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Substance Use Disorder

Antidepressive, anxiolytic, and antiaddictive effects of ayahuasca, psilocybin and lysergic acid diethylamide (LSD): a systematic review of clinical trials published in the last 25 years

March 18, 2016 / Anxiety Disorders / PTSD, Ayahuasca, Depressive Disorders, LSD, Mushrooms / Psilocybin, Papers, Psychology, Publications, Substance Use Disorder / By / , , , , ,

Abstract

To date, pharmacological treatments for mood and anxiety disorders and for drug dependence show limited efficacy, leaving a large number of patients suffering severe and persistent symptoms. Preliminary studies in animals and humans suggest that ayahuasca, psilocybin and lysergic acid diethylamide (LSD) may have antidepressive, anxiolytic, and antiaddictive properties. Thus, we conducted a systematic review of clinical trials published from 1990 until 2015, assessing these therapeutic properties. Electronic searches were performed using the PubMed, LILACS, and SciELO databases. Only clinical trials published in peer-reviewed journals were included. Of these, 151 studies were identified, of which six met the established criteria. Reviewed studies suggest beneficial effects for treatment-resistant depression, anxiety and depression associated with life-threatening diseases, and tobacco and alcohol dependence. All drugs were well tolerated. In conclusion, ayahuasca, psilocybin and LSD may be useful pharmacological tools for the treatment of drug dependence, and anxiety and mood disorders, especially in treatment-resistant patients. These drugs may also be useful pharmacological tools to understand psychiatric disorders and to develop new therapeutic agents. However, all studies reviewed had small sample sizes, and half of them were open-label, proof-of-concept studies. Randomized, double-blind, placebo-controlled studies with more patients are needed to replicate these preliminary findings.

dos Santos, R. G., Osório, F. L., Crippa, J. A. S., Riba, J., Zuardi, A. W., & Hallak, J. E. (2016). Antidepressive, anxiolytic, and antiaddictive effects of ayahuasca, psilocybin and lysergic acid diethylamide (LSD): a systematic review of clinical trials published in the last 25 years. Therapeutic Advances in Psychopharmacology, 2045125316638008.

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Ascending single-dose, double-blind, placebo-controlled safety study of noribogaine in opioid-dependent patients

February 10, 2016 / Iboga / Ibogaine, Papers, Publications, Substance Use Disorder / By / , , , , , ,

Abstract

Ibogaine is a psychoactive substance that may reduce opioid withdrawal symptoms. This was the first clinical trial of noribogaine, ibogaine’s active metabolite, in patients established on methadone opioid substitution therapy (OST). In this randomized, double-blind, placebo-controlled, single ascending dose study, we evaluated the safety, tolerability, and pharmacokinetics of noribogaine in 27 patients seeking to discontinue methadone OST, who had been switched to morphine during the previous week. Noribogaine doses were 60, 120 or 180mg (n = 6/dose level) or matching placebo (n = 3/dose level). Noribogaine was well tolerated. The most frequent treatment-emergent adverse events were non-euphoric changes in light perception at ∼1h post dose, headache and nausea. Noribogaine had dose-linear increases for AUC and Cmax, and was slowly eliminated (mean t1/2 range 24–30h). There was a concentration-dependent increase in QTcI (0.17msec/ng/mL) with largest observed mean effect of ∼16msec, 28msec, and 42msec in the 60mg, 120mg, and 180mg groups, respectively. Noribogaine showed a non-statistically significant trend to decrease total scores in opioid withdrawal ratings, most notably at the 120mg dose, however the study design may have confounded evaluations of time to resumption of OST. Future exposure-controlled multiple-dose noribogaine studies are planned that will address these safety and design issues.

Glue, P., Cape, G., Tunnicliff, D., Lockhart, M., Lam, F., Hung, N., … & Howes, J. (2016). Ascending single‐dose, double‐blind, placebo‐controlled safety study of noribogaine in opioid‐dependent patients. Clinical Pharmacology in Drug Development. http://dx.doi.org/10.1002/cpdd.254
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The therapeutic potentials of ayahuasca: possible effects against various diseases of civilization

February 8, 2016 / Ayahuasca, Papers, Psychology, Publications, Substance Use Disorder / By / , ,

Abstract

Ayahuasca is an Amazonian psychoactive brew of two main components. Its active agents are β-carboline and tryptamine derivatives. As a sacrament, ayahuasca is still a central element of many healing ceremonies in the Amazon Basin and its ritual consumption has become common among the mestizo populations of South America. Ayahuasca use amongst the indigenous people of the Amazon is a form of traditional medicine and cultural psychiatry. During the last two decades, the substance has become increasingly known among both scientists and laymen, and currently its use is spreading all over in the Western world. In the present paper we describe the chief characteristics of ayahuasca, discuss important questions raised about its use, and provide an overview of the scientific research supporting its potential therapeutic benefits. A growing number of studies indicate that the psychotherapeutic potential of ayahuasca is based mostly on the strong serotonergic effects, whereas the sigma-1 receptor agonist effect of its active ingredient dimethyltryptamine raises the possibility that the ethnomedical observations on the diversity of treated conditions can be scientifically verified. Moreover, in the right therapeutic or ritual setting with proper preparation and mindset of the user, followed by subsequent integration of the experience, ayahuasca has proven effective in the treatment of substance dependence. This article has two important take-home messages: 1) the therapeutic effects of ayahuasca are best understood from a bio-psycho-socio-spiritual model, and 2) on the biological level ayahuasca may act against chronic low grade inflammation and oxidative stress via the sigma-1 receptor which can explain its widespread therapeutic indications.

Frecska, E., Bokor, P., & Winkelman, M. (2016). The therapeutic potentials of ayahuasca: possible effects against various diseases of civilization. Frontiers in Pharmacology, 7, 35. http://dx.doi.org/10.3389/fphar.2016.00035
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Salvia divinorum: An overview of the usage, misuse, and addiction processes

November 29, 2015 / Papers, Psychology, Publications, Salvia / Salvinorin A, Substance Use Disorder / By / , , , ,

Abstract

Salvia divinorum, a sage plant with leaves that can produce a psychoactive high, has been used for hundreds of years for its psycho-mimetic effects in religious rituals in South America. Salvia has now become popular mainly with adolescents and young adults for the short-lived relatively pleasant experiences many consider a “legal high” and its ready availability through Internet purchases. The main (psycho)active compound in salvia is Salvinorin A, a potent κ-opioid agonist and although the short and long-term effects have not been examined in sufficient detail, it is widely believed to have low addictive potential and low toxicity. Recent findings, however, seem to suggest that Salvinorin A can precipitate psychiatric symptoms and negatively affect cognition. Its ready availability and increasingly widespread use requires clinicians to have knowledge and awareness of its effects.

Mahendran, R., Lim, H. A., Tan, J., Chua, S. M., & Winslow, M. (2015). Salvia divinorum: An overview of the usage, misuse, and addiction processes. Asia‐Pacific Psychiatry. http://dx.doi.org/10.1111/appy.12225
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Comparative phenomenology of psilocybin experiences in research and non-research settings

November 1, 2015 / Mushrooms / Psilocybin, Papers, Psychology, Publications, Substance Use Disorder / By / , , ,

Abstract

This study sought to compare questionnaire ratings of subjective experiences after psilocybin when administered in controlled research settings vs. uncontrolled, non-research settings.

Carbonaro, T. M., Klinedinst, M., Johnson, M. W., & Griffiths, R. R. (2015). Comparative phenomenology of psilocybin experiences in research and non-research settings. Drug and Alcohol Dependence, 156, e36-e37.  http://dx.doi.org/10.1016/j.drugalcdep.2015.07.1017
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Long-term follow-up of psilocybin-facilitated smoking cessation: Abstinence outcomes and qualitative analysis of participant accounts

November 1, 2015 / Mushrooms / Psilocybin, Papers, Psychology, Publications, Substance Use Disorder / By / , , , , , ,

Abstract

We assessed long-term (>12 months) outcomes of psilocybin-facilitated smoking cessation, and qualitatively analyzed participants’ accounts to inform potential psychological mechanisms of treatment efficacy.

Garcia-Romeu, A. P., Noorani, T., Griffiths, R. R., Johnson, M. W., Garey, L., Zvolensky, M. J., & Schmidt, N. B. (2015). Long-term follow-up of psilocybin-facilitated smoking cessation: Abstinence outcomes and qualitative analysis of participant accounts. Drug and Alcohol Dependence, 156, e78.  http://dx.doi.org/10.1016/j.drugalcdep.2015.07.1130
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Noribogaine is a G-Protein Biased κ-Opioid Receptor Agonist

August 21, 2015 / Iboga / Ibogaine, Neuroscience, Papers, Psychology, Publications, Substance Use Disorder / 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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The potential utility of some legal highs in CNS disorders

July 29, 2015 / Anxiety Disorders / PTSD, Depressive Disorders, Ketamine, LSD, MDMA, Mushrooms / Psilocybin, Papers, Psychiatry & Medicine, Psychology, Publications, Substance Use Disorder / By / ,

Abstract

Over the last decade there has been an explosion of new drugs of abuse, so called legal highs or novel psychoactive substances (NPS). Many of these abused drugs have unknown pharmacology, but their biological effects can be anticipated from their molecular structure and possibly also from online user reports. When considered with the findings that some prescription medications are increasingly abused and that some abused drugs have been tested clinically one could argue that there has been a blurring of the line between drugs of abuse and clinically used drugs. In this review we examine these legal highs/NPS and consider whether, based on their known or predicted pharmacology, some might have the potential to be clinically useful in CNS disorders.

Davidson, C., & Schifano, F. (2015). The potential utility of some legal highs in CNS disorders. Progress in Neuro-Psychopharmacology and Biological Psychiatry. https://dx.doi.org/10.1016/j.pnpbp.2015.07.010
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Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression

June 29, 2015 / Depressive Disorders, Ketamine, Papers, Psychology, Publications, Substance Use Disorder / By / , , , , ,

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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Noribogaine reduces nicotine self-administration in rats

May 20, 2015 / Iboga / Ibogaine, Papers, Psychology, Publications, Substance Use Disorder / 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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