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Psychopharmacology

Serotonin, But Not N-Methyltryptamines, Activates the Serotonin 2A Receptor Via a β-Arrestin2/Src/Akt Signaling Complex In Vivo

October 6, 2010 / Other subjects, Other substances, Papers, Psychopharmacology, Publications / By / ,

Abstract

Hallucinogens mediate many of their psychoactive effects by activating serotonin 2A receptors (5-HT2AR). Although serotonin is the cognate endogenous neurotransmitter and is not considered hallucinogenic, metabolites of serotonin also have high affinity at 5-HT2AR and can induce hallucinations in humans. Here we report that serotonin differs from the psychoactiveN-methyltryptamines by its ability to engage a β-arrestin2-mediated signaling cascade in the frontal cortex. Serotonin and 5-hydroxy-L-tryptophan (5-HTP) induce a head-twitch response in wild-type (WT) mice that is a behavioral proxy for 5-HT2AR activation. The response in β-arrestin2 knock-out (βarr2-KO) mice is greatly attenuated until the doses are elevated, at which point, βarr2-KO mice display a head-twitch response that can exceed that of WT mice. Direct administration of N-methyltryptamines also produces a greater response in βarr2-KO mice. Moreover, the inhibition of N-methyltransferase blocks 5-HTP-induced head twitches in βarr2-KO mice, indicating that N-methyltryptamines, rather than serotonin, primarily mediate this response. Biochemical studies demonstrate that serotonin stimulates Akt phosphorylation in the frontal cortex and in primary cortical neurons through the activation of a β-arrestin2/phosphoinositide 3-kinase/Src/Akt cascade, whereas N-methyltryptamines do not. Furthermore, disruption of any of the components of this cascade prevents 5-HTP-induced, but not N-methyltryptamine-induced, head twitches. We propose that there is a bifurcation of 5-HT2AR signaling that is neurotransmitter and β-arrestin2 dependent. This demonstration of agonist-directed 5-HT2AR signaling in vivo may significantly impact drug discovery efforts for the treatment of disorders wherein hallucinations are part of the etiology, such as schizophrenia, or manifest as side effects of treatment, such as depression.

Schmid, C. L., & Bohn, L. M. (2010). Serotonin, But Not N-Methyltryptamines, Activates the Serotonin 2A Receptor Via a β-Arrestin2/Src/Akt Signaling Complex In Vivo. The Journal of Neuroscience, 30(40), 13513-13524. http://dx.doi.org/10.1523/JNEUROSCI.1665-10.2010

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Salvinorin A fails to substitute for the discriminative stimulus effects of LSD or ketamine in Sprague–Dawley rats

September 28, 2010 / Ketamine, LSD, Other subjects, Papers, Psychopharmacology, Publications, Salvia / Salvinorin A / By / , ,

Abstract

Salvia divinorum is a small perennial shrub that has gained recent popularity among the drug-using subculture as a legal alternative to hallucinogens. Salvinorin A, the main active compound found in the S. divinorum plant, is an atypical hallucinogen with pharmacological selectivity at kappa opioid (KOP) receptor sites and is a unique non-nitrogenous neoclerodane diterpene which is structurally distinct from other opioid compounds. The novel structure of salvinorin A and its specific binding affinity to KOP receptors provide a unique opportunity to investigate neurochemical mechanisms of hallucination and hallucinogenic compounds. The current investigation assessed the substitution of salvinorin A in 16 male Sprague–Dawley rats trained to discriminate either the prototypical serotonergic hallucinogen, LSD (0.08 mg/kg, S.C., n = 8) or the dissociative anesthetic and glutamatergic hallucinogen, ketamine (8.0 mg/kg, I.P., n = 8) from vehicle under a FR 20 schedule of food-reinforced responding. Results indicated that neither LSD nor ketamine discrimination generalized to salvinorin A. These findings are consistent with the growing body of evidence that salvinorin A is pharmacologically distinct from other traditional hallucinogenic compounds.

Killingera, B. A., Peeta, M. M., & Baker, L. E. (2010). Salvinorin A fails to substitute for the discriminative stimulus effects of LSD or ketamine in Sprague–Dawley rats. Pharmacology Biochemistry and Behavior, 96(3), 260-265. http://dx.doi.org/10.1016/j.pbb.2010.05.014
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Glutamatergic Model Psychoses: Prediction Error, Learning, and Inference

September 22, 2010 / Ketamine, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Psychosis, Publications / By / , , ,

Abstract

Modulating glutamatergic neurotransmission induces alterations in conscious experience that mimic the symptoms of early psychotic illness. We review studies that use intravenous administration of ketamine, focusing on interindividual variability in the profundity of the ketamine experience. We will consider this individual variability within a hypothetical model of brain and cognitive function centered upon learning and inference. Within this model, the brains, neural systems, and even single neurons specify expectations about their inputs and responding to violations of those expectations with new learning that renders future inputs more predictable. We argue that ketamine temporarily deranges this ability by perturbing both the ways in which prior expectations are specified and the ways in which expectancy violations are signaled. We suggest that the former effect is predominantly mediated by NMDA blockade and the latter by augmented and inappropriate feedforward glutamatergic signaling. We suggest that the observed interindividual variability emerges from individual differences in neural circuits that normally underpin the learning and inference processes described. The exact source for that variability is uncertain, although it is likely to arise not only from genetic variation but also from subjects’ previous experiences and prior learning. Furthermore, we argue that chronic, unlike acute, NMDA blockade alters the specification of expectancies more profoundly and permanently. Scrutinizing individual differences in the effects of acute and chronic ketamine administration in the context of the Bayesian brain model may generate new insights about the symptoms of psychosis; their underlying cognitive processes and neurocircuitry.

Corlett, P. R., Honey, G. D., Krystal, J. H., & Fletcher, P. C. (2011). Glutamatergic Model Psychoses: Prediction Error, Learning, and Inference. Neuropsychopharmacology Reviews, 36, 294–315. http://dx.doi.org/10.1038/npp.2010.163
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Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies

September 20, 2010 / Mushrooms / Psilocybin, Papers, Psychology, Psychopharmacology, Psychosis, Publications, Safety / By / , , ,

Abstract

Psilocybin and related hallucinogenic compounds are increasingly used in human research. However, due to limited information about potential subjective side effects, the controlled medical use of these compounds has remained controversial. We therefore analysed acute, short- and longterm subjective effects of psilocybin in healthy humans by pooling raw data from eight double-blind placebo-controlled experimental studies conducted between 1999 and 2008. The analysis included 110 healthy subjects who had received 1–4 oral doses of psilocybin (45–315mg/kg body weight). Although psilocybin dose-dependently induced profound changes in mood, perception, thought and self-experience, most subjects described the experience as pleasurable, enriching and non-threatening. Acute adverse drug reactions, characterized by strong dysphoria and/or anxiety/panic, occurred only in the two highest dose conditions in a relatively small proportion of subjects. All acute adverse drug reactions were successfully managed by providing interpersonal support and did not need psychopharmacological intervention. Follow-up questionnaires indicated no subsequent drug abuse, persisting perception disorders, prolonged psychosis or other long-term impairment of functioning in any of our subjects. The results suggest that the administration of moderate doses of psilocybin to healthy, high-functioning and well-prepared subjects in the context of a carefully monitored research environment is associated with an acceptable level of risk.

Studerus, E., Kometer, M., Hasler, F., & Vollenweider, F. X. (2010). Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies. Journal of Psychopharmacology, 25(11), 1434-1452. http://dx.doi.org/10.1177/0269881110382466
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The neurobiology of psychedelic drugs: implications for the treatment of mood disorders

September 10, 2010 / Cacti / Mescaline, Depression, DMT, Ketamine, LSD, Mushrooms / Psilocybin, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / ,

Abstract

After a pause of nearly 40 years in research into the effects of psychedelic drugs, recent advances in our understanding of the neurobiology of psychedelics, such as lysergic acid diethylamide (LSD), psilocybin and ketamine have led to renewed interest in the clinical potential of psychedelics in the treatment of various psychiatric disorders. Recent behavioural and neuroimaging data show that psychedelics modulate neural circuits that have been implicated in mood and affective disorders, and can reduce the clinical symptoms of these disorders. These findings raise the possibility that research into psychedelics might identify novel therapeutic mechanisms and approaches that are based on glutamate-driven neuroplasticity.

Vollenweider, F. X., & Kometer, M. (2010). The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nature Reviews Neuroscience, 11, 642-651. http://dx.doi.org/10.1038/nrn2884
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Intrahippocampal LSD accelerates learning and desensitizes the 5-HT2A receptor in the rabbit

September 9, 2010 / LSD, Other subjects, Other substances, Papers, Psychopharmacology, Publications / By / , , , , , ,

Abstract

Rationale: Parenteral injections of d-lysergic acid diethylamide (LSD), a serotonin 5-HT2A receptor agonist, enhance eyeblink conditioning. Another hallucinogen, (±)-1(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), was shown to elicit a 5-HT2A-mediated behavior (head bobs) after injection into the hippocampus, a structure known to mediate trace eyeblink conditioning.

Objective: This study aims to determine if parenteral injections of the hallucinogens LSD, d,l-2,5-dimethoxy-4-methylamphetamine, and 5-methoxy-dimethyltryptamine elicit the 5-HT2A-mediated behavior of head bobs and whether intrahippocampal injections of LSD would produce head bobs and enhance trace eyeblink conditioning.

Materials and methods: LSD was infused into the dorsal hippocampus just prior to each of eight conditioning sessions. One day after the last infusion of LSD, DOI was infused into the hippocampus to determine whether there had been a desensitization of the 5-HT2A receptor as measured by a decrease in DOI-elicited head bobs.

Results: Acute parenteral or intrahippocampal LSD elicited a 5-HT2A but not a 5-HT2C-mediated behavior, and chronic administration enhanced conditioned responding relative to vehicle controls. Rabbits that had been chronically infused with 3 or 10 nmol per side of LSD during Pavlovian conditioning and then infused with DOI demonstrated a smaller increase in head bobs relative to controls.

Conclusions: LSD produced its enhancement of Pavlovian conditioning through an effect on 5-HT2A receptors located in the dorsal hippocampus. The slight, short-lived enhancement of learning produced by LSD appears to be due to the development of desensitization of the 5-HT2A receptor within the hippocampus as a result of repeated administration of its agonist (LSD).

Romano, A. G., Quinn, J. L., Li, L., Dave, K. D., Schindler, E. A., Aloyo, V. J., & Harvey, J. A. (2010). Intrahippocampal LSD accelerates learning and desensitizes the 5-HT2A receptor in the rabbit. Psychopharmacology, 212(3), 441–448. http://dx.doi.org/10.1007/s00213-010-2004-7
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A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression

August 9, 2010 / Depression, Ketamine, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , , , , ,

Abstract

Context: Existing therapies for bipolar depression have a considerable lag of onset of action. Pharmacological strategies that produce rapid antidepressant effects—for instance, within a few hours or days—would have an enormous impact on patient care and public health.

Objective: To determine whether an N-methyl-Daspartate–receptor antagonist produces rapid antidepressant effects in subjects with bipolar depression.

Design: A randomized, placebo-controlled, doubleblind, crossover, add-on study conducted from October 2006 to June 2009.

Setting: Mood Disorders Research Unit at the National Institute of Mental Health, Bethesda, Maryland.

Patients: Eighteen subjects with DSM-IV bipolar depression (treatment-resistant).

Interventions: Subjects maintained at therapeutic levels of lithium or valproate received an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days 2 weeks apart. The Montgomery- Asberg Depression Rating Scale was used to rate subjects at baseline and at 40, 80, 110, and 230 minutes and on days 1, 2, 3, 7, 10, and 14 postinfusion.

Results: Within 40 minutes, depressive symptoms significantly improved in subjects receiving ketamine compared with placebo (d=0.52, 95% confidence interval [CI], 0.28-0.76); this improvement remained significant through day 3. The drug difference effect size was largest at day 2 (d=0.80, 95% CI, 0.55-1.04). Seventy-one percent of subjects responded to ketamine and 6% responded to placebo at some point during the trial. One subject receiving ketamine and 1 receiving placebo developed manic symptoms. Ketamine was generally well tolerated; the most common adverse effect was dissociative symptoms, only at the 40-minute point.

Diazgranados, N.,  Ibrahim, L. Brutsche, N. E., Newberg, A., Kronstein, P.,  Khalife, S., … Zarate Jr., Z. A. (2010). A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression. Archives of General Psychiatry, 67(8). http://dx.doi.org/10.1001/archgenpsychiatry.2010.90
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The safety and efficacy of ±3,4-methylenedioxymethamphetamineassisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder

July 19, 2010 / Anxiety disorders / PTSD, MDMA, Papers, Psychiatry, Psychology, Psychopharmacology, Psychotherapy, Publications, Safety / By / , , , ,

Abstract

Case reports indicate that psychiatrists administered 3,4-methylenedioxymethamphetamine (MDMA) as a catalyst to psychotherapy before recreational use of MDMA as ‘Ecstasy’ resulted in its criminalization in 1985. Over two decades later, this study is the first completed clinical trial evaluating MDMA as a therapeutic adjunct. Twenty patients with chronic posttraumatic stress disorder, refractory to both psychotherapy and psychopharmacology, were randomly assigned to psychotherapy with concomitant active drug (n¼12) or inactive placebo (n¼8) administered during two 8-h experimental psychotherapy sessions. Both groups received preparatory and follow-up non-drug psychotherapy. The primary outcome measure was the Clinician- Administered PTSD Scale, administered at baseline, 4 days after each experimental session, and 2 months after the second session. Neurocognitive testing, blood pressure, and temperature monitoring were performed. After 2-month follow-up, placebo subjects were offered the option to re-enroll in the experimental procedure with open-label MDMA. Decrease in Clinician-Administered PTSD Scale scores from baseline was significantly greater for the group that received MDMA than for the placebo group at all three time points after baseline. The rate of clinical response was 10/12 (83%) in the active treatment group versus 2/8 (25%) in the placebo group. There were no drug-related serious adverse events, adverse neurocognitive effects or clinically significant blood pressure increases. MDMA-assisted psychotherapy can be administered to posttraumatic stress disorder patients without evidence of harm, and it may be useful in patients refractory to other treatments.

Mithoefer, M. C., Wagner, M. T., Mithoefer, A. T., Jerome, L., & Doblin, R. (2010). The safety and efficacy of ±3,4-methylenedioxymethamphetamineassisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. Journal of Psychopharmacology, 25(4), 439-452. http://dx.doi.org/10.1177/0269881110378371
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Composition, Standardization and Chemical Profiling of Banisteriopsis caapi, a Plant for the Treatment of Neurodegenerative Disorders Relevant to Parkinson’s Disease

April 21, 2010 / Ayahuasca, Chemistry, Ethnobotany, Medicine, Other subjects, Papers, Psychopharmacology, Publications / By / , , , , , ,

Abstract

Ethnopharmacological relevance

Banisteriopsis caapi, a woody vine from the Amazonian basin, is popularly known as an ingredient of a sacred drink ayahuasca, widely used throughout the Amazon as a medicinal tea for healing and spiritual exploration. The usefulness of Banisteriopsis caapi has been established for alleviating symptoms of neurological disorders including Parkinson’s disease.

Aim of the study

Primary objective of this study was to develop the process for preparing standardized extracts of Banisteriopsis caapi to achieve high potency for inhibition of human monoamine oxidases (MAO) and antioxidant properties. The aqueous extracts prepared from different parts of the plant collected from different geographical locations and seasons were analyzed by HPLC for principal bioactive markers. The extracts were simultaneously tested in vitro for inhibition of human MAOs and antioxidant activity for analysis of correlation between phytochemical composition of the extracts and bioactivities.

Materials and methods

Reversed-phase HPLC with photodiode array detection was employed to profile the alkaloidal and non-alkaloidal components of the aqueous extract of Banisteriopsis caapi. The Banisteriopsis caapi extracts and standardized compositions were tested in vitro for inhibition of recombinant preparations of human MAO-A and MAO-B. In vitro cell-based assays were employed for evaluation of antioxidant property and mammalian cell cytotoxicity of these preparations.

Results

Among the different aerial parts, leaves, stems/large branches and stem bark of Banisteriopsis caapi, HPLC analysis revealed that most of the dominant chemical and bioactive markers (1, 2, 5, 7–9) were present in high concentrations in dried bark of large branch. A library of HPLC chromatograms has also been generated as a tool for fingerprinting and authentication of the studied Banisteriopsis caapi species. The correlation between potency of MAO inhibition and antioxidant activity with the content of the main active constituents of the aqueous Banisteriopsis caapi extracts and standardized compositions was established. Phytochemical analysis of regular/commercial Banisteriopsis caapi dried stems, obtained from different sources, showed a similar qualitative HPLC profile, but relatively low content of dominant markers 1, 2, 7, and 9, which led to decreased MAO inhibitory and antioxidant potency compared to Banisteriopsis caapi Da Vine.

Conclusion

The ethnopharmacological use of bark of matured stem/large branch of Banisteriopsis caapi as well as whole matured stem is supported by the results obtained in this investigation. Among various constituents of Banisteriopsis caapi, harmine (7), harmaline (6) and tetrahydroharmine (5) are responsible for MAO-A inhibition, while two major proanthocyanidines, epicatechin (8) and procyanidine B2 (9) produce antioxidant effects. The compounds 1–9 can serve as reliable markers for identification and standardization of Banisteriopsis caapi aerial parts, collected in different seasons and/or from different geographical regions.

Wang, Y. H., Samoylenko, V., Tekwani, B. L., Khan, I. A., Miller, L. S., Chaurasiya, N. D., … & Muhammad, I. (2010). Composition, standardization and chemical profiling of Banisteriopsis caapi, a plant for the treatment of neurodegenerative disorders relevant to Parkinson’s disease. Journal of ethnopharmacology, 128(3), 662-671. http://dx.doi.org/10.1016/j.jep.2010.02.013
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The persistence of the subjective in neuropsychopharmacology: observations of contemporary hallucinogen research

February 26, 2010 / Ayahuasca, Cacti / Mescaline, DMT, Iboga / Ibogaine, Ketamine, LSD, MDMA, Mushrooms / Psilocybin, Neuroscience, Other disciplines, Other subjects, Other substances, Papers, Psychology, Psychopharmacology, Publications, Salvia / Salvinorin A / By /

Abstract

The elimination of subjectivity through brain research and the replacement of so-called ‘folk psychology’ by a neuroscientifically enlightened worldview and self-conception has been both hoped for and feared. But this cultural revolution is still pending. Based on nine months of fieldwork on the revival of hallucinogen research since the ‘Decade of the Brain,’ this paper examines how subjective experience appears as epistemic object and practical problem in a psychopharmacological laboratory. In the quest for neural correlates of (drug-induced altered states of) consciousness, introspective accounts of test subjects play a crucial role in neuroimaging studies. Firsthand knowledge of the drugs’ flamboyant effects provides researchers with a personal knowledge not communicated in scientific publications, but key to the conduct of their experiments. In many cases, the ‘psychedelic experience’ draws scientists into the field and continues to inspire their self-image and way of life. By exploring these domains the paper points to a persistence of the subjective in contemporary neuropsychopharmacology.

Langlitz, N. (2010). The persistence of the subjective in neuropsychopharmacology: observations of contemporary hallucinogen research. History of Human Sciences, 23(1), 37-57. http://dx.doi.org/10.1177/0952695109352413
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