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Substance Use Disorder

Dimethyltryptamine: Endogenous Role and Therapeutic Potential.

April 25, 2019 / Anxiety Disorders / PTSD, Depressive Disorders, DMT, Papers, Psychology, Publications, Substance Use Disorder / By / , ,

Abstract

N, N-dimethyltryptamine (DMT) is an indole alkaloid produced by a number of plants and animals, including humans. Its psychoactive effects were first described in 1956 by Stephen Szára, but have been exploited for centuries by South American indigenous populations in the form of ayahuasca. In the present review, we assess the state of the art regarding a putative role for endogenous DMT and potential clinical applications of ayahuasca and DMT. A review assessing the pharmacological profile of DMT and its clinical effects in humans was performed using the PubMed data base until 5 August 2018 with the words: ayahuasca and N,N-dimethyltryptamine. While the role of endogenous DMT remains unclear, ayahuasca has promising results in anxiety, depression and substance dependence. Since ayahuasca has a good safety profile, it is crucial to conduct further research aimed at developing new treatments for psychiatric disorders.
Rodrigues, A. V., Almeida, F. J., & Vieira-Coelho, M. A. (2019). Dimethyltryptamine: endogenous role and therapeutic potential. Journal of psychoactive drugs, 1-12., https://doi.org/10.1080/02791072.2019.1602291
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Serotonin transporter-ibogaine complexes illuminate mechanisms of inhibition and transport

April 24, 2019 / Anxiety Disorders / PTSD, Iboga / Ibogaine, Neuroscience, Papers, Publications, Substance Use Disorder / By / , , , , ,

Abstract

The serotonin transporter (SERT) regulates neurotransmitter homeostasis through the sodium- and chloride-dependent recycling of serotonin into presynaptic neurons. Major depression and anxiety disorders are treated using selective serotonin reuptake inhibitors-small molecules that competitively block substrate binding and thereby prolong neurotransmitter action. The dopamine and noradrenaline transporters, together with SERT, are members of the neurotransmitter sodium symporter (NSS) family. The transport activities of NSSs can be inhibited or modulated by cocaine and amphetamines, and genetic variants of NSSs are associated with several neuropsychiatric disorders including attention deficit hyperactivity disorder, autism and bipolar disorder. Studies of bacterial NSS homologues-including LeuT-have shown how their transmembrane helices (TMs) undergo conformational changes during the transport cycle, exposing a central binding site to either side of the membrane. However, the conformational changes associated with transport in NSSs remain unknown. To elucidate structure-based mechanisms for transport in SERT we investigated its complexes with ibogaine, a hallucinogenic natural product with psychoactive and anti-addictive properties. Notably, ibogaine is a non-competitive inhibitor of transport but displays competitive binding towards selective serotonin reuptake inhibitors. Here we report cryo-electron microscopy structures of SERT-ibogaine complexes captured in outward-open, occluded and inward-open conformations. Ibogaine binds to the central binding site, and closure of the extracellular gate largely involves movements of TMs 1b and 6a. Opening of the intracellular gate involves a hinge-like movement of TM1a and the partial unwinding of TM5, which together create a permeation pathway that enables substrate and ion diffusion to the cytoplasm. These structures define the structural rearrangements that occur from the outward-open to inward-open conformations, and provide insight into the mechanism of neurotransmitter transport and ibogaine inhibition.

Coleman, J. A., Yang, D., Zhao, Z., Wen, P. C., Yoshioka, C., Tajkhorshid, E., & Gouaux, E. (2019). Serotonin transporter–ibogaine complexes illuminate mechanisms of inhibition and transport. Nature, 569(7754), 141., 10.1038/s41586-019-1135-1
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Ibogaine and Subjective Experience: Transformative States and Psychopharmacotherapy in the Treatment of Opioid Use Disorder

April 9, 2019 / Iboga / Ibogaine, Papers, Psychology, Publications, Substance Use Disorder / By / , ,

Abstract

This article examines the therapeutic potential of ibogaine, a powerful oneiric alkaloid derived from Tabernanthe iboga, through exploring the subjective experiences of 44 participants from two observational treatment studies for opioid use disorder. Following treatment with ibogaine HCl, the participants (Mexico, n = 30; New Zealand, n = 14) completed the States of Consciousness Questionnaire (SCQ) to quantify the magnitude of their psychotropic experience. Participants were asked to provide written transcripts of their experiences, with those supplied being analyzed thematically through an iterative process, to produce a set of coded themes. Mean SCQ scores in many domains exceeded 0.6, the cutoff score for a “complete mystical experience,” with 43% of participants achieving this in more than five of seven domains. Qualitative data described multiple phenomenological themes, including auditory and visual phenomena. Ibogaine’s strong oneiric action promoted cyclic visions leading to confronting realizations involving remorse and regret for participants’ actions towards others, but also release from feelings of guilt and worthlessness. Many participants reported feeling a sense of spiritual transformation. We propose that the reported experiences support the meaningfulness of ibogaine’s oneiric effects as a discrete element in its capacity for healing, which is distinct from pharmacological actions associated with reduced withdrawal and craving.

Brown, T. K., Noller, G. E., & Denenberg, J. O. (2019). Ibogaine and Subjective Experience: Transformative States and Psychopharmacotherapy in the Treatment of Opioid Use Disorder. Journal of psychoactive drugs, 1-11., https://doi.org/10.1080/02791072.2019.1598603
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A Review of 3,4-methylenedioxymethamphetamine (MDMA)-Assisted Psychotherapy.

March 20, 2019 / Anxiety Disorders / PTSD, MDMA, Papers, Psychology, Publications, Substance Use Disorder / By / , ,

Abstract

This paper provides a brief review of the history, proposed pharmacological mechanisms, safety issues, and clinical applications of the medicine 3,4-methylenedioxymethamphetamine (MDMA). Most clinical MDMA research in patients to date has focused on MDMA-assisted psychotherapy to treat posttraumatic stress disorder (PTSD). In this review paper other potential therapeutic applications for MDMA therapy are described, including contemporary studies treating anxiety associated with autism and the authors’ ongoing study exploring the potential role for MDMA-assisted psychotherapy to treat alcohol use disorder. MDMA therapy for PTSD is now entering the final Phase 3 stage of drug development, with a target set for licensing by the FDA and EMA in 2021. This means that if clinical efficacy criteria are achieved, MDMA would become a medicine.
Sessa, B., Higbed, L., & Nutt, D. (2019). A Review of 3, 4-methylenedioxymethamphetamine (MDMA)-Assisted Psychotherapy. Frontiers in Psychiatry, 10, 138., https://doi.org/10.3389/fpsyt.2019.00138
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Ibogaine Administration Modifies GDNF and BDNF Expression in Brain Regions Involved in Mesocorticolimbic and Nigral Dopaminergic Circuits.

March 5, 2019 / Iboga / Ibogaine, Neuroscience, Papers, Psychology, Publications, Substance Use Disorder / By / , , , , , ,

Abstract

Ibogaine is an atypical psychedelic alkaloid, which has been subject of research due to its reported ability to attenuate drug-seeking behavior. Recent work has suggested that ibogaine effects on alcohol self-administration in rats are related to the release of Glial cell Derived Neurotrophic Factor (GDNF) in the Ventral Tegmental Area (VTA), a mesencephalic region which hosts the soma of dopaminergic neurons. Although previous reports have shown ibogaine’s ability to induce GDNF expression in rat midbrain, there are no studies addressing its effect on the expression of GDNF and other neurotrophic factors (NFs) such as Brain Derived Neurotrophic Factor (BDNF) or Nerve Growth Factor (NGF) in distinct brain regions containing dopaminergic neurons. In this work, we examined the effect of ibogaine acute administration on the expression of these NFs in the VTA, Prefrontal Cortex (PFC), Nucleus Accumbens (NAcc) and the Substantia Nigra (SN). Rats were i.p. treated with ibogaine 20 mg/kg (I20), 40 mg/kg (I40) or vehicle, and NFs expression was analyzed after 3 and 24 h. At 24 h an increase of the expression of the NFs transcripts was observed in a site and dose dependent manner. Only for I40, GDNF was selectively upregulated in the VTA and SN. Both doses elicited a large increase in the expression of BDNF transcripts in the NAcc, SN and PFC, while in the VTA a significant effect was found only for I40. Finally, NGF mRNA was upregulated in all regions after I40, while I20 showed a selective upregulation in PFC and VTA. Regarding protein levels, an increase of GDNF was observed in the VTA only for I40 but no significant increase for BDNF was found in all the studied areas. Interestingly, an increase of proBDNF was detected in the NAcc for both doses. These results show for the first time a selective increase of GDNF specifically in the VTA for I40 but not for I20 after 24 h of administration, which agrees with the effective dose found in previous self-administration studies in rodents. Further research is needed to understand the contribution of these changes to ibogaine’s ability to attenuate drug-seeking behavior.
Marton, S., González, B., Rodríguez, S., Miquel, E., Martínez-Palma, L., Pazos, M., … & Scorza, C. (2019). Ibogaine administration modifies GDNF and BDNF expression in brain regions involved in mesocorticolimbic and nigral dopaminergic circuits. Frontiers in pharmacology, 10, 193., https://doi.org/10.3389/fphar.2019.00193
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The tripping point: The potential role of psychedelic-assisted therapy in the response to the opioid crisis

February 7, 2019 / Papers, Psychology, Publications, Substance Use Disorder / By / , ,

Abstract

The increasing contamination of the drug supply with illicitly manufactured fentanyl and related analogs in North America has resulted in the most severe drug-overdose crisis in history. Available pharmacotherapy options for the treatment of opioid use disorder have had limited success in curbing the current crisis, and a growing body of evidence highlights the need for innovative interventions that target underlying social-structural drivers of opioid use disorder. Re-emerging clinical research suggests that psychedelic-assisted therapy has potential as an alternative treatment for refractory substance use disorders and related comorbidities. Based on the available evidence, our viewpoint supports advancing research on the potential role of psychedelic-assisted therapy within a multifaceted response to the opioid crisis.

Argento, E., Tupper, K. W., & Socias, M. E. (2019). The tripping point: The potential role of psychedelic-assisted therapy in the response to the opioid crisis. International Journal of Drug Policy, 66, 80-81., 10.1016/j.drugpo.2018.11.006
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A systematic study of microdosing psychedelics

February 6, 2019 / Anxiety Disorders / PTSD, Ayahuasca, Depressive Disorders, DMT, Iboga / Ibogaine, Mescaline / Cacti, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications, Substance Use Disorder / By / ,

Abstract

The phenomenon of ‘microdosing’, that is, regular ingestion of very small quantities of psychedelic substances, has seen a rapid explosion of popularity in recent years. Individuals who microdose report minimal acute effects from these substances yet claim a range of long-term general health and wellbeing benefits. There have been no published empirical studies of microdosing and the current legal and bureaucratic climate makes direct empirical investigation of the effects of psychedelics difficult. In Study One we conducted a systematic, observational investigation of individuals who microdose. We tracked the experiences of 98 microdosing participants, who provided daily ratings of psychological functioning over a six week period. 63 of these additionally completed a battery of psychometric measures tapping mood, attention, wellbeing, mystical experiences, personality, creativity, and sense of agency, at baseline and at completion of the study. Analyses of daily ratings revealed a general increase in reported psychological functioning across all measures on dosing days but limited evidence of residual effects on following days. Analyses of pre and post study measures revealed reductions in reported levels of depression and stress; lower levels of distractibility; increased absorption; and increased neuroticism. To better understand these findings, in Study Two we investigated pre-existing beliefs and expectations about the effects of microdosing in a sample of 263 naïve and experienced microdosers, so as to gauge expectancy bias. All participants believed that microdosing would have large and wide-ranging benefits in contrast to the limited outcomes reported by actual microdosers. Notably, the effects believed most likely to change were unrelated to the observed pattern of reported outcomes. The current results suggest that dose controlled empirical research on the impacts of microdosing on mental health and attentional capabilities are needed.

Polito, V., & Stevenson, R. J. (2019). A systematic study of microdosing psychedelics. PloS one, 14(2), e0211023., 10.1371/journal.pone.0211023.
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How effective and safe is medical cannabis as a treatment of mental disorders? A systematic review.

January 31, 2019 / Anxiety Disorders / PTSD, Papers, Psychology, Psychotic Disorders, Publications, Substance Use Disorder / By / , , , , ,

Abstract

We conducted a review of systematic reviews (SRs) and randomized-controlled trials (RCTs) to analyze efficacy and safety of cannabis-based medication in patients with mental disorders. Five data bases were systematically searched (2006-August 2018); 4 SRs (of 11 RCTs) and 14 RCTs (1629 participants) were included. Diagnoses were: dementia, cannabis and opioid dependence, psychoses/schizophrenia, general social anxiety, posttraumatic stress disorder, anorexia nervosa, attention-deficit hyperactivity disorder, and Tourette`s disorder. Outcome variables were too heterogeneous to conduct a  meta-analysis. A narrative synthesis method was applied. The study quality was assessed using the risk-of-bias tool and SIGN-checklists. THC- and CBD-based medicines, given as adjunct to pharmaco- and psychotherapy, were associated with improvements of several symptoms of mental disorders, but not with remission. Side effects occurred, but severe adverse effects were mentioned in single cases only. In order to provide reliable treatment recommendations, more and larger RCTs with follow-up assessments, consistent outcome measures and active comparisons are needed.
Hoch, E., Niemann, D., von Keller, R., Schneider, M., Friemel, C. M., Preuss, U. W., … & Pogarell, O. (2019). How effective and safe is medical cannabis as a treatment of mental disorders? A systematic review. European archives of psychiatry and clinical neuroscience, 269(1), 87-105., https://doi.org/10.1007/s00406-019-00984-4
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Effects of acute and repeated treatment with serotonin 5-HT2A receptor agonist hallucinogens on intracranial self-stimulation in rats

January 10, 2019 / Depressive Disorders, LSD, Mescaline / Cacti, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications, Substance Use Disorder / By / , , , , ,

Abstract

The prototype 5-HT2A receptor agonist hallucinogens LSD, mescaline, and psilocybin are classified as Schedule 1 drugs of abuse by the U.S. Drug Enforcement Administration. Accumulating clinical evidence has also suggested that acute or repeated “microdosing” with these drugs may have utility for treatment of some mental health disorders, including drug abuse and depression. The goal of the present study was to evaluate LSD, mescaline, and psilocybin effects on intracranial self-stimulation (ICSS), a procedure that has been used to evaluate abuse-related effects of other classes of abused drugs. Effects of repeated LSD were also examined to evaluate potential changes in its own effects on ICSS or changes in effects produced by the abused psychostimulant methamphetamine or the prodepressant kappa opioid receptor (KOR) agonist U69,593. Male Sprague-Dawley rats were implanted with microelectrodes targeting the medial forebrain bundle and trained to respond under a “frequency-rate” ICSS procedure, in which many drugs of abuse increase (or “facilitate”) ICSS. In acute dose-effect and time-course studies, evidence for abuse-related ICSS facilitation was weak and inconsistent; the predominant effect of all 3 drugs was dose- and time-dependent ICSS depression. Repeated LSD treatment failed to alter either its own ICSS depressant effects or the abuse-related effects of methamphetamine; however, repeated LSD did attenuate ICSS depression by U69,593. These results extend those of previous preclinical studies to suggest weak expression of abuse-related effects by 5-HT2A agonist hallucinogens and provide supportive evidence for therapeutic effects of repeated LSD dosing to attenuate KOR-mediated depressant effects but not abuse potential of psychostimulants.

Sakloth, F., Leggett, E., Moerke, M. J., Townsend, E. A., Banks, M. L., & Negus, S. S. (2019). Effects of acute and repeated treatment with serotonin 5-HT2A receptor agonist hallucinogens on intracranial self-stimulation in rats. Experimental and clinical psychopharmacology., 10.1037/pha0000253.
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Association of Combined Naltrexone and Ketamine With Depressive Symptoms in a Case series of Patients With Depression and Alcohol Use Disorder

January 9, 2019 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychiatry & Medicine, Publications, Substance Use Disorder / By / , ,

Abstract

Ketamine has rapid and robust antidepressant effects. However, there are concerns about the abuse liability of ketamine. This concern was heightened recently owing to a preliminary report suggesting that antidepressant effects of ketamine might be dependent on opiate receptor stimulation. Below, we present pilot data that indicate that the antidepressant effects of ketamine are not attenuated by naltrexone pretreatment. As a result, the combination of opiate receptor antagonism with ketamine might be a strategy to reduce addiction risk among patients with depression at risk for substance abuse.

Yoon, G., Petrakis, I. L., & Krystal, J. H. (2019). Association of Combined Naltrexone and Ketamine With Depressive Symptoms in a Case series of Patients With Depression and Alcohol Use Disorder. JAMA psychiatry., 10.1001/jamapsychiatry.2018.3990.
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