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How toxic is ibogaine?

Abstract

CONTEXT:

Ibogaine is a psychoactive indole alkaloid found in the African rainforest shrub Tabernanthe Iboga. It is unlicensed but used in the treatment of drug and alcohol addiction. However, reports of ibogaine’s toxicity are cause for concern.

OBJECTIVES:

To review ibogaine’s pharmacokinetics and pharmacodynamics, mechanisms of action and reported toxicity.

METHODS:

A search of the literature available on PubMed was done, using the keywords “ibogaine” and “noribogaine”. The search criteria were “mechanism of action”, “pharmacokinetics”, “pharmacodynamics”, “neurotransmitters”, “toxicology”, “toxicity”, “cardiac”, “neurotoxic”, “human data”, “animal data”, “addiction”, “anti-addictive”, “withdrawal”, “death” and “fatalities”. The searches identified 382 unique references, of which 156 involved human data. Further research revealed 14 detailed toxicological case reports. Pharmacokinetics and pharmacodynamics: Ibogaine is metabolized mainly by CYP2D6 to the primary metabolite noribogaine (10-hydroxyibogamine). Noribogaine is present in clinically relevant concentrations for days, long after ibogaine has been cleared. Mechanisms of action: Ibogaine and noribogaine interact with multiple neurotransmitter systems. They show micromolar affinity for N-methyl-D-aspartate (NMDA), κ- and μ-opioid receptors and sigma-2 receptor sites. Furthermore, ibogaine has been shown to interact with the acetylcholine, serotonin and dopamine systems; it alters the expression of several proteins including substance P, brain-derived neurotrophic factor (BDNF), c-fos and egr-1. Neurotoxicity: Neurodegeneration was shown in rats, probably mediated by stimulation of the inferior olive, which has excitotoxic effects on Purkinje cells in the cerebellum. Neurotoxic effects of ibogaine may not be directly relevant to its anti-addictive properties, as no signs of neurotoxicity were found following doses lower than 25 mg/kg intra-peritoneal in rats. Noribogaine might be less neurotoxic than ibogaine. Cardiotoxicity: Ether-a-go-go-related gene (hERG) potassium channels in the heart might play a crucial role in ibogaine’s cardiotoxicity, as hERG channels are vital in the repolarization phase of cardiac action potentials and blockade by ibogaine delays this repolarization, resulting in QT (time interval between the start of the Q wave and the end of the T wave in the electrical cycle of the heart) interval prolongation and, subsequently, in arrhythmias and sudden cardiac arrest. Twenty-seven fatalities have been reported following the ingestion of ibogaine, and pre-existing cardiovascular conditions have been implicated in the death of individuals for which post-mortem data were available. However, in this review, 8 case reports are presented which suggest that ibogaine caused ventricular tachyarrhythmias and prolongation of the QT interval in individuals without any pre-existing cardiovascular condition or family history. Noribogaine appears at least as harmful to cardiac functioning as ibogaine. Toxicity from drug-drug interaction: Polymorphism in the CYP2D6 enzyme can influence blood concentrations of both ibogaine and its primary metabolite, which may have implications when a patient is taking other medication that is subject to significant CYP2D6 metabolism.

CONCLUSIONS:

Alternative therapists and drug users are still using iboga extract, root scrapings, and ibogaine hydrochloride to treat drug addiction. With limited medical supervision, these are risky experiments and more ibogaine-related deaths are likely to occur, particularly in those with pre-existing cardiac conditions and those taking concurrent medications.

Litjens, R. P., & Brunt, T. M. (2016). How toxic is ibogaine?. Clinical Toxicology, 1-6. http://dx.doi.org/10.3109/15563650.2016.1138226
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Influence of caffeine on 3,4-methylenedioxymethamphetamine-induced dopaminergic neuron degeneration and neuroinflammation is age-dependent

Abstract

Previous studies have demonstrated that caffeine administration to adult mice potentiates glial activation induced by 3,4-methylenedioxymethamphetamine (MDMA). As neuroinflammatory response seems to correlate with neurodegeneration, and the young brain is particularly vulnerable to neurotoxicity, we evaluated dopamine neuron degeneration and glial activation in the caudate-putamen (CPu) and substantia nigra pars compacta (SNc) of adolescent and adult mice. Mice were treated with MDMA (4 × 20 mg/kg), alone or with caffeine (10 mg/kg). Interleukin (IL)-1β, tumor necrosis factor (TNF)-α, neuronal nitric oxide synthase (nNOS) were evaluated in CPu, whereas tyrosine hydroxylase (TH), glial fibrillary acidic protein, and CD11b were evaluated in CPu and SNc by immunohistochemistry. MDMA decreased TH in SNc of both adolescent and adult mice, whereas TH-positive fibers in CPu were only decreased in adults. In CPu of adolescent mice, caffeine potentiated MDMA-induced glial fibrillary acidic protein without altering CD11b, whereas in SNc caffeine did not influence MDMA-induced glial activation. nNOS, IL-1β, and TNF-α were increased by MDMA in CPu of adults, whereas in adolescents, levels were only elevated after combined MDMA plus caffeine. Caffeine alone modified only nNOS. Results suggest that the use of MDMA in association with caffeine during adolescence may exacerbate the neurotoxicity and neuroinflammation elicited by MDMA. Previous studies have demonstrated that caffeine potentiated glial activation induced by 3,4-methylenedioxymethamphetamine (MDMA) in adult mice. In this study, caffeine was shown to potentiate MDMA-induced dopamine neuron degeneration in substantia nigra pars compacta, astrogliosis, and TNF-α levels in caudate-putamen of adolescent mice. Results suggest that combined use of MDMA plus caffeine during adolescence may worsen the neurotoxicity and neuroinflammation elicited by MDMA.

Frau, L., Costa, G., Porceddu, P. F., Khairnar, A., Castelli, M. P., Ennas, M. G., … & Morelli, M. (2016). Influence of caffeine on 3, 4‐methylenedioxymethamphetamine‐induced dopaminergic neuron degeneration and neuroinflammation is age‐dependent. Journal of neurochemistry, 136(1), 148-162. http://dx.doi.org/10.1111/jnc.13377

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Neuroimaging in moderate MDMA use: A systematic review

Abstract

MDMA (“ecstasy”) is widely used as a recreational drug, although there has been some debate about its neurotoxic effects in humans. However, most studies have investigated subjects with heavy use patterns, and the effects of transient MDMA use are unclear. In this review, we therefore focus on subjects with moderate use patterns, in order to assess the evidence for harmful effects. We searched for studies applying neuroimaging techniques in man. Studies were included if they provided at least one group with an average of <50 lifetime episodes of ecstasy use or an average lifetime consumption of <100 ecstasy tablets. All studies published before July 2015 were included. Of the 250 studies identified in the database search, 19 were included.

There is no convincing evidence that moderate MDMA use is associated with structural or functional brain alterations in neuroimaging measures. The lack of significant results was associated with high methodological heterogeneity in terms of dosages and co-consumption of other drugs, low quality of studies and small sample sizes.

Mueller, F., Lenz, C., Steiner, M., Dolder, P. C., Walter, M., Lang, U. E., … & Borgwardt, S. (2016). Neuroimaging in moderate MDMA use: A systematic review. Neuroscience & Biobehavioral Reviews, 62, 21-34. http://dx.doi.org/10.1016/j.neubiorev.2015.12.010
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“Herbal seizures” – atypical symptoms after ibogaine intoxication: a case report

Abstract

INTRODUCTION:

Misuse of various new psychotropic substances such as ibogaine is increasing rapidly. Knowledge of their negative side effects is sparse.

CASE PRESENTATION:

We present a case of intoxication with the herbal substance ibogaine in a 22-year-old white man. After taking a cumulative dose of 38 g (taken in two doses), he developed visual memories, nausea and vomiting. He developed a generalized tonic-clonic seizure with additional grand mal seizures. He was treated with midazolam and levetiracetam. Extended drug screenings and computed tomography and magnetic resonance imaging findings were all negative.

CONCLUSIONS:

Knowledge of the side effects of ibogaine has mainly come from reports of cardiovascular complications; seizures are rarely mentioned and experimental findings are inconsistent. It seems that ibogaine acts like a proconvulsive drug at high doses.

Breuer, L., Kasper, B. S., Schwarze, B., Gschossmann, J. M., Kornhuber, J., & Müller, H. H. (2015). “Herbal seizures”–atypical symptoms after ibogaine intoxication: a case report. Journal of medical case reports, 9(1), 1-5. http://dx.doi.org/10.1186/s13256-015-0731-4
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"Herbal seizures" – atypical symptoms after ibogaine intoxication: a case report

Abstract

INTRODUCTION:

Misuse of various new psychotropic substances such as ibogaine is increasing rapidly. Knowledge of their negative side effects is sparse.

CASE PRESENTATION:

We present a case of intoxication with the herbal substance ibogaine in a 22-year-old white man. After taking a cumulative dose of 38 g (taken in two doses), he developed visual memories, nausea and vomiting. He developed a generalized tonic-clonic seizure with additional grand mal seizures. He was treated with midazolam and levetiracetam. Extended drug screenings and computed tomography and magnetic resonance imaging findings were all negative.

CONCLUSIONS:

Knowledge of the side effects of ibogaine has mainly come from reports of cardiovascular complications; seizures are rarely mentioned and experimental findings are inconsistent. It seems that ibogaine acts like a proconvulsive drug at high doses.

Breuer, L., Kasper, B. S., Schwarze, B., Gschossmann, J. M., Kornhuber, J., & Müller, H. H. (2015). “Herbal seizures”–atypical symptoms after ibogaine intoxication: a case report. Journal of medical case reports, 9(1), 1-5. http://dx.doi.org/10.1186/s13256-015-0731-4
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Psychedelic medicine: a re-emerging therapeutic paradigm

Introduction

In clinical research settings around the world, renewed investigations are taking place on the use of psychedelic substances for treating illnesses such as addiction, depression, anxiety and posttraumatic stress disorder (PTSD). Since the termination of a period of research from the 1950s to the early 1970s, most psychedelic substances have been classified as “drugs of abuse” with no recognized medical value. However, controlled clinical studies have recently been conducted to assess the basic psychopharmacological properties and therapeutic efficacy of these drugs as adjuncts to existing psychotherapeutic approaches. Central to this revival is the re-emergence of a paradigm that acknowledges the importance of set (i.e., psychological expectations), setting (i.e., physical environment) and the therapeutic clinician–patient relationship as critical elements for facilitating healing experiences and realizing positive outcomes [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][…]
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Yensen, R., & Johnson, M. W. (2015). Psychedelic medicine: a re-emerging therapeutic paradigm. https://dx.doi.org/
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Entheogens, Society, and Law – Towards a Politics of Consciousness, Autonomy and Responsibility

Entheogens, Society & Law: Towards a Politics of Consciousness, Autonomy & Responsibility by Daniel Waterman, edited by Casey William Hardison, Melrose Books, 2013.

Psychoactive substances are strongly intertwined with society. They produce highly subjective effects, and are simultaneously highly politicized. Likewise, the cultural and societal context determines to a large extent the content and interpretation of the experience. Daniel Waterman’s ‘Entheogens, Society & Law’ is about this interplay. In his book, he discusses the interrelation of consciousness and ethics and argues that a reconsideration of regulatory choices is necessary for a more beneficial way of dealing with these substances. It is a broad-ranging book that addresses a large variety of subjects.

After a brief personal introduction, Waterman shows how the way we talk about psychoactive substances influences not just the experience, but also its interpretation and whether the outcome is beneficial. Similarly, he argues that law stratifies such beliefs we hold about psychoactive substances and that this in turn influences both the way we see them and the way we see ourselves.

The second chapter is an elaboration on the different ways in which psychoactives have been conceptualised throughout history, and the results of these conceptualisations. Drugs and drug users have many faces and Waterman gives a thorough analysis of all the different roles they play within society, both positive and negative. He shows the complexity of these concepts and how many different interpretations are possible. This analysis contributes to a fuller understanding of psychedelics and the psychedelic experience and has not been published elsewhere to such an extent.

In the third chapter we find a large section on the work of Professor Jan Bastiaans, a Dutch psychiatrist who treated people suffering from what was then called ‘concentration camp syndrome’ with LSD. Concentration camp syndrome would later be incorporated into the more recent category PTSD. Bastiaans was educated in classical psychoanalysis and went on to apply these techniques in psychedelic therapy. In the late eighties, Bastiaans would come into disregard for not maintaining proper archives, preventing anyone from evaluating the effectiveness of his treatment. Although largely based on the work of Stephen Snelders and the biography by Bram Enning, this book provides one of the first extensive reviews of Bastiaans’ work in English and it is a welcome addition to the historical study of psychedelic research.

The book continues with a section on the transpersonal psychology of Stanislav Grof. While a giant in the field, Grof is not often compared and contrasted to his predecessors, starting with Sigmund Freud and his heirs Carl Jung, Otto Rank and Wilhelm Reich, and with peers like Abraham Maslow. This comparison helps us understand Grof as part of a lineage of psychoanalysts. By placing Grof in this lineage, we can see how he both learned from his tradition and elaborated upon it by working intensively with LSD in the Czech Republic and the US.

In his final chapter, the author shows how the transpersonal experience is central to a variety of religions and argues that these experiences help people integrate on a personal and social level. In that sense, Waterman posits, they are the epitome of ethics itself, because they require us to take responsibility for our actions on a grander scale. Conversely, prohibiting (some ways to achieve) such experiences prevents people from becoming more conscious and, consequently, more compassionate and kind.

The book is not neutral and doesn’t claim to be. Both author and editor are outspoken proponents of cognitive liberty and the freedom to alter consciousness. However, their claims are supported by relevant research and their political stance is rooted in a strong tradition of scientific research and philosophical thought, although conservatives might label it as radical.

The book does have flaws, the biggest of which is that it is often unclear where the argument is taking the reader. Because many subjects are dealt with extensively, it is easy to lose track of the line of reasoning. More elaboration on how digressions fit in with the general argument would have allowed for a more focused book. As it stands, the book’s topics, while interesting in themselves, often remain unconnected. The effect is that the reader has to piece the argument together himself, which makes for a sometimes challenging read, requiring a strong focus on the part of the reader.

Another flaw is that some ideas are explained in both footnotes and in the main text. This unnecessary repetition, along with some mistakes and sloppiness in the footnotes, stain an otherwise well annotated text. Both these issues should have been mended in the editorial process.

But there are enough diamonds in the rough. This book broadens one’s perspective well beyond the boundaries of what is normally found within the literature on psychedelics. The author discusses many questions that are usually left unanswered and still manages to fit everything together. It is a book for those interested in the interplay between how we think about altered states and the substances that induce them, how this influences the experience, and how these feedback loops influence the way we deal with them as a society.

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Developmental outcomes of 3,4-methylenedioxymethamphetamine (ecstasy)-exposed infants in the UK

Abstract

OBJECTIVE: This paper aims to review findings from a longitudinal study of prenatal methylenedioxymethamphetamine (MDMA, “ecstasy”) on infant development.

METHODS: In a prospective, longitudinal cohort design, we followed 28 MDMA-exposed and 68 non-MDMA-exposed infants from birth to 2 years of age. Women recruited voluntarily into a study of recreational drug use during pregnancy were interviewed to obtain type, frequency, and amount of recreational drug use. Their children were followed for a 2-year period after birth. A large number of drug and environmental covariates were controlled. Infants were seen at 1, 4, 12, 18, and 24 months using standardized normative tests of mental and motor development.

RESULTS: There were no differences between MDMA-exposed and non-MDMA-exposed infants at birth except that MDMA-exposed infants were more likely to be male. Motor delays were evident in MDMA infants at each age and amount of MDMA exposure predicted motor deficits at 12 months in a dose-dependent fashion.

CONCLUSIONS: Prenatal MDMA exposure is related to fine and gross motor delays in the first 2 years of life. Follow-up studies are needed to determine long-term effects.

Singer, L. T., Moore, D. G., Min, M. O., Goodwin, J., Turner, J. J., Fulton, S., & Parrott, A. C. (2015). Developmental outcomes of 3, 4‐methylenedioxymethamphetamine (ecstasy)‐exposed infants in the UK. Human Psychopharmacology: Clinical and Experimental, 30(4), 290-294. http://dx.doi.org/0.1002/hup.2459

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Ayahuasca Alters Structural Parameters of the Rat Aorta

Abstract

Ayahuasca is a hallucinogenic brew traditionally used by Northwestern Amazonian indigenous groups for therapeutic purposes. It is prepared by the decoction of Banisteriopsis caapi with the leaves of Psychotria viridis. Banisteriopsis caapi contains β-carbolines that are inhibitors of monoamine oxidase and P. viris is rich in dimethyltryptamine, a 5-HT1A/2A/2C agonist. Acute ayahuasca administration produces moderate cardiovascular effects in healthy volunteers, but information regarding long-term use is lacking. This study investigated the effects of ayahuasca (2–4 mL/kg) in the rat aorta after acute and chronic (14 days) administration. Ayahuasca caused flattening and stretching of vascular smooth muscle cells and changes in the arrangement and distribution of collagen and elastic fibers. Chronic treatment with the higher dose significantly increased media thickness and the ratio of media thickness to lumen diameter. More research is needed on the cardiovascular function of long-term ayahuasca consumers.

Pitol, D. L., Siéssere, S., Dos Santos, R. G., Nunes, M. R. M., Cecilio, H. J., Scalize, P. H., … & Hallak, R. S. (2015). Ayahuasca alters structural parameters of the rat aorta. Journal of cardiovascular pharmacology. http://dx.doi.org/10.1097/FJC.0000000000000243
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Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression

Abstract

Objective The authors conducted a systematic review and meta-analysis of ketamine and other N-methyl-d-aspartate (NMDA) receptor antagonists in the treatment of major depression.

Method Searches of MEDLINE, PsycINFO, and other databases were conducted for placebo-controlled, double-blind, randomized clinical trials of NMDA antagonists in the treatment of depression. Primary outcomes were rates of treatment response and transient remission of symptoms. Secondary outcomes included change in depression symptom severity and the frequency and severity of dissociative and psychotomimetic effects. Results for each NMDA antagonist were combined in meta-analyses, reporting odds ratios for dichotomous outcomes and standardized mean differences for continuous outcomes.

Results Ketamine (seven trials encompassing 147 ketamine-treated participants) produced a rapid, yet transient, antidepressant effect, with odds ratios for response and transient remission of symptoms at 24 hours equaling 9.87 (4.37–22.29) and 14.47 (2.67–78.49), respectively, accompanied by brief psychotomimetic and dissociative effects. Ketamine augmentation of ECT (five trials encompassing 89 ketamine-treated participants) significantly reduced depressive symptoms following an initial treatment (Hedges’ g=0.933) but not at the conclusion of the ECT course. Other NMDA antagonists failed to consistently demonstrate efficacy; however, two partial agonists at the NMDA coagonist site, d-cycloserine and rapastinel, significantly reduced depressive symptoms without psychotomimetic or dissociative effects.

Conclusions The antidepressant efficacy of ketamine, and perhaps D-cycloserine and rapastinel, holds promise for future glutamate-modulating strategies; however, the ineffectiveness of other NMDA antagonists suggests that any forthcoming advances will depend on improving our understanding of ketamine’s mechanism of action. The fleeting nature of ketamine’s therapeutic benefit, coupled with its potential for abuse and neurotoxicity, suggest that its use in the clinical setting warrants caution.

Newport, D. J., Carpenter, L. L., McDonald, W. M., Potash, J. B., Tohen, M., & Nemeroff, C. B. (2015). Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression. American Journal of Psychiatry, 172(10), 950-966. http://dx.doi.org/10.1176/appi.ajp.2015.15040465

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