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Ketamine for Depression, 1: Clinical Summary of Issues Related to Efficacy, Adverse Effects, and Mechanism of Action

/ Depressive Disorders, Ketamine, Papers, Psychology / /

Abstract

Ketamine is an anesthetic drug that is also used for off-label indications such as the mediation of analgesia and sedation in various settings. It is additionally recognized as an agent with antidepressant potential. For depression, it is most commonly administered as a slow intravenous infusion in subanesthetic doses (usually 0.5 mg/kg). As an antidepressant, is strikingly different from conventional antidepressant drugs in that it brings about rapid and marked attenuation of depressive symptoms even in patients with refractory depression. The benefits are observed within hours of administration, peak after about a day, and are lost 3-12 days later. Patients who do not benefit after the initial dose may benefit with serial dosing or at higher doses. Benefits can be maintained for weeks to months by the continuation of ketamine sessions at 2- to 4-day intervals. Adverse effects include dissociative and psychotomimetic changes that are almost always mild and transient, if present; transient elevation of heart rate and blood pressure often occur. These changes are usually well tolerated and are very seldom responsible for treatment discontinuation. Whereas ketamine is an N-methyl-d-aspartate receptor antagonist, and whereas much is known about its different biological effects, its actions that mediate the antidepressant response are presently not known for certain. Although big data on ketamine are presently unavailable, the drug holds promise in the treatment of depression, especially refractory depression.
Andrade, C. (2017). Ketamine for Depression, 1: Clinical Summary of Issues Related to Efficacy, Adverse Effects, and Mechanism of Action. The Journal of clinical psychiatry, 78(4), e415. 10.4088/JCP.17f11567
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Psychoactive Drugs as a Route to Development of Novel Anti-parasitic Agents

/ LSD, Papers, Psychiatry & Medicine / / ,

Abstract

Over a third of the world’s population is infected with parasitic worms. One of the most burdensome infections underpins the neglected tropical disease schistosomiasis (Bilharzia) caused by parasitic flatworms of the genus Schistosoma, which afflicts ~200 million people worldwide. Consequently, there is a need to discover and develop next generation anthelmintics, active against a broad spectrum of parasitic helminths.

Flatworm musculature is regulated by bioaminergic signalling: addition of exogenous 5-HT to isolated flatworm muscle fibres causes contraction. This effect is likely mediated by engagement of serotonergic G protein coupled receptors (GPCRs). For example, in free living planarians, knockdown of a serotonergic GPCR (S7.1) impairs worm motility. Here, we demonstrate that the psychoactive agent, lysergic acid diethylamide (LSD) acts as a agonist at the planarian S7.1 receptor (EC50 = 1.3±0.5nM, Emax 99±5% of 5-HT response). LSD evoked contraction inhibited the motility of free living planarian worms (distance moved 16±2% versus control worms) and potently blocked bipolar regeneration evoked by praziquantel (IC50 = 0.5±0.2nM). These data raises the possibility that other psychoactive drugs, including psychotropics with known activity at human 5-HT2 receptors, could serve as efficacious lead compounds to disrupt flatworm mobility.

Therefore, we screened a variety of psychoactive agents on the motility of free living planarian flatworms, as well as the functionality of heterologously expressed S7.1 using a real time cAMP biosensor. Agents were discovered that modulated flatworm movement and regeneration, and efficacy of the screened molecules provided information about structural features necessary for activity at this abundant flatworm serotonergic GPCR. These data also identify features of ligands conveying activity at flatworm 5-HT GPCRs.

Woodhouse, K., Chan, J. D., & Marchant, J. (2017). Psychoactive Drugs as a Route to Development of Novel Anti-parasitic Agents. The FASEB Journal, 31(1 Supplement), 1002-2.
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Anti-inflammatory effects of serotonin 5-HT2A receptor activation in ovalbumin-induced allergic asthma models

/ Neuroscience, Papers, Psychiatry & Medicine / / , ,

Abstract

Only recently has the full therapeutic value of serotonin [5-hydroxytryptophan (5-HT)] receptor activation begun to be explored. Currently there are two 5-HT2A receptor agonists in human clinical trials for the treatment of depression and obesity. An exciting new therapeutic avenue in which 5-HT2A agonists might be employed is the modulation of inflammation in allergic airways disease. Our lab has previously used an ovalbumin (OVA)-induced asthma model to demonstrate that administration of (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI] prior to allergen challenge prevents many of the symptoms of allergic asthma. Here we have utilized a modified protocol to test the effectiveness of (R)-DOI in treating persistent allergic asthma. We demonstrate that administration of (R)-DOI in a chronic model attenuates the elevated airway hyperresponsiveness (AHR) typically observed in an asthmatic response. We also have probed for the expression of inflammatory markers in the lung and BALF. We concurrently are testing for the impact psilocybin and other tryptamines have on AHR in rodents using our OVA model. Overall our strategy is to develop 5-HT2A receptor agonism as a viable treatment modality against asthma and other inflammatory disorders.
Flanagan, T. W., Sebastian, M. N., & Nichols, C. D. (2017). Anti-inflammatory effects of serotonin 5-HT2A receptor activation in ovalbumin-induced allergic asthma models. The FASEB Journal, 31(1 Supplement), 820-4.
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A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders

/ Depressive Disorders, Ketamine, Papers, Psychology / / , , , , , ,

Abstract

IMPORTANCE:
Several studies now provide evidence of ketamine hydrochloride’s ability to produce rapid and robust antidepressant effects in patients with mood and anxiety disorders that were previously resistant to treatment. Despite the relatively small sample sizes, lack of longer-term data on efficacy, and limited data on safety provided by these studies, they have led to increased use of ketamine as an off-label treatment for mood and other psychiatric disorders.
OBSERVATIONS:
This review and consensus statement provides a general overview of the data on the use of ketamine for the treatment of mood disorders and highlights the limitations of the existing knowledge. While ketamine may be beneficial to some patients with mood disorders, it is important to consider the limitations of the available data and the potential risk associated with the drug when considering the treatment option.
CONCLUSIONS AND RELEVANCE:
The suggestions provided are intended to facilitate clinical decision making and encourage an evidence-based approach to using ketamine in the treatment of psychiatric disorders considering the limited information that is currently available. This article provides information on potentially important issues related to the off-label treatment approach that should be considered to help ensure patient safety.

Sanacora, G., Frye, M. A., McDonald, W., Mathew, S. J., Turner, M. S., Schatzberg, A. F., … & Nemeroff, C. B. (2017). A consensus statement on the use of ketamine in the treatment of mood disorders. Jama psychiatry, 74(4), 399-405. 10.1001/jamapsychiatry.2017.0080
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Use of Ketamine in Clinical PracticeA Time for Optimism and Caution

/ Depressive Disorders, Ketamine, Papers, Psychology / / ,

Abstract

Increasing evidence, primarily from small studies, supports the idea that the dissociative anesthetic ketamine has rapid antidepressant effects in patients with treatment-refractory major depression.1 The beneficial effects of ketamine are observed within hours of administration and can last approximately 1 week. Given that up to one-third of patients with major depression fail current treatments,2 there is a clear need for novel and more effective treatments. Results to date have led to increasing off-label use of ketamine in clinical practices, with little guidance about clinical administration. In this issue of the JAMA Psychiatry, Sanacora and colleagues3 provide a much-needed consensus statement to help guide clinical use of ketamine.
Zorumski, C. F., & Conway, C. R. (2017). Use of ketamine in clinical practice: a time for optimism and caution. Jama psychiatry, 74(4), 405-406. 10.1001/jamapsychiatry.2017.0078
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Limitations to ‘Psychedelics and the science of self experience’

/ Papers, Philosophy & Religious Studies, Psychology / / , ,

Abstract

We read Matthew Nour and Robin Carhart-Harris editorial with enthusiasm. The Section History Ethics & Philosophy of Psychiatry Queensland meets once a month in the Brisbane area. The writers of this eLetter met at the end of March 2017and discussed this editorial. We congratulate and we agree with Derek K Tracy in “highlights of this issue” that it is a mesmerising read. We found that the editorial is well composed, interesting in its logic and we notice the structure to the editorial. There are 6 separate headings: defining the self, self in neuroscience, self disturbance , psychedelics as a window into the self, therapeutic implications, and conclusions. We discussed that overall the paper only presents a reductionist, non-compatabilist, materialist theory of self, which becomes a fallacy of a circular argument. For the purpose of this editorial such a reduction of a complex philosophical area is indeed suitable, but ignores other models and we miss a paragraph on these limitations. We feel that it would have assisted if there had been frank comments on the reductionist approach and the diverse facets to self relevant to psychiatry.
The quantitative meta analysis locates self experience to default mode network in a cortical median and anterior cingulate brain anatomy. Other theories of the self in the light of memories and emotions for example, made us curious about FMRI findings in the amygdala and hippocampal areas. However acknowledging FMRI as “correlation”, the subtext is identity with the subject of the correlation.
We were reminded that after all the self is a very complex philosophical area that preoccupied many eminent thinkers in the past (Remes P& Sihvola) We believe that also a discussion of other pathologies of self, multiple selves associated with dissociation and multiple personality disorder would have been more inclusive. We were curious about the role of language especially in people who speak several languages as the narrative (McAdams) of the self is based on semantics.
We believe that a paragraph highlighting the limitations to the approach would have made this a more balanced editorial. Also referencing evidence on psychedelics and clinical experience of their use, references that highlight a number of the risks and side effects (Larsen JK and Johnson M et al) would have added . There are merits in to including that psychedelics are also a potential double edged sword.
Beckmann, K. M., Brennan, R., & Arnold, J. (2017). Limitations to’Psychedelics and the science of self experience’.
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Limitations to 'Psychedelics and the science of self experience'

/ Papers, Philosophy & Religious Studies, Psychology / / , ,

Abstract

We read Matthew Nour and Robin Carhart-Harris editorial with enthusiasm. The Section History Ethics & Philosophy of Psychiatry Queensland meets once a month in the Brisbane area. The writers of this eLetter met at the end of March 2017and discussed this editorial. We congratulate and we agree with Derek K Tracy in “highlights of this issue” that it is a mesmerising read. We found that the editorial is well composed, interesting in its logic and we notice the structure to the editorial. There are 6 separate headings: defining the self, self in neuroscience, self disturbance , psychedelics as a window into the self, therapeutic implications, and conclusions. We discussed that overall the paper only presents a reductionist, non-compatabilist, materialist theory of self, which becomes a fallacy of a circular argument. For the purpose of this editorial such a reduction of a complex philosophical area is indeed suitable, but ignores other models and we miss a paragraph on these limitations. We feel that it would have assisted if there had been frank comments on the reductionist approach and the diverse facets to self relevant to psychiatry.
The quantitative meta analysis locates self experience to default mode network in a cortical median and anterior cingulate brain anatomy. Other theories of the self in the light of memories and emotions for example, made us curious about FMRI findings in the amygdala and hippocampal areas. However acknowledging FMRI as “correlation”, the subtext is identity with the subject of the correlation.
We were reminded that after all the self is a very complex philosophical area that preoccupied many eminent thinkers in the past (Remes P& Sihvola) We believe that also a discussion of other pathologies of self, multiple selves associated with dissociation and multiple personality disorder would have been more inclusive. We were curious about the role of language especially in people who speak several languages as the narrative (McAdams) of the self is based on semantics.
We believe that a paragraph highlighting the limitations to the approach would have made this a more balanced editorial. Also referencing evidence on psychedelics and clinical experience of their use, references that highlight a number of the risks and side effects (Larsen JK and Johnson M et al) would have added . There are merits in to including that psychedelics are also a potential double edged sword.
Beckmann, K. M., Brennan, R., & Arnold, J. (2017). Limitations to’Psychedelics and the science of self experience’.
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Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults

/ Mushrooms / Psilocybin, Papers, Psychology, Publications / / , , , , , ,

Abstract

INTRODUCTION: Psilocybin is a psychedelic tryptamine that has shown promise in recent clinical trials for the treatment of depression and substance use disorders. This open-label study of the pharmacokinetics of psilocybin was performed to describe the pharmacokinetics and safety profile of psilocybin in sequential, escalating oral doses of 0.3, 0.45, and 0.6 mg/kg in 12 healthy adults.

METHODS: Eligible healthy adults received 6-8 h of preparatory counseling in anticipation of the first dose of psilocybin. The escalating oral psilocybin doses were administered at approximately monthly intervals in a controlled setting and subjects were monitored for 24 h. Blood and urine samples were collected over 24 h and assayed by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for psilocybin and psilocin, the active metabolite. The pharmacokinetics of psilocin were determined using both compartmental (NONMEM) and noncompartmental (WinNonlin) methods.

RESULTS: No psilocybin was found in plasma or urine, and renal clearance of intact psilocin accounted for less than 2% of the total clearance. The pharmacokinetics of psilocin were linear within the twofold range of doses, and the elimination half-life of psilocin was 3 h (standard deviation 1.1). An extended elimination phase in some subjects suggests hydrolysis of the psilocin glucuronide metabolite. Variation in psilocin clearance was not predicted by body weight, and no serious adverse events occurred in the subjects studied.

CONCLUSIONS: The small amount of psilocin renally excreted suggests that no dose reduction is needed for subjects with mild-moderate renal impairment. Simulation of fixed doses using the pharmacokinetic parameters suggest that an oral dose of 25 mg should approximate the drug exposure of a 0.3 mg/kg oral dose of psilocybin. Although doses of 0.6 mg/kg are in excess of likely therapeutic doses, no serious physical or psychological events occurred during or within 30 days of any dose.

Brown, R. T., Nicholas, C. R., Cozzi, N. V., Gassman, M. C., Cooper, K. M., Muller, D., … & Hutson, P. R. (2017). Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults. Clinical Pharmacokinetics, 1-12. 10.1007/s40262-017-0540-6
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An online survey of tobacco smoking cessation associated with naturalistic psychedelic use

/ LSD, Mushrooms / Psilocybin, Papers, Psychology, Publications, Substance Use Disorder / / , , ,

Abstract

Data suggest psychedelics such as psilocybin and lysergic acid diethylamide (LSD) may hold therapeutic potential in the treatment of addictions, including tobacco dependence. This retrospective cross-sectional anonymous online survey characterized 358 individuals (52 females) who reported having quit or reduced smoking after ingesting a psychedelic in a non-laboratory setting ⩾1 year ago. On average, participants smoked 14 cigarettes/day for 8 years, and had five previous quit attempts before their psychedelic experience. Of the 358 participants, 38% reported continuous smoking cessation after psychedelic use (quitters). Among quitters, 74% reported >2 years’ abstinence. Of the 358 participants, 28% reported a persisting reduction in smoking (reducers), from a mode of 300 cigarettes/month before, to a mode of 1 cigarette/month after the experience. Among reducers, 62% reported >2 years of reduced smoking. Finally, 34% of the 358 participants (relapsers) reported a temporary smoking reduction before returning to baseline smoking levels, with a mode time range to relapse of 3–6 months. Relapsers rated their psychedelic experience significantly lower in personal meaning and spiritual significance than both other groups. Participants across all groups reported less severe affective withdrawal symptoms (e.g. depression, craving) after psychedelic use compared with previous quit attempts, suggesting a potential mechanism of action for psychedelic-associated smoking cessation/reduction. Changes in life priorities/values were endorsed as the most important psychological factor associated with smoking cessation/reduction. Results suggest psychedelics may hold promise in treating tobacco addiction as potentially mediated by spiritual experience, changed priorities/values, and improved emotional regulation.

Johnson, M. W., Garcia-Romeu, A., Johnson, P. S., & Griffiths, R. R. (2017). An online survey of tobacco smoking cessation associated with naturalistic psychedelic use. Journal of Psychopharmacology, 0269881116684335. 10.1177/0269881116684335
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Classic Hallucinogens and Mystical Experiences: Phenomenology and Neural Correlates

/ Anxiety Disorders / PTSD, Depressive Disorders, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications, Substance Use Disorder / / ,

Abstract

This chapter begins with a brief review of descriptions and definitions of mystical-type experiences and the historical connection between classic hallucinogens and mystical experiences. The chapter then explores the empirical literature on experiences with classic hallucinogens in which claims about mystical or religious experiences have been made. A psychometrically validated questionnaire is described for the reliable measurement of mystical-type experiences occasioned by classic hallucinogens. Controlled laboratory studies show that under double-blind conditions that provide significant controls for expectancy bias, psilocybin can occasion complete mystical experiences in the majority of people studied. These effects are dose-dependent, specific to psilocybin compared to placebo or a psychoactive control substance, and have enduring impact on the moods, attitudes, and behaviors of participants as assessed by self-report of participants and ratings by community observers. Other studies suggest that enduring personal meaning in healthy volunteers and therapeutic outcomes in patients, including reduction and cessation of substance abuse behaviors and reduction of anxiety and depression in patients with a life-threatening cancer diagnosis, are related to the occurrence of mystical experiences during drug sessions. The final sections of the chapter draw parallels in human neuroscience research between the neural bases of experiences with classic hallucinogens and the neural bases of meditative practices for which claims of mystical-type experience are sometimes made. From these parallels, a functional neural model of mystical experience is proposed, based on changes in the default mode network of the brain that have been observed after the administration of classic hallucinogens and during meditation practices for which mystical-type claims have been made.
Barrett, F. S., & Griffiths, R. R. (2017). Classic Hallucinogens and Mystical Experiences: Phenomenology and Neural Correlates. 10.1007/7854_2017_474
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Psychedelics in Palliative Care: Clinical and Ethical Considerations - October 27th

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