agent to treat posttraumatic stress disorder (PTSD). With its unique receptor profile and a relatively well-tolerated subjective experience of drug effects when used clinically, MDMA Therapy is ideally suited to allow a patient to explore and address painful memories without being overwhelmed by negative affect. Given that alcohol use disorder is so often associated with early traumatic experiences, the author is proposing in a current on-going UK-based study that patients with alcohol use disorder who have undergone a medical detoxification from alcohol might benefit from a course of MDMA-assisted psychotherapy.
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Psychedelic drugs, such as lysergic acid diethylamide (LSD), mescaline, and psilocybin, exert profound effects on brain and behavior. After decades of difficulties in studying these compounds, psychedelics are again being tested as potential treatments for intractable biomedical disorders. Preclinical research of psychedelics complements human neuroimaging studies and pilot clinical trials, suggesting these compounds as promising treatments for addiction, depression, anxiety, and other conditions. However, many questions regarding the mechanisms of action, safety, and efficacy of psychedelics remain. Here, we summarize recent preclinical and clinical data in this field, discuss their pharmacological mechanisms of action, and outline critical areas for future studies of psychedelic drugs, with the goal of maximizing the potential benefits of translational psychedelic biomedicine to patients.
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Background and aims: Very few studies have reported the effectiveness of ibogaine as a treatment for chronic opioid use. Therefore, this study evaluated the acute subjective effects of ibogaine, outcomes on problematic opioid consumption, and the long-term associations with psychological functioning. Methods: Using online data collection, 88 patients who received ibogaine treatment in Mexico between 2012 and 2015 completed our survey. Results: Most participants (72%) had used opioids for at least 4 years and 69% reported daily use. Most (80%) indicated that ibogaine eliminated or drastically reduced withdrawal symptoms. Fifty percent reported that ibogaine reduced opioid craving, some (25%) reporting a reduction in craving lasting at least 3 months. Thirty percent of participants reported never using opioids again following ibogaine treatment. And over one half (54%) of these abstainers had been abstinent for at least 1 year, with 31% abstinent for at least 2 years. At the time of survey, 41% of all participants reported sustained abstinence (>6 months). Although 70% of the total sample reported a relapse following treatment, 48% reported decreased use from pretreatment levels and an additional 11% eventually achieved abstinence. Treatment responders had the lowest rates of depressive and anxious symptoms, the highest levels of subjective well-being and rated their ibogaine treatment as more spiritually meaningful compared with treatment non-responders. Conclusion: The results suggest that ibogaine is associated with reductions in opioid use, including complete abstinence, and has long-term positive psychological outcomes. Future research should investigate the efficacy of ibogaine treatment using rigorous longitudinal and controlled designs.
Article
A disorder of metamemory, expressed as unawareness of mnemonic ability, is typically associated with the profound amnesia of Korsakoff’s Syndrome (KS). A similar but less severe type of limited awareness can also occur in non-KS alcoholism and is observed as an impairment in generating Feeling-of-Knowing (FOK) predictions about future recognition performance. We previously found that FOK accuracy was selectively related to volumes of the insula in alcoholics involved in the present study. Unknown, however, are the neural substrates of unawareness of memory impairment in alcoholism. A task-activated fMRI paradigm served to identify neural nodes and networks implicated in inaccurate self-estimation of mnemonic ability in sober alcoholics while they made prospective FOK judgments in an episodic memory paradigm. Lower activation in the right insula correlated with greater overestimations of future memory abilities in alcoholics. Weaker connectivity of the right insula with the left dorsal anterior cingulate cortex, a node of the salience network, and stronger connectivity of the right insula with the right ventromedial prefrontal cortex, a node of the default mode network (DMN), co-occurred in alcoholics relative to the controls. Specifically, alcoholics, who failed to desynchronize insula-vmPFC activity, had greater overestimation of their memory predictions and poorer recognition performance. This study provides novel support that deviant functional activation and connectivity involving the right insula, a hub of the salience network, appears to participate in disrupting metamemory functioning in alcoholics. Compromised FOK performance might result from disturbance of the switching mechanism between brain networks serving self-referential processes (i.e., DMN network) and networks serving externally-driven activities like memory monitoring (i.e., fronto-parietal network). Thus, compromise in insular network coupling could be a neural mechanism underlying anosognosia for subtle mnemonic impairment in nonamnesic alcoholism.
Chapter
This chapter begins with a brief review of descriptions and definitions of mystical-type experiences and the historical connection between classic hallucinogens and mystical experiences. The chapter then explores the empirical literature on experiences with classic hallucinogens in which claims about mystical or religious experiences have been made. A psychometrically validated questionnaire is described for the reliable measurement of mystical-type experiences occasioned by classic hallucinogens. Controlled laboratory studies show that under double-blind conditions that provide significant controls for expectancy bias, psilocybin can occasion complete mystical experiences in the majority of people studied. These effects are dose-dependent, specific to psilocybin compared to placebo or a psychoactive control substance, and have enduring impact on the moods, attitudes, and behaviors of participants as assessed by self-report of participants and ratings by community observers. Other studies suggest that enduring personal meaning in healthy volunteers and therapeutic outcomes in patients, including reduction and cessation of substance abuse behaviors and reduction of anxiety and depression in patients with a life-threatening cancer diagnosis, are related to the occurrence of mystical experiences during drug sessions. The final sections of the chapter draw parallels in human neuroscience research between the neural bases of experiences with classic hallucinogens and the neural bases of meditative practices for which claims of mystical-type experience are sometimes made. From these parallels, a functional neural model of mystical experience is proposed, based on changes in the default mode network of the brain that have been observed after the administration of classic hallucinogens and during meditation practices for which mystical-type claims have been made.
Article
Psychedelic drugs have historically been used for ritualistic purposes and to help individuals gain insight. Ibogaine, a naturally occurring psychoactive substance, has been reported to have anti-addictive properties that aid in the treatment of substance use disorders. An online survey obtained retrospective data from individuals who used ibogaine in the past. Individuals who used ibogaine tended to describe thematically similar experiences post-treatment. This study adds to the literature by using the 5d-ASC, a psychometrically sound measure of altered states of consciousness (ASCs), to examine the ASCs induced by ibogaine and discusses the demographic characteristics of those who seek ibogaine treatment (N = 27). The study also examined several aspects of ibogaine treatment experience, including reasons for seeking treatment, course of treatment, and treatment outcome. Results indicated a positive correlation between the various dimensions of the ASCs and the outcome (ability to make changes in one’s life, cravings, and how changed the person was as a result of ibogaine treatment). While this study is limited in generalizability due to high attrition and low sample size, it deepens the understanding of the phenomenological experience of ibogaine and explores the possible utility of ibogaine in the treatment of substance use disorders.
Chapter
Iboga alkaloids are a particular class of indolomonoterpenes most often characterized by an isoquinuclidine nucleus. Their first occurrence was detected in the roots of Tabernanthe iboga, a sacred plant to the people of Gabon, which made it cult object. Ibogaine is the main representative of this class of alkaloids and its psychoactive properties are well documented. It has been proposed as a drug cessation treatment and has a wide range of activities in targeting opioids, cocaine, and alcohol. The purpose of this chapter is to provide a background on this molecule and related compounds and to update knowledge on the most recent advances made. Difficulties linked to the status of ibogaine as a drug in several countries have hampered its development, but 18-methoxycoronaridine is currently under evaluation for the same purposes and for the treatment of leishmaniasis. The chapter is divided into six parts: an introduction aiming at defining what is called an iboga alkaloid, and this is followed by current knowledge on their biosynthesis, which unfortunately remains a “black box” as far as the key construction step is concerned. Many of these alkaloids are still being discovered and the third and fourth parts of the chapter discuss the analytical tools in use for this purpose and give lists of new monomeric and dimeric alkaloids belonging to this class. When necessary, the structures are discussed especially with regard to absolute configuration determinations, which remain a point of weakness in their assignments. Part V gives an account of progress made in the synthesis, partial and total, which the authors believe is key to providing solid solutions to the industrial development of the most promising molecules. The last part of the chapter is devoted to the biological properties of iboga alkaloids, with particular emphasis on ibogaine and 18-methoxycoronaridine.
Article
Objective: To estimate the rate and severity of traumatic brain injury (TBI) among people with co-occurring mental health and substance use disorders and to compare demographic, diagnostic, and institutionalization differences between those who screen positive or negative. Setting: Outpatient community mental health center in Washington, District of Columbia. Participants: A total of 295 people with co-occurring mental health and substance use disorders enrolled in a prospective study of integrated treatment of substance abuse. Design: Cross-sectional baseline assessment. Main measures: The Ohio State University TBI Identification Method. Standardized measures assessed psychiatric diagnoses, symptom severity, current and lifetime substance use, and history of institutionalization. Results: Eighty percent screened positive for TBI, and 25% reported at least 1 moderate or severe TBI. TBI was associated with current alcohol use and psychiatric symptom severity and with lifetime institutionalization and homelessness. It was more common among participants with posttraumatic stress disorder, borderline personality disorder, and antisocial personality disorder. Men (vs women) and participants with psychotic disorders (vs those with mood disorders) had an earlier age of first TBI with loss of consciousness. Conclusion: TBI is common among people with co-occurring mental health and substance use disorders. Repeated and serious TBIs are common in this population. Failure to detect TBI in people with co-occurring disorders who are seeking integrated treatment could lead to misdiagnosis and inappropriately targeted treatment and rehabilitation.
Article
Among learning and memory processes, fear memories are crucial in some psychiatric disorders like post-traumatic stress disorder (PTSD). Accumulating evidence shows that the sigma-1 receptor (Sig-1R) has comprehensive involvement in cognitive impairment and neuroprotective effects. It has also been reported that BDNF appears to enhance extinction of fear in anxiety disorders via the MAPK signaling cascade. However, it remains unclear whether BDNF-TrkB-MAPK pathway may be mechanistically involved in the therapeutic effect of sigma-1 receptor in the development of PTSD. To address this question, rats were subjected to a classical single-prolonged stress procedure (SPS) and kept undisturbed for 7 days. After that, rats were re-stressed by re-exposure to the forced swim component of SPS (RSPS). Behavior tests were subsequently performed to assess anxiety and cognitive impairments. Furthermore, we analyzed the expression of BDNF and the phosphorylation of TrkB and three MAPK pathways, namely, the ERK, JNK and p38. We found that the levels of BDNF and p-TrkB were increased following the RSPS procedure, which were reversed by the administration of PRE-084. Meanwhile, among the three MAPK signaling pathways, only the p-ERK expression was increased following the RSPS procedure. Collectively, our results indicate that BDNF-TrkB-ERK signaling pathway may be involved in the activation of sigma-1 receptor to yield therapeutic benefits for PTSD.
Article
Ethnopharmacological relevance: Root bark from Tabernanthe iboga has been used traditionally in West Africa as a psychoactive substance in religious rituals. In smaller doses it is reported anecdotally to have stimulant properties. Aim of the study: To evaluate the influence of a single 20mg ibogaine dose on psychological variables reflecting subjective mood state and a range of cognitive functions. Materials and methods: 21 healthy male volunteers received single 20mg doses of ibogaine after 6 days pretreatment with double-blind paroxetine or placebo. We compared responses to a battery of psychometric tests and subjective mood ratings performed before and 2h after ibogaine dosing, and assessed relationships between changes in test scores and concentrations of active moiety (the sum of molar noribogaine and ibogaine concentrations). Psychological tests were chosen based on responsiveness to opioid and serotonergic ligands. Results: Ibogaine had minimal influence on psychological tests and mood ratings. The ability to selectively ignore distracting spatial information showed some evidence of modulation; however because this effect was limited to the less challenging condition calls into question the reliability of this result. Conclusion: We were unable to identify stimulant effects after single 20mg doses of ibogaine. Future research is needed to confirm whether active moiety concentrations impact selective attention abilities while leaving other cognitive functions and mood state unaffected.
Article
Current pharmacological treatments for alcohol dependence have focused on reducing alcohol consumption, but to date there are few treatments that also address the negative affective symptoms during acute and protracted alcohol withdrawal which are often exacerbated in people with comorbid anxiety and depression. Selective serotonin reuptake inhibitors (SSRIs) are sometimes prescribed to ameliorate these symptoms but can exacerbate anxiety and cravings in a select group of patients. In this critical review, we discuss recent literature describing an association between alcohol dependence, the SERT linked polymorphic region (5-HTTLPR), and pharmacological response to SSRIs. Given the heterogeneity in responsiveness to serotonergic drugs across the spectrum of alcoholic subtypes, we assess the contribution of specific 5-HT circuits to discrete endophenotypes of alcohol dependence. 5-HT circuits play a distinctive role in reward, stress, and executive function which may account for the variation in response to serotonergic drugs. New optogenetic and chemogenetic methods for dissecting 5-HT circuits in alcohol dependence may provide clues leading to more effective pharmacotherapies. Although our current understanding of the role of 5-HT systems in alcohol dependence is incomplete, there is some evidence to suggest that 5-HT3 receptor antagonists are effective in people with the L/L genotype of the 5-HTTLPR polymorphism while SSRIs may be more beneficial to people with the S/L or S/S genotype. Studies that assess the impact of serotonin transporter polymorphisms on 5-HT circuit function and the subsequent development of alcohol use disorders will be an important step forward in treating alcohol dependence.
Chapter
Alcohol addiction is a costly and detrimental chronic relapsing disorder, characterized by compulsive alcohol use despite the negative consequences; it is thought to be associated with aberrant learning and memory processes. The NMDA-type glutamate receptor (NMDAR) plays an essential role in synaptic plasticity and learning and memory. Not surprisingly, it is well established that the NMDAR is a major target of alcohol (ethanol) in the brain and has been implicated in ethanol-associated phenotypes such as tolerance, dependence, withdrawal, craving, and relapse. This chapter focuses on studies elucidating molecular mechanisms that underlie ethanol’s actions on the NMDAR, and discusses the physiological and behavioral consequences of ethanol’s actions. Finally, we summarize information regarding the potential use of modulators of NMDAR function as medication to treat the adverse effects of alcoholism.