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Substance Use Disorder

Mechanisms of antiaddictive actions of ibogaine

February 7, 2006 / Iboga / Ibogaine, Papers, Psychology, Publications, Substance Use Disorder / By / ,

Abstract

Ibogaine, an alkaloid extracted from Tabemanthe iboga, is being studied as a potential long-acting treatment for oploid and stimulant abuse as well as for alcoholism and smoking. Studies in this laboratory have used animal models to characterize ibogaine’s interactions with drugs of abuse, and to investigate the mechanisms responsible. Ibogaine, as well as its metabolite, noribogaine, can decrease both morphine and cocaine self-administration for several days in some rats; shorter-lasting effects appear to occur on ethanol and nicotine intake. Acutely, both ibogaine and noribogaine decrease extracellular levels of dopamine in the nucleus accumbens of rat brain. Ibogaine pretreatment (19 hours beforehand) blocks morphine-induced dopamine release and morphine-induced locomotor hyperactivity while, in contrast, it enhances similar effects of stimulants (cocaine and amphetamine). Ibogaine pretreatment also blocks nicotine-induced dopamine release. Both ibogaine and noribogaine bind to kappa opioid and N-methyl-D-aspartate (NMDA) receptors and to serotonin uptake sites; ibogaine also binds to sigma-2 and nicotinic receptors. The relative contributions of these actions are being assessed. Our ongoing studies in rats suggest that kappa agonist and NMDA antagonist actions contribute to ibogaine’s effects on opioid and stimulant self-administration, while the serotonergic actions may be more important for ibogaine-induced decreases in alcohol intake. A nicotinic antagonist action may mediate ibogaine-induced reduction of nicotine preferences in rats. A sigma-2 action of ibogaine appears to mediate its neurotoxicity. Some effects of ibogaine (e.g., on morphine and cocaine self-administration, morphine-induced hyperactivity, cocaine-induced increases in nucleus accumbens dopamine) are mimicked by kappa agonist (U50,488) and/or a NMDA antagonist (MK-801). Moreover, a combination of a kappa antagonist and a NMDA agonist will partially reverse several of ibogaine’s effects. Ibogaine’s long-term effects may be mediated by slow release from fat tissue (where ibogaine is sequestered) and conversion to noribogaine. Different receptors, or combinations of receptors, may mediate interactions of ibogaine with different drugs of abuse.

Glick, S. D., & Maisonneuve, I. S. (1998). Mechanisms of antiaddictive actions of ibogaine. Annals of the New York Academy of Sciences, 844, 214-226. http://dx.doi.org/10.1111/j.1749-6632.1998.tb08237.x
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Hallucinogens

January 28, 2004 / Humanities & Art, LSD, Neuroscience, Papers, Psychiatry & Medicine, Psychotic Disorders, Publications, Substance Use Disorder / By /

Abstract

Hallucinogens (psychedelics) are psychoactive substances that powerfully alter perception, mood, and a host of cognitive processes. They are considered physiologically safe and do not produce dependence or addiction. Their origin predates written history, and they were employed by early cultures in a variety of sociocultural and ritual contexts. In the 1950s, after the virtually contemporaneous discovery of both serotonin (5-HT) and lysergic acid diethylamide (LSD-25), early brain research focused intensely on the possibility that LSD or other hallucinogens had a serotonergic basis of action and reinforced the idea that 5-HT was an important neurotransmitter in brain. These ideas were eventually proven, and today it is believed that hallucinogens stimulate 5-HT2A receptors, especially those expressed on neocortical pyramidal cells. Activation of 5-HT2A receptors also leads to increased cortical glutamate levels presumably by a presynaptic receptor-mediated release from thalamic afferents. These findings have led to comparisons of the effects of classical hallucinogens with certain aspects of acute psychosis and to a focus on thalamocortical interactions as key to understanding both the action of these substances and the neuroanatomical sites involved in altered states of consciousness (ASC). In vivo brain imaging in humans using [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”][18F]fluorodeoxyglucose has shown that hallucinogens increase prefrontal cortical metabolism, and correlations have been developed between activity in specific brain areas and psychological elements of the ASC produced by hallucinogens. The 5-HT2A receptor clearly plays an essential role in cognitive processing, including working memory, and ligands for this receptor may be extremely useful tools for future cognitive neuroscience research. In addition, it appears entirely possible that utility may still emerge for the use of hallucinogens in treating alcoholism, substance abuse, and certain psychiatric disorders.

Nichols, D. E. (2004). Hallucinogens. Pharmacology & therapeutics, 101(2), 131-181. https://dx.doi.org/10.1016/j.pharmthera.2003.11.002

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Hallucinogens: An update

September 1, 2003 / Humanities & Art, MDMA, Papers, Publications, Salvia / Salvinorin A, Substance Use Disorder / By /

Abstract

Research of hallucinogen abuse rarely extends beyond epidemiology and observed pathology. Even less research has been completed on the special circumstances surrounding the religious use of hallucinogens or on potential therapeutic applications. Rather than offer another basic review on the well-known hazards of illicit hallucinogen use, this paper provides an overview and practice recommendations on compounds the clinician may be less familiar with, such as the botanical plant Salvia divinorum, the drug 3,4-methylenedioxymethamphetamine (“ecstasy”) and synthetic hallucinogen analogs. The often-warned, but rarely occurring, hazard of hallucinogen persisting perception disorder (“flashbacks”) is also reviewed with treatment recommendations provided. The current status of clinical research with the hallucinogens is presented, with case vignettes suggesting hallucinogens may have anti-addictive applications. The special circumstances surrounding the religious, nondrug use of hallucinogens as sacred sacraments in the US and elsewhere are also presented. It is hoped that the reader will gain a more nuanced understanding of how these physiologically nonaddictive drugs may offer legitimate benefits in modern society. By appreciating that such benefits may one day be borne out by careful, methodologically sound research, clinicians should be better armed in raising the topic of hallucinogen use and abuse with their patients.

Halpern, J. H. (2003). Hallucinogens: an update. Current psychiatry reports, 5(5), 347-354. https://dx.doi.org/10.1007/s11920-003-0067-4

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Ketamine psychotherapy for heroin addiction: immediate effects and two-year follow-up

June 24, 2002 / Ketamine, Papers, Psychology, Publications, Substance Use Disorder / By / , , , , ,

Abstract

Seventy detoxified heroin-addicted patients were randomly assigned to one of two groups receiving ketamine psychotherapy (KPT) involving two different doses of ketamine. The patients of the experimental group received existentially oriented psychotherapy in combination with a hallucinogenic (“psychedelic”) dose of ketamine (2.0 mg/kg im). The patients of the control group received the same psychotherapy combined with a low, non-hallucinogenic (non-psychedelic), dose of ketamine (0.2 mg/kg im). Both the psychotherapist and patient were blind to the dose of ketamine. The therapy included preparation for the ketamine session, the ketamine session itself, and the post session psychotherapy aimed to help patients to integrate insights from their ketamine session into everyday life. The results of this double blind randomized clinical trial of KPT for heroin addiction showed that high dose (2.0 mg/kg) KPT elicits a full psychedelic experience in heroin addicts as assessed quantitatively by the Hallucinogen Rating Scale. On the other hand, low dose KPT (0.2 mg/kg) elicits “sub-psychedelic” experiences and functions as ketamine-facilitated guided imagery. High dose KPT produced a significantly greater rate of abstinence in heroin addicts within the first two years of follow-up, a greater and longer-lasting reduction in craving for heroin, as well as greater positive change in nonverbal unconscious emotional attitudes than did low dose KPT.

Krupitsky, E., Burakov, A., Romanova, T., Dunaevsky, I., Strassman, R., & Grinenko, A. (2002). Ketamine psychotherapy for heroin addiction: immediate effects and two-year follow-up. Journal of substance abuse treatment, 23(4), 273-283. http://dx.doi.org/10.1016/S0740-5472(02)00275-1
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Ketamine psychedelic therapy (KPT): a review of the results of ten years of research

January 1, 1997 / Ketamine, Neuroscience, Papers, Psychology, Publications, Substance Use Disorder / By / ,

Abstract

Ketamine is a prescription drug used for general anesthesia. In subanesthetic doses, it induces profound psychedelic experiences and hallucinations. The subanesthetic effect of ketamine was the hypothesized therapeutic mechanism in the authors’ use of ketamine-assisted psychotherapy for alcoholism. The results of a controlled clinical trial demonstrated a considerable increase in efficacy of the authors’ standard alcoholism treatment when supplemented by ketamine psychedelic therapy (KPT). Total abstinence for more than one year was observed in 73 out of 111 (65.8%) alcoholic patients in the KPT group, compared to 24% (24 out of 100 patients) of the conventional treatment control group (p < 0.01). The authors’ studies of the underlying psychological mechanisms of KPT have indicated that ketamine-assisted psychedelic therapy of alcoholic patients induces a harmonization of the Minnesota Multiphasic Personality Inventory (MMPI) personality profile, positive transformation of nonverbalized (mostly unconscious) self-concept and emotional attitudes to various aspects of self and other people, positive changes in life values and purposes, important insights into the meaning of life and an increase in the level of spiritual development. Most importantly, these psychological changes were shown to favor a sober lifestyle. The data from biochemical investigations showed that pharmacological action of KPT affects both monoaminergic and opioidergic neurotransmitter metabolism, i.e., those neurochemical systems which are involved in the pathogenesis of alcohol dependence. The data from EEG computer-assisted analysis demonstrated that ketamine increases theta activity in cerebrocortical regions of alcoholic patients. This is evidence of the reinforcement of limbic cortex interaction during KPT session.

Krupitsky, E. M., & Grinenko, A. Y. (1997). Ketamine psychedelic therapy (KPT): a review of the results of ten years of research. Journal of psychoactive drugs, 29(2), 165-183. https://dx.doi.org/10.1080/02791072.1997.10400185

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Receptor binding profile suggests multiple mechanisms of action are responsible for ibogaine's putative anti-addictive activity

April 2, 1995 / Iboga / Ibogaine, Papers, Publications, Substance Use Disorder / By / , , , , , ,

Abstract

The indole alkaloid ibogaine (NIH 10567, Endabuse) is currently being examined for its potential utility in the treatment of cocaine and opioid addiction. However, a clearly defined molecular mechanism of action for ibogaine’s putative anti-addictive properties has not been delineated. Radioligand binding assays targeting over 50 distinct neurotransmitter receptors, ion channels, and select second messenger systems were employed to establish a broad in vitro pharmacological profile for ibogaine. These studies revealed that ibogaine interacted with a wide variety of receptors at concentrations of 1-100 microM. These included the mu, delta, kappa, opiate, 5HT2, 5HT3, and muscarinic1 and 2 receptors, and the dopamine, norepinephrine, and serotonin uptake sites. In addition, ibogaine interacted with N-methyl-D-aspartic acid (NMDA) associated ion and sodium ion channels as determined by the inhibition of [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”][3H]MK-801 and [3H]bactrachotoxin A 20-alpha-benzoate binding (BTX-B), respectively. This broad spectrum of activity may in part be responsible for ibogaine’s putative anti-addictive activity.

Sweetnam, P. M., Lancaster, J., Snowman, A., Collins, J. L., Perschke, S., Bauer, C., & Ferkany, J. (1995). Receptor binding profile suggests multiple mechanisms of action are responsible for ibogaine’s putative anti-addictive activity. Psychopharmacology, 118(4), 369-376.
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DPT as an adjunct in psychotherapy of alcoholics.

January 1, 1973 / DMT, Papers, Psychology, Publications, Substance Use Disorder / By / , , ,

Abstract

The usefulness of dipropyltryptamine (DPT) as an adjunct to psychedelic therapy was explored in a pilot study carried out on 51 alcoholic patients from the Alcoholic Rehabilitation Unit at Spring Grove State Hospital. The evaluation of the results was based on the comparison of pre- and posttreatment results of a battery of psychological tests and of pretreatment and follow-up ratings of an independent team of social workers. The psychological tests involved the Minnesota multiphasic personality inventory (MMPI), Personal orientation inventory (POI), Raven progressive matrices, Psychiatric evaluation profile (PEP), and Benton visual retention test. The social history questionnaire used by the social workers for assessment of the patients’ adjustment consisted of 0-10-point scales measuring residential, occupational and interpersonal adjustment, abstinence, and global adjustment.
Grof, S., Soskin, R. A., Richards, W. A., & Kurland, A. A. (1973). DPT as an adjunct in psychotherapy of alcoholics. International pharmacopsychiatry, 8, 104-115., 10.1159/000467979
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