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D. Mash

Ibogaine Detoxification Transitions Opioid and Cocaine Abusers Between Dependence and Abstinence: Clinical Observations and Treatment Outcomes

June 5, 2018 / Addiction, Iboga / Ibogaine, Papers, Psychology, Psychopharmacology, Psychotherapy, Publications / By / , , ,

Abstract

Ibogaine may be effective for transitioning opioid and cocaine dependent individuals to sobriety. American and European self-help groups provided public testimonials that ibogaine alleviated drug craving and opioid withdrawal symptoms after only a single dose administration. Preclinical studies in animal models of addiction have provided proof-of-concept evidence in support of these claims. However, the purported therapeutic benefits of ibogaine are based on anecdotal reports from a small series of case reports that used retrospective recruitment procedures. We reviewed clinical results from an open label case series (N = 191) of human volunteers seeking to detoxify from opioids or cocaine with medical monitoring during inpatient treatment. Whole blood was assayed to obtain pharmacokinetic measures to determine the metabolism and clearance of ibogaine. Clinical safety data and adverse events (AEs) were studied in male and female subjects. There were no significant adverse events following administration of ibogaine in a dose range that was shown to be effective for blocking opioid withdrawal symptoms in this study. We used multi-dimensional craving questionnaires during inpatient detoxification to test if ibogaine was effective in diminishing heroin and cocaine cravings. Participants also completed standardized questionnaires about their health and mood before and after ibogaine treatment, and at program discharge. One-month follow-up data were reviewed where available to determine if ibogaine’s effects on drug craving would persist outside of an inpatient setting. We report here that ibogaine therapy administered in a safe dose range diminishes opioid withdrawal symptoms and reduces drug cravings. Pharmacological treatments for opioid dependence include detoxification, narcotic antagonists and long-term opioid maintenance therapy. Our results support product development of single oral dose administration of ibogaine for the treatment of opioid withdrawal during medically supervised detoxification to transition drug dependent individuals to abstinence.
Mash, D. C., Duque, L., Page, B., & Allen-Ferdinand, K. (2018). Ibogaine Detoxification Transitions Opioid and Cocaine Abusers Between Dependence and Abstinence: Clinical Observations and Treatment Outcomes. Frontiers in Pharmacology, 9. 10.3389/fphar.2018.00529
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Breaking the cycle of opioid use disorder with Ibogaine

December 7, 2017 / Addiction, Iboga / Ibogaine, Neuroscience, Papers, Psychology, Psychopharmacology, Psychotherapy, Publications / By /

Abstract

Ibogaine is an indole alkaloid that comes from the root of the West African shrub Tabernanthe iboga. Ibogaine has been used for centuries in spiritual celebrations, coming of age rituals, and healings among the Babongo and Mitsogo people of West Central Africa. In Africa today, approximately 2–3 million members of the Bwiti religion scattered in groups throughout the countries of the Gabon, Zaire, and the Cameroun take large doses for the “Bwiti initiation ritual”—a powerful “rebirth” ceremony that group members typically undergo before the commencement of their teenage years.
The discovery that ibogaine eliminates the signs and symptoms of opioid withdrawal and diminishes craving for opioids was first made in the 1960s by a group of self-treating individuals with heroin use disorder; a single oral dose administration of ibogaine was associated with a disruption of five addicted individual’s use of opiates for up to 6 months . An underground railroad of individuals in recovery helping others with addictions arose, using ibogaine to help people break their cycle of addiction to heroin, cocaine, and alcohol. Ibogaine is thought to enable individuals with opioid use disorder to transition to abstinence and establish a substance-free recovery through an ibogaine-induced experience that has personal meaning and/or other benefits. Ibogaine’s long-lasting metabolite noribogaine may reset brain circuits to block the intractable cravings and desire to use opioids that set the addiction relapse cycle into motion.
C. Mash, D. (2017). Breaking the cycle of opioid use disorder with Ibogaine. The American Journal of Drug and Alcohol Abuse, 1-3. 10.1080/00952990.2017.1357184
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Oral noribogaine shows high brain uptake and anti-withdrawal effects not associated with place preference in rodents

April 4, 2016 / Addiction, Iboga / Ibogaine, Neuroscience, Papers, Psychopharmacology, Publications / By / , , , ,

Abstract

This study investigated the effects of noribogaine, the principal metabolite of the drug ibogaine, on substance-related disorders. In the first experiment, mice chronically treated with morphine were subjected to naloxone-precipitated withdrawal two hours after oral administration of noribogaine. Oral noribogaine dose dependently decreased the global opiate withdrawal score by up to 88% of vehicle control with an ED50of 13 mg/kg. In the second experiment, blood and brain levels of noribogaine showed a high brain penetration and a brain/blood ratio of 7±1 across all doses tested. In a third experiment, rats given oral noribogaine up to 100 mg/kg were tested for abuse liability using a standard biased conditioned place paradigm. Noribogaine-treated rats did not display place preference, suggesting that noribogaine is not perceived as a hedonic stimulus in rodents. Retrospective review of published studies assessing the efficacy of ibogaine on morphine withdrawal shows that the most likely cause of the discrepancies in the literature is the different routes of administration and time of testing following ibogaine administration. These results suggest that the metabolite noribogaine rather than the parent compound mediates the effects of ibogaine on blocking naloxone-precipitated withdrawal. Noribogaine may hold promise as a non-addicting alternative to standard opiate replacement therapies to transition patients to opiate abstinence.

Mash, D. C., Ameer, B., Prou, D., Howes, J. F., & Maillet, E. L. (2016). Oral noribogaine shows high brain uptake and anti-withdrawal effects not associated with place preference in rodents. Journal of psychopharmacology (Oxford, England). http://dx.doi.org/10.1177/0269881116641331

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Noribogaine is a G-Protein Biased κ-Opioid Receptor Agonist

August 21, 2015 / Addiction, Iboga / Ibogaine, Neuroscience, Other disciplines, Papers, Psychology, Psychopharmacology, Psychotherapy, Publications / By / , , , , , ,

Abstract

Noribogaine is the long-lived human metabolite of the anti-addictive substance ibogaine. Noribogaine efficaciously reaches the brain with concentrations up to 20 μM after acute therapeutic dose of 40 mg/kg ibogaine in animals. Noribogaine displays atypical opioid-like components in vivo, anti-addictive effects and potent modulatory properties of the tolerance to opiates for which the mode of action remained uncharacterized thus far. Our binding experiments and computational simulations indicates that noribogaine may bind to the orthosteric morphinan binding site of the opioid receptors. Functional activities of noribogaine at G-protein and non G-protein pathways of the mu and kappa opioid receptors were characterized. Noribogaine was a weak mu antagonist with a functional inhibition constants (Ke) of 20 μM at the G-protein and β-arrestin signaling pathways. Conversely, noribogaine was a G-protein biased kappa agonist 75% as efficacious as dynorphin A at stimulating GDP-GTP exchange (EC50 = 9 μM) but only 12% as efficacious at recruiting β-arrestin, which could contribute to the lack of dysphoric effects of noribogaine. In turn, noribogaine functionally inhibited dynorphin-induced kappa β-arrestin recruitment and was more potent than its G-protein agonistic activity with an IC50 of 1 μM. This biased agonist/antagonist pharmacology is unique to noribogaine in comparison to various other ligands including ibogaine, 18-MC, nalmefene, and 6’-GNTI. We predict noribogaine to promote certain analgesic effects as well as anti-addictive effects at effective concentrations >1 μM in the brain. Because elevated levels of dynorphins are commonly observed and correlated with anxiety, dysphoric effects, and decreased dopaminergic tone, a therapeutically relevant functional inhibition bias to endogenously released dynorphins by noribogaine might be worthy of consideration for treating anxiety and substance related disorders.

Maillet, E. L., Milon, N., Heghinian, M. D., Fishback, J., Schürer, S. C., Garamszegi, N., & Mash, D. C. (2015). Noribogaine is a G-Protein Biased κ-Opioid Receptor Agonist. Neuropharmacology. https://dx.doi.org/10.1016/j.neuropharm.2015.08.032
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Noribogaine reduces nicotine self-administration in rats

May 20, 2015 / Addiction, Iboga / Ibogaine, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , ,

Abstract

Noribogaine, a polypharmacological drug with activities at opioid receptors, ionotropic nicotinic receptors, and serotonin reuptake transporters, has been investigated for treatment of substance abuse-related disorders. Smoking cessation has major benefits for both individuals and society, therefore the aim of this study was to evaluate the potential of noribogaine for use as a treatment for nicotine dependence. Adult male Sprague-Dawley rats were trained to self-administer nicotine intravenous. After initial food pellet training, followed by 26 sessions of nicotine self-administration training, the rats were administered noribogaine (12.5, 25 or 50 mg/kg orally), noribogaine vehicle, varenicline or saline using a within-subject design with a Latin square test schedule. Noribogaine dose-dependently decreased nicotine self-administration by up to 64% of saline-treated rats’ levels and was equi-effective to 1.7 mg/kg intraperitoneal varenicline. Noribogaine was less efficient at reducing food pellets self-administration than at nicotine self-administration, inhibiting the nondrug reinforcing effects of palatable pellets by 23% at the highest dose. These results suggest that noribogaine dose-dependently attenuates drug-taking behavior for nicotine, attenuates the reinforcing effects of nicotine and is comparable to varenicline power in that regard. The findings from the present study hold promise for a new therapy to aid smoking cessation.

Chang, Q., Hanania, T., Mash, D. C., & Maillet, E. L. (2015). Noribogaine reduces nicotine self-administration in rats. Journal of Psychopharmacology, 29(6), 704-711. http://dx.doi.org/10.1177/0269881115584461
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Pharmacokinetics of Hoasca alkaloids in healthy humans

June 1, 1999 / Ayahuasca, DMT, Ethnobotany, Indigenous use, Papers, Psychopharmacology, Publications / By / , , , , , ,

Abstract

N,N-Dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine (THH) are the characteristic alkaloids found in Amazonian sacraments known as hoasca, ayahuasca, and yajè. Such beverages are characterized by the presence of these three harmala alkaloids, where harmine and harmaline reversibly inhibit monoamine oxidase A (MAO-A) while tetrahydroharmine weakly inhibits the uptake of serotonin. Together, both actions increase central and peripheral serotonergic activity while facilitating the psychoactivity of DMT. Though the use of such ‘teas’ has be known to western science for over 100 years, little is known of their pharmacokinetics. In this study, hoasca was prepared and administered in a ceremonial context. All four alkaloids were measured in the tea and in the plasma of 15 volunteers, subsequent to the ingestion of 2 ml hoasca/kg body weight, using gas (GC) and high pressure liquid chromatographic (HPLC) methods. Pharmacokinetic parameters were calculated and peak times of psychoactivity coincided with high alkaloid concentrations, particularly DMT which had an average Tmax of 107.5±32.5 min. While DMT parameters correlated with those of harmine, THH showed a pharmacokinetic profile relatively independent of harmine’s.

Callaway, J. C., McKenna, D. J., Grob, C. S., Brito, G. S., Raymon, L. P., Poland, R. E., … & Mash, D. C. (1999). Pharmacokinetics of Hoasca alkaloids in healthy humans. Journal of ethnopharmacology, 65(3), 243-256. 10.1016/S0378-8741(98)00168-8
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7 May - Psychedelics, Nature & Mental Health with Sam Gandy

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