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K. Alper

LSD Administered as a Single Dose Reduces Alcohol Consumption in C57BL/6J Mice.

August 31, 2018 / LSD, Papers, Psychology, Publications, Substance Use Disorder / By / , , , ,

Abstract

There is a substantive clinical literature on classical hallucinogens, most commonly lysergic acid diethylamide (LSD) for the treatment of alcohol use disorder. However, there has been no published research on the effect of LSD on alcohol consumption in animals. This study evaluated the effect of LSD in mice using a two-bottle choice alcohol drinking paradigm. Adult male C57BL/6J mice were exposed to ethanol to develop preference and divided into three groups of equal ethanol consumption, and then treated with single intraperitoneal injection of saline or 25 or 50 μg/kg LSD and offered water and 20% ethanol. The respective LSD-treated groups were compared to the control group utilizing a multilevel model for repeated measures. In mice treated with 50 μg/kg LSD ethanol consumption was reduced relative to controls (p= 0.0035), as was ethanol preference (p = 0.0024), with a group mean reduction of ethanol consumption of 17.9% sustained over an interval of 46 days following LSD administration. No significant effects on ethanol consumption or preference were observed in mice treated with 25 μg/kg LSD. Neither total fluid intake nor locomotor activity in the LSD-treated groups differed significantly from controls. These results suggest that classical hallucinogens in the animal model merit further study as a potential approach to the identification of targets for drug discovery and investigation of the neurobiology of addiction.
Alper, K., Dong, B., Shah, R., Sershen, H., & Vinod, K. Y. (2018). LSD administered as a single dose reduces alcohol consumption in C57BL/6J mice. Frontiers in pharmacology, 9, 994., 10.3389/fphar.2018.00994
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Treatment of opioid use disorder with ibogaine: detoxification and drug use outcomes

May 25, 2017 / Iboga / Ibogaine, Papers, Psychology, Publications, Substance Use Disorder / By / ,

Abstract

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.
Brown, T. K., & Alper, K. (2017). Treatment of opioid use disorder with ibogaine: detoxification and drug use outcomes. The American Journal of Drug and Alcohol Abuse, 1-13. 10.1080/00952990.2017.1320802
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Ibogaine: a review

December 4, 2013 / Anthropology & Sociology, Biology & Ethnobotany, Iboga / Ibogaine, Papers, Pharmacology & Chemistry, Psychology, Publications, Substance Use Disorder / By /

Publisher Summary

The chapter discusses ibogaine, which is a naturally occurring plant alkaloid with a history of use as a medicinal and ceremonial agent in West Central Africa and has been alleged to be effective in the treatment of drug abuse. The National Institute on Drug Abuse (NIDA) has given significant support to animal research, and the U.S. Food and Drug Administration (FDA) has approved Phase I studies in humans. The chapter discusses the first International Conference on Ibogaine. A major focus of the Conference was the possible mechanism(s) of action of ibogaine. Another important focus of the Conference was to discuss human experience with ibogaine and preclinical and clinical evidence of efficacy and safety. The Conference also featured presentations related to the sociological and anthropological aspects of the sacramental context of the use of iboga in Africa and the distinctive ibogaine subculture of the U.S and Europe. Ibogaine is the most abundant alkaloid in the root bark of the Apocynaceous shrub Tabernanthe iboga, which grows in West Central Africa. The chapter presents a timeline that outlines the historical events relating to the development of ibogaine as a treatment for drug dependence. Ibogaine and serotonin both contain an indole ring in their structure, and ibogaine has been shown to bind to the serotonin transporter and to increase serotonin levels in the nucleus accumbens (NAc). Stereotypy is a methodologic issue that might explain some of the disparate results regarding ibogaine’s interaction with the locomotor response to cocaine.

Alper, K. R. (2001). Ibogaine: a review. The alkaloids: Chemistry and Biology, 56, 1-38. http://dx.doi.org/10.1016/S0099-9598(01)56005-8
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Effect of Iboga Alkaloids on µ-Opioid Receptor-Coupled G Protein Activation

October 16, 2013 / Iboga / Ibogaine, Papers, Publications / By / , , , , , ,

Abstract

Objective

The iboga alkaloids are a class of small molecules defined structurally on the basis of a common ibogamine skeleton, some of which modify opioid withdrawal and drug self-administration in humans and preclinical models. These compounds may represent an innovative approach to neurobiological investigation and development of addiction pharmacotherapy. In particular, the use of the prototypic iboga alkaloid ibogaine for opioid detoxification in humans raises the question of whether its effect is mediated by an opioid agonist action, or if it represents alternative and possibly novel mechanism of action. The aim of this study was to independently replicate and extend evidence regarding the activation of μ-opioid receptor (MOR)-related G proteins by iboga alkaloids.

Methods

Ibogaine, its major metabolite noribogaine, and 18-methoxycoronaridine (18-MC), a synthetic congener, were evaluated by agonist-stimulated guanosine-5´-O-(γ-thio)-triphosphate ([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”][35S]GTPγS) binding in cells overexpressing the recombinant MOR, in rat thalamic membranes, and autoradiography in rat brain slices.

Results And Significance

In rat thalamic membranes ibogaine, noribogaine and 18-MC were MOR antagonists with functional Ke values ranging from 3 uM (ibogaine) to 13 uM (noribogaine and 18MC). Noribogaine and 18-MC did not stimulate [35S]GTPγS binding in Chinese hamster ovary cells expressing human or rat MORs, and had only limited partial agonist effects in human embryonic kidney cells expressing mouse MORs. Ibogaine did not did not stimulate [35S]GTPγS binding in any MOR expressing cells. Noribogaine did not stimulate [35S]GTPγS binding in brain slices using autoradiography. An MOR agonist action does not appear to account for the effect of these iboga alkaloids on opioid withdrawal. Taken together with existing evidence that their mechanism of action also differs from that of other non-opioids with clinical effects on opioid tolerance and withdrawal, these findings suggest a novel mechanism of action, and further justify the search for alternative targets of iboga alkaloids.

Antonio, T., Childers, S. R., Rothman, R. B., Dersch, C. M., King, C., Kuehne, M., … & Alper, K. (2013). Effect of Iboga Alkaloids on µ-Opioid Receptor-Coupled G Protein Activation. PloS one, 8(10), https://dx.doi.org/10.1371/journal.pone.0077262
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