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Can psychedelic compounds play a part in drug dependence therapy?

January 5, 2015 / Ayahuasca, Iboga / Ibogaine, Ketamine, LSD, Mescaline / Cacti, Mushrooms / Psilocybin, Papers, Psychology, Publications, Substance Use Disorder / By / ,

Abstract

After a 40-year hiatus there is now a revisiting of psychedelic drug therapy throughout psychiatry, with studies examining the drugs psilocybin, ketamine, ibogaine and ayahuasca in the treatment of drug dependence. Limitations to these therapies are both clinical and legal, but the possibility of improving outcomes for patients with substance dependency imposes an obligation to research this area.

Sessa, B., & Johnson, M. W. (2015). Can psychedelic compounds play a part in drug dependence therapy? The British Journal of Psychiatry, 206, 1-3. https://dx.doi.org/10.1192/bjp.bp.114.148031

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Psychedelic-facilitated smoking cessation: An online survey

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

Abstract

Aims:
Pilot laboratory results suggest psilocybin may be an efficacious adjunct to smoking cessation treatment. However, no study has examined smoking cessation after psychedelic use in naturalistic settings.
Methods:
We are conducting an online survey collecting demographics, smoking history, and other data from people who self-report quitting/reducing smoking after taking a psychedelic.
Results:
Among current completers (N=164), LSD (49%) and psilocybin (32%) were the drugs most commonly associated with quitting/reducing, with a mode of 2-5 lifetime uses each. Participants reported smoking a mean of 12 cigs/day for a mean of 8 yrs before the experience. 62(38%) reported total and continuing abstinence after their experience, with 29 of the 62 (47%) reporting >1yr abstinence, and 7 (11%) reporting >10 yrs abstinence. Another 67 of the 164 (41%) reported persisting smoking reduction, from a mode of 10-20 cigs/day before, to a mode of <1 cig/month after the experience. The remaining 35 (21%) reported temporary reduction, with 6 of the 35 (17%) reporting >1 yr reduction. Although the majority of withdrawal symptoms were rated as equal in severity to previous quit attempts, depression, irritability, anxiety, and craving were rated as “much less severe.” 141 of the 164 (86%) reported no premeditated intention to quit/reduce smoking, and 159 (97%) described their experience as highly meaningful, with
97 (59%) considering it among the 10 most meaningful experiences of their lives. Participants cited changed life priorities/values (26%), strengthened belief in their ability to quit (26%), and changed future orientation (17%) as the most important effects leading to quitting/reducing. Other changes reported after psychedelic use included reduced alcohol (38%) and other drug use (23%).
Conclusions:
Psychedelics may prompt temporary or prolonged smoking cessation, suggesting that careful administration in a treatment context may enhance motivation in changing addictive behaviors. Psychological and neurobiological mechanisms underlying such behavioral changes require further investigation.

Garcia-Romeu, A. P., Griffiths, R. R., & Johnson, M. W. (2015). Psychedelic-facilitated smoking cessation: An online survey. Drug and Alcohol Dependence, (146), e120. http://dx.doi.org/10.1016/j.drugalcdep.2014.09.245
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Serotonin 5-HT₂ receptor activation prevents allergic asthma in a mouse model.

January 1, 2015 / Neuroscience, Papers, Psychiatry & Medicine, Publications / By / , , , , ,

Abstract

Asthma is an inflammatory disease of the lung characterized by airways hyper-responsiveness (AHR), inflammation, and mucus hyperproduction. Current mainstream therapies include bronchodilators that relieve bronchoconstriction and inhaled glucocorticoids to reduce inflammation. The small molecule hormone and neurotransmitter serotonin has long been known to be involved in inflammatory processes; however, its precise role in asthma is unknown. We have previously established that activation of serotonin 5-hydroxytryptamine (5-HT)(2A) receptors has potent anti-inflammatory activity in primary cultures of vascular tissues and in the whole animal in vasculature and gut tissues. The 5-HT(2A) receptor agonist, (R)-2,5-dimethoxy-4-iodoamphetamine [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”][(R)-DOI] is especially potent. In this work, we have examined the effect of (R)-DOI in an established mouse model of allergic asthma. In the ovalbumin mouse model of allergic inflammation, we demonstrate that inhalation of (R)-DOI prevents the development of many key features of allergic asthma, including AHR, mucus hyperproduction, airways inflammation, and pulmonary eosinophil recruitment. Our results highlight a likely role of the 5-HT2 receptors in allergic airways disease and suggest that 5-HT2 receptor agonists may represent an effective and novel small molecule-based therapy for asthma.

Nau, F., Miller, J., Saravia, J., Ahlert, T., Yu, B., Happel, K. I., … & Nichols, C. D. (2015). Serotonin 5-HT2 receptor activation prevents allergic asthma in a mouse model. American Journal of Physiology-Lung Cellular and Molecular Physiology, 308(2), L191-L198.
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The Philosophy of Psychedelic Transformation

January 1, 2015 / Papers, Philosophy & Religious Studies / By /

Abstract

Recent scientific research into the therapeutic potential and mechanisms of psychedelic drugs raises intriguing and hitherto largely unexplored philosophical questions. A brief overview of the relevant science is given before addressing these questions. It is argued that psychedelic transformation is a distinctive psycho- pharmacological intervention because its mechanism of action ineliminably involves conscious mental representations, and thus is more transparent to the subject than the mechanisms of other drug therapies. This argument connects with issues in the philosophy of (cognitive) scientific explanation. It is also argued that transformative psychedelic experiences may well confer three distinct kinds of epistemic benefits: knowledge by acquaintance of the subject’s psychological potential, knowledge by acquaintance of the meta-physical nature of the (sense of) self, and revitalized capacities for the acquisition of modal knowledge. Non-naturalistic metaphysical and epistemological claims abound in psychedelic circles; thus, it is important to realize that psychedelics may yield naturalistically acceptable epistemic benefits.
Letheby, C. (2015). The philosophy of psychedelic transformation. Journal of Consciousness Studies, 22(9-10), 170-193.
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Ketamine interactions with biomarkers of stress: A randomized placebo-controlled repeated measures resting-state fMRI and PCASL pilot study in healthy men

December 29, 2014 / Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Ketamine, an NMDA receptor antagonist, is increasingly used to study the link between glutamatergic signaling dysregulation and mood and chronic pain disorders. Glutamatergic neurotransmission and stress corticosteroids (cortisol in human) are critical for Ca2 + mediated neuroplasticity and behavioral adaptation. The mechanisms of action of glutamatergic neurotransmission and stress corticosteroids on the NMDA-receptors of the hippocampus have been long studied in animals, but given little attention in human studies. In this randomized single-blinded placebo-controlled crossover study (12 healthy young men), five sets of resting-state fMRI (RSFMRI), pseudocontinuous arterial spin labeling (PCASL), and corresponding salivary cortisol samples were acquired over 4 h, at given intervals under pharmacokinetically-controlled infusion of subanesthetic ketamine (20 & 40 mg/70 kg/h). An identical procedure was repeated under a sham placebo condition. Differences in the profile of ketamine versus placebo effect over time were examined. Compared to placebo, ketamine mimicked a stress-like response (increased cortisol, reduced calmness and alertness, and impaired working memory). Ketamine effects on the brain included a transient prefrontal hyperperfusion and a dose-related reduction of relative hippocampal perfusion, plus emerging hyperconnectivity between the hippocampus and the occipital, cingulate, precuneal, cerebellar and basal ganglia regions. The spatiotemporal profiles of ketamine effects on different hippocampal subnetworks suggest a topographically dissociable change in corticohippocampal functional connectivity. We discuss our findings in the context of the negative feedback inhibition theory of the hippocampal stress control. This pilot study provides a methodological framework for multimodal functional neuroimaging under resting-state conditions, which may be generalized for translational studies of glutamatergic- or stress-related etiology of neuropsychiatric disorders.

Mahani, N. K., Niesters, M., van Osch, M. J., Oitzl, M., Veer, I., de Rooij, M., … & Dahan, A. (2014). Ketamine Interactions with Biomarkers of Stress: A randomized placebo-controlled repeated measures resting-state fMRI and PCASL pilot study in healthy men. NeuroImage. https://dx.doi.org/10.1016/j.neuroimage.2014.12.050
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Development and validation of a rapid turboflow LC-MS/MS method for the quantification of LSD and 2-oxo-3-hydroxy LSD in serum and urine samples of emergency toxicological cases

December 27, 2014 / LSD, Papers, Psychiatry & Medicine, Publications / By / , ,

Abstract

Lysergic acid diethylamide (LSD) is a widely used recreational drug. The aim of the present study is to develop a quantitative turboflow LC-MS/MS method that can be used for rapid quantification of LSD and its main metabolite 2-oxo-3-hydroxy LSD (O-H-LSD) in serum and urine in emergency toxicological cases without time-consuming extraction steps. The method was developed on an ion-trap LC-MS/MS instrument coupled to a turbulent-flow extraction system. The validation data showed no significant matrix effects and no ion suppression has been observed in serum and urine. Mean intraday accuracy and precision for LSD were 101 and 6.84 %, in urine samples and 97.40 and 5.89 % in serum, respectively. For O-H-LSD, the respective values were 97.50 and 4.99 % in urine and 107 and 4.70 % in serum. Mean interday accuracy and precision for LSD were 100 and 8.26 % in urine and 101 and 6.56 % in serum, respectively. For O-H-LSD, the respective values were 101 and 8.11 % in urine and 99.8 and 8.35 % in serum, respectively. The lower limit of quantification for LSD was determined to be 0.1 ng/ml. LSD concentrations in serum were expected to be up to 8 ng/ml. 2-Oxo-3-hydroxy LSD concentrations in urine up to 250 ng/ml. The new method was accurate and precise in the range of expected serum and urine concentrations in patients with a suspected LSD intoxication. Until now, the method has been applied in five cases with suspected LSD intoxication where the intake of the drug has been verified four times with LSD concentrations in serum in the range of 1.80–14.70 ng/ml and once with a LSD concentration of 1.25 ng/ml in urine. In serum of two patients, the O-H-LSD concentration was determined to be 0.99 and 0.45 ng/ml. In the urine of a third patient, the O-H-LSD concentration was 9.70 ng/ml.

Dolder, P. C., Liechti, M. E., & Rentsch, K. M. (2015). Development and validation of a rapid turboflow LC-MS/MS method for the quantification of LSD and 2-oxo-3-hydroxy LSD in serum and urine samples of emergency toxicological cases. Analytical and bioanalytical chemistry, 407(6), 1577-1584. http://dx.doi.org/10.1007/s00216-014-8388-1

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Rapid-onset antidepressant action of ketamine: potential revolution in understanding and future pharmacologic treatment of depression

December 26, 2014 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Summary

What is known and objective

The current pharmacotherapeutic treatment of major depressive disorder (MDD) generally takes weeks to be effective. As the molecular action of these drugs is immediate, the mechanistic basis for this lag is unclear. A drug that has a more rapid onset of action would be a major therapeutic advance and also be a useful comparator to provide valuable mechanistic insight into the disorder and its treatment.

Comment

Recent evidence suggests that ketamine produces rapid-onset antidepressant action. Important questions are as follows: is it specific or coincidental to other effects; is there a dose–response relationship; and is the mechanism related to that of current antidepressants. NMDA receptor antagonism is unlikely the explanation for ketamine’s antidepressant action.

What is new and conclusion

It is not an exaggeration to state that the new findings, if validated, might produce a revolution in understanding and treating depressive disorders.

Drewniany, E., Han, J., Hancock, C., Jones, R. L., Lim, J., Nemat Gorgani, N., … & Raffa, R. B. (2014). Rapid‐onset antidepressant action of ketamine: potential revolution in understanding and future pharmacologic treatment of depression. Journal of Clinical Pharmacy and Therapeutics. https://dx.doi.org/10.1111/jcpt.12238
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Synthesis and κ-opioid receptor activity of furan-substituted salvinorin A analogues

December 26, 2014 / Papers, Pharmacology & Chemistry, Publications, Salvia / Salvinorin A, Substance Use Disorder / By / , , , , ,

Abstract

The neoclerodane diterpene salvinorin A, found in the leaves of Salvia divinorum, is a potent κ-opioid receptor agonist, making it an attractive scaffold for development into a treatment for substance abuse. Although several successful semisynthetic studies have been performed to elucidate structure-activity relationships, the lack of analogues with substitutions to the furan ring of salvinorin A has prevented a thorough understanding of its role in binding to the κ-opioid receptor. Herein we report the synthesis of several salvinorin A derivatives with modified furan rings. Evaluation of these compounds in a functional assay indicated that sterically less demanding substitutions are preferred, suggesting the furan ring is bound in a congested portion of the binding pocket. The most potent of the analogues successfully reduced drug-seeking behavior in an animal model of drug-relapse without producing the sedation observed with other κ-opioid agonists.

Riley, A. P., Groer, C. E., Young, D., Ewald, A. W., Kivell, B. M., & Prisinzano, T. E. (2014). Synthesis and Kappa Opioid Receptor Activity of Furan-Substituted Salvinorin A Analogues. Journal of medicinal chemistry. https://dx.doi.org/10.1021/jm501521d
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Neurocognitive Effects of Ketamine and Association with Antidepressant Response in Individuals with Treatment-Resistant Depression: A Randomized Controlled Trial

December 17, 2014 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , , , ,

Abstract

The glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine displays rapid antidepressant effects in patients with treatment-resistant depression (TRD); however, the potential for adverse neurocognitive effects in this population has not received adequate study. The current study was designed to investigate the delayed neurocognitive impact of ketamine in TRD and examine baseline antidepressant response predictors in the context of a randomized controlled trial. In the current study, 62 patients (mean age=46.2±12.2) with TRD free of concomitant antidepressant medication underwent neurocognitive assessments using components of the MATRICS Consensus Cognitive Battery (MCCB) before and after a single intravenous infusion of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg). Participants were randomized to ketamine or midazolam in a 2:1 fashion under double-blind conditions and underwent depression symptom assessments at 24, 48, 72 h, and 7 days post treatment using the Montgomery–Asberg Depression Rating Scale (MADRS). Post-treatment neurocognitive assessment was conducted once at 7 days. Neurocognitive performance improved following the treatment regardless of treatment condition. There was no differential effect of treatment on neurocognitive performance and no association with antidepressant response. Slower processing speed at baseline uniquely predicted greater improvement in depression at 24 h following ketamine (t=2.3, p=0.027), while controlling for age, depression severity, and performance on other neurocognitive domains. In the current study, we found that ketamine was devoid of adverse neurocognitive effects at 7 days post treatment and that slower baseline processing speed was associated with greater antidepressant response. Future studies are required to further define the neurocognitive profile of ketamine in clinical samples and to identify clinically useful response moderators.

Murrough, J. W., Burdick, K. E., Levitch, C. F., Perez, A. M., Brallier, J. W., Chang, L. C., … & Iosifescu, D. V. (2014). Neurocognitive Effects of Ketamine and Association with Antidepressant Response in Individuals with Treatment-Resistant Depression: A Randomized Controlled Trial. Neuropsychopharmacology. https://dx.doi.org/10.1038/npp.2014.298

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Medical Drug or Shamanic Power Plant: The Uses of Kambô in Brazil

December 11, 2014 / Anthropology & Sociology, Biology & Ethnobotany, Depressive Disorders, Papers, Psychiatry & Medicine, Publications / By / ,

Abstract

The secretion from the frog Phyllomedusa bicolor, known in Portuguese as kambô, has traditionally been used as a stimulant and an invigorating agent for hunting by indigenous groups such as the Katukina, Yawanawa, and the Kaxinawa in the southeast Amazon. Since the mid 90s, its use has expanded to large cities in Brazil and, since the late 2000s, abroad to Europe and the US. The urban diffusion of the use of kambô has taken place via healing clinics offering alternative therapies, by way of members of the Brazilian ayahuasca religions, and through travel, mainly by Amazonian rubber tappers, the Katukina, and the Kawinawa Indians. In this article, we present an ethnography of the expansion and reinvention of the use of kambô. We describe the individuals who apply the substance, who are a diverse group, including indigenous healers, ex-rubber tappers, holistic therapists, and doctors. We argue that the frog secretion has a double appeal among this new urban clientele: as a “remedy of science,” in which its biochemical properties are stressed; and as a “remedy of spirit,” in which its “indigenous origin” is more valued, as if kambô was a kind of shamanic power plant analogous to peyote and ayahuasca.

Labate, B. C., & Lima, E. C. D. (2014). Medical Drug or Shamanic Power Plant: The Uses of Kambô in Brazil. Ponto Urbe. Revista do núcleo de antropologia urbana da USP, (15).
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