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Ketamine and depression: a narrative review.

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

Abstract

Depression is the third leading cause of disability in the world. Depressive symptoms may be reduced within several weeks after the start of conventional antidepressants, but treatment resistance concerns one-third of patients who fail to achieve recovery. Over the last 20 years, ketamine, an antagonist of the N-methyl-D-aspartate receptor, has been described to have antidepressant properties. A literature review was conducted through an exhaustive electronic search. It was restricted to Cochrane reviews, meta-analyses, and randomized controlled trials (RCTs) of ketamine for major depressive disorder and/or bipolar disorder. This review included two Cochrane reviews, 14 meta-analyses and 15 trials. Ketamine was studied versus placebo, versus other comparators and as an anesthetic adjuvant before electroconvulsive therapy. In 14 publications, ketamine provided a rapid antidepressant effect with a maximum efficacy reached at 24 hrs. Its effect lasted for 1-2 weeks after infusion, but a longer-term effect is little reported. Ketamine does not seem to improve depressive symptoms at the end of electroconvulsive sessions. Safety and tolerability profiles with ketamine at low single dose are generally good in depressed patients. However, there is a lack of data concerning ketamine with repeated administration at higher doses. The clinical use of ketamine is increasing. Intranasal (S)-ketamine has recently been approved for depression by the Food and Drug Administration. It could be a promising treatment in depressed patients with suicidal ideation. Collectively, the level of proof of efficacy remains low and more RCTs are needed to explore efficacy and safety issues of ketamine in depression.
Corriger, A., & Pickering, G. (2019). Ketamine and depression: a narrative review. Drug design, development and therapy, 13, 3051., https://doi.org/10.2147/DDDT.S221437
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Efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for posttraumatic stress disorder: A systematic review and meta-analysis.

/ Anxiety Disorders / PTSD, MDMA, Papers, Psychology, Publications / / , , ,

Abstract

BACKGROUND:
Posttraumatic stress disorder (PTSD) is a common psychiatric condition that can develop following a traumatic experience. PTSD is associated with significant disability, a large economic burden, and despite the range of therapies to treat PTSD, response to antidepressants is limited. A growing body of clinical research suggests the efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in individuals with treatment-refractory PTSD.
AIM:
To assess the effectiveness and safety of MDMA-assisted psychotherapy for reducing symptoms of PTSD, a systematic review and meta-analysis was undertaken.
METHODS:
Six online databases were searched from inception to December 2018. Reference lists of relevant articles were manually searched as well as electronic sources of ongoing trials and conference proceedings. Researchers active in the subject were also contacted. Eligible studies included randomized and quasi-randomized clinical trials using MDMA-assisted psychotherapy for PTSD in comparison with other medications, placebo or no medication (supportive care). We used standard methodological procedures expected by the Cochrane Collaboration. Two authors assessed studies for inclusion and extracted data. Using random-effects meta-analysis with Cochrane’s Review Manager 5.3, we obtained standardized mean differences [SMD] and rate ratios [RR] for reduction in PTSD symptomatology.
RESULTS:
A total of 5 trials met inclusion criteria, totaling 106 participants (average age: 35-40 years, 70% female). Studies were rated as moderate in quality. MDMA-assisted psychotherapy demonstrated a high rate of clinical response (RR = 3.47, 95% CI: 1.70, 7.06), remission (RR = 2.63, 95% CI: 1.37, 5.02), with a large effect size at reducing the symptoms of PTSD (SMD = 1.30, 95% CI: 0.66, 1.94). Available evidence indicates that MDMA was well-tolerated, with few serious adverse events reported across studies.
CONCLUSIONS:
MDMA-assisted psychotherapy appears to be a potentially safe, effective, and durable treatment for individuals with chronic, treatment-refractory PTSD. However, future studies involving larger samples and longer durations of treatment and follow-up are warranted-and underway.
Bahji, A., Forsyth, A., Groll, D., & Hawken, E. R. (2019). Efficacy of 3, 4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for posttraumatic stress disorder: A systematic review and meta-analysis. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 109735., https://doi.org/10.1016/j.pnpbp.2019.109735
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Psilocybin-assisted mindfulness training modulates self-consciousness and brain default mode network connectivity with lasting effects

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

Abstract

Both psychedelics and meditation exert profound modulatory effects on consciousness, perception and cognition, but their combined, possibly synergistic effects on neurobiology are unknown. Accordingly, we conducted a randomized, double-blind, placebo-controlled study with 38 participants following a single administration of the psychedelic psilocybin (315 μg/kg p.o.) during a 5-day mindfulness retreat. Brain dynamics were quantified directly pre- and post-intervention by functional magnetic resonance imaging during the resting state and two meditation forms. The analysis of functional connectivity identified psilocybin-related and mental state–dependent alterations in self-referential processing regions of the default mode network (DMN). Notably, decoupling of medial prefrontal and posterior cingulate cortices, which is thought to mediate sense of self, was associated with the subjective ego dissolution effect during the psilocybin-assisted mindfulness session. The extent of ego dissolution and brain connectivity predicted positive changes in psycho-social functioning of participants 4 months later. Psilocybin, combined with meditation, facilitated neurodynamic modulations in self-referential networks, subserving the process of meditation by acting along the anterior–posterior DMN connection. The study highlights the link between altered self-experience and subsequent behavioral changes. Understanding how interventions facilitate transformative experiences may open novel therapeutic perspectives. Insights into the biology of discrete mental states foster our understanding of non-ordinary forms of human self-consciousness and their concomitant brain substrate.

Smigielski, L., Scheidegger, M., Kometer, M., & Vollenweider, F. X. (2019). Psilocybin-assisted mindfulness training modulates self-consciousness and brain default mode network connectivity with lasting effects. NeuroImage, 196, 207-215., https://doi.org/10.1016/j.neuroimage.2019.04.009
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Promises and concerns regarding the use of ketamine and esketamine in the treatment of depression.

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

Pérez‐Esparza, R., Kobayashi‐Romero, L. F., García‐Mendoza, A. M., Lamas‐Aguilar, R. M., & Fonseca‐Perezamador, A. (2019). Promises and concerns regarding the use of ketamine and esketamine in the treatment of depression. Acta Psychiatrica Scandinavica, 140(2), 182-183., https://doi.org/10.1111/acps.13063
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Classical psychedelics for the treatment of depression and anxiety: A systematic review.

/ Anxiety Disorders / PTSD, Ayahuasca, Depressive Disorders, LSD, Mushrooms / Psilocybin, Papers, Psychology, Publications / / , ,

Abstract

BACKGROUND:
Depression and anxiety are prevalent psychiatric disorders that carry significant morbidity. Pharmacological and psychosocial interventions are used to manage these conditions, but their efficacy is limited. Recent interest into the use of psychedelic-assisted therapy using ayahuasca, psilocybin or lysergic acid diethylamide (LSD) may be a promising alternative for patients unresponsive to traditional treatments. This review aims to determine the efficacy and tolerability of psychedelics in the management of resistant depression.
METHODS:
Clinical trials investigating psychedelics in patients with depression and/or anxiety were searched via MEDLINE, EMBASE and PsychINFO. Efficacy was assessed by measuring symptom improvement from baseline, and tolerability was evaluated by noting the incidence and type of adverse effects reported. Risk of bias was assessed.
RESULTS:
Seven studies, with 130 patients, were analysed in this review. Three were conducted in patients with depression, two in patients with anxiety and two in patients with both. In a supportive setting, ayahuasca, psilocybin, and LSD consistently produced immediate and significant anti-depressant and anxiolytic effects that were endured for several months. Psychedelics were well-tolerated. The most common adverse effects were transient anxiety, short-lived headaches, nausea and mild increases in heart rate and blood pressure.
LIMITATIONS:
At present, the number of studies on this subject is very limited; and the number of participating patients within these is also limited as the treatment under investigations is a relatively novel concept.
CONCLUSIONS:
Though further evidence is required, psychedelics appear to be effective in significantly reducing symptoms of depression and anxiety and are well-tolerated.

Muttoni, S., Ardissino, M., & John, C. (2019). Classical psychedelics for the treatment of depression and anxiety: a systematic review. Journal of affective disorders., https://doi.org/10.1016/j.jad.2019.07.076
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Ketamine Enhances Visual Sensory Evoked Potential Long-term Potentiation in Patients With Major Depressive Disorder

/ Depressive Disorders, Ketamine, Neuroscience, Papers / Leave a Comment / / , , , , , , , , , , ,

Abstract

Background: The rapid-acting clinical effects of ketamine as a novel treatment for depression along with its complex pharmacology have made it a growing research area. One of the key mechanistic hypotheses for how ketamine works to alleviate depression is by enhancing long-term potentiation (LTP)-mediated neural plasticity.

Methods: The objective of this study was to investigate the plasticity hypothesis in 30 patients with depression noninvasively using visual LTP as an index of neural plasticity. In a double-blind, active placebo-controlled crossover trial, electroencephalography-based LTP was recorded approximately 3 to 4 hours following a single 0.44-mg/kg intravenous dose of ketamine or active placebo (1.7 ng/mL remifentanil) in 30 patients. Montgomery-Åsberg Depression Rating Scale scores were used to measure clinical symptoms. Visual LTP was measured as a change in the visually evoked potential following high-frequency visual stimulation. Dynamic causal modeling investigated the underlying neural architecture of visual LTP and the contribution of ketamine.

Results: Montgomery-Åsberg Depression Rating Scale scores revealed that 70% of participants experienced 50% or greater reduction in their depression symptoms within 1 day of receiving ketamine. LTP was demonstrated in the N1 (p = .00002) and P2 (p = 2.31 × 10-11) visually evoked components. Ketamine specifically enhanced P2 potentiation compared with placebo (p = .017). Dynamic causal modeling replicated the recruitment of forward and intrinsic connections for visual LTP and showed complementary effects of ketamine indicative of downstream and proplasticity modulation.

Conclusions: This study provides evidence that LTP-based neural plasticity increases within the time frame of the antidepressant effects of ketamine in humans and supports the hypothesis that changes to neural plasticity may be key to the antidepressant properties of ketamine.

Sumner, R. L., McMillan, R., Spriggs, M. J., Campbell, D., Malpas, G., Maxwell, E., Deng, C., Hay, J., Ponton, R., Kirk, I. J., Sundram, F., & Muthukumaraswamy, S. D. (2020). Ketamine Enhances Visual Sensory Evoked Potential Long-term Potentiation in Patients With Major Depressive Disorder. Biological psychiatry. Cognitive neuroscience and neuroimaging, 5(1), 45–55. https://doi.org/10.1016/j.bpsc.2019.07.002

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Metabolism of lysergic acid diethylamide (LSD): an update.

/ LSD, Papers, Pharmacology & Chemistry, Psychology, Publications / /

Abstract

Lysergic acid diethylamide (LSD) is the most potent hallucinogen known and its pharmacological effect results from stimulation of central serotonin receptors (5-HT2). Since LSD is seen as physiologically safe compound with low toxicity, its use in therapeutics has been renewed during the last few years. This review aims to discuss LSD metabolism, by presenting all metabolites as well as clinical and toxicological relevance. LSD is rapidly and extensively metabolized into inactive metabolites; whose detection window is higher than parent compound. The metabolite 2-oxo-3-hydroxy LSD is the major human metabolite, which detection and quantification is important for clinical and forensic toxicology. Indeed, information about LSD pharmacokinetics in humans is limited and for this reason, more research studies are needed.
Libânio Osório Marta, R. F. (2019). Metabolism of lysergic acid diethylamide (LSD): an update. Drug metabolism reviews, 51(3), 378-387. https://doi.org/10.1080/03602532.2019.1638931
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Esketamine for treatment resistant depression.

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

Abstract

Introduction: Treatment Resistant Depression (TRD) is a common and burdensome condition with poor outcomes and few treatment options. Esketamine is the S-enantiomer of ketamine and has recently been FDA approved in the United States for treating depression that has failed to respond to trials of two or more antidepressants. Areas covered: This review will briefly discuss current treatment options for TRD, then review esketamine. Relevant literature was identified through online database searches, and clinical trial data were provided by Janssen Pharmaceuticals. Pharmacology, including kinetics and dynamics, is discussed, then clinical data regarding efficacy and safety for esketamine from Phase 2-3 trials are reviewed. Expert opinion: In the expert opinion, the authors discuss multiple factors including patient, physician, and social factors that will influence the use of esketamine. While the efficacy of esketamine compared to off-label use of racemic ketamine remains unclear, both esketamine’s approval for use in TRD and longer-term safety data may position it preferentially above racemic ketamine, although factors such as cost and monitoring requirements may limit its use. While questions remain regarding duration and frequency of treatment, as well as addictive potential, esketamine is a novel treatment option offering new hope for TRD.
Swainson, J., Thomas, R. K., Archer, S., Chrenek, C., MacKay, M. A., Baker, G., … & Demas, M. L. (2019). Esketamine for treatment resistant depression. Expert review of neurotherapeutics, 1-13., https://doi.org/10.1080/14737175.2019.1640604
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Effects of the synthetic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) on ethanol consumption and place conditioning in male mice.

/ Papers, Psychology, Publications, Substance Use Disorder / / , , , ,

Abstract

RATIONALE:
Approximately 20 million adults in the USA have an alcohol use disorder (AUD). There are clinical and preclinical data suggesting that psychedelics may have benefits for AUD.
OBJECTIVE:
To investigate the effects of the synthetic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) on the behavioral effects of ethanol.
METHODS:
The effects of DOI were examined using ethanol-induced place conditioning (1.8 g/kg ethanol) and 2-bottle choice ethanol drinking (20% v/v), using a dose of DOI (3 mg/kg) that produced the maximal response in the serotonin 2A (5-HT2A) receptor-dependent head-twitch assay. Interactions between DOI and ethanol (3 g/kg) were examined using the ethanol-induced loss of righting reflex procedure and blood-ethanol analysis. To examine additional mechanisms by which psychedelics may interact with ethanol, we determined whether DOI reverses ethanol-induced nitric oxide release in macrophages, a marker of inflammation.
RESULTS:
DOI significantly attenuated ethanol-induced place conditioning and ethanol drinking. DOI-induced suppression of alcohol drinking depended upon 5-HT2A receptors, was selective for alcohol over water, and was selective for high alcohol-preferring subjects. DOI had no apparent pharmacokinetic interactions with ethanol, and DOI reduced ethanol-induced nitric oxide release.
CONCLUSIONS:
Our findings demonstrate that DOI blocks ethanol place conditioning and selectively reduces voluntary ethanol consumption. This may be related to modulation of the effects of ethanol in the reward circuitry of the brain, ethanol-induced neuroinflammation, or a combination of both. Additional studies to elucidate the mechanisms through which psychedelics attenuate the effects of ethanol would inform the pathophysiology of AUD and potentially provide new treatment options.
Oppong-Damoah, A., Curry, K. E., Blough, B. E., Rice, K. C., & Murnane, K. S. (2019). Effects of the synthetic psychedelic 2, 5-dimethoxy-4-iodoamphetamine (DOI) on ethanol consumption and place conditioning in male mice. Psychopharmacology, 1-12., https://doi.org/10.1007/s00213-019-05328-7
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Microdosing psychedelics: More questions than answers? An overview and suggestions for future research.

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

Abstract

BACKGROUND:
In the past few years, the issue of ‘microdosing’ psychedelics has been openly discussed in the public arena where claims have been made about their positive effect on mood state and cognitive processes such as concentration. However, there are very few scientific studies that have specifically addressed this issue, and there is no agreed scientific consensus on what microdosing is.
AIM:
This critique paper is designed to address questions that need to be answered by future scientific studies and to offer guidelines for these studies.
APPROACH:
Owing to its proximity for a possible approval in clinical use and short-lasting pharmacokinetics, our focus is predominantly on psilocybin. Psilocybin is allegedly, next to lysergic acid diethylamide (LSD), one of the two most frequently used psychedelics to microdose. Where relevant and available, data for other psychedelic drugs are also mentioned.
CONCLUSION:
It is concluded that while most anecdotal reports focus on the positive experiences with microdosing, future research should also focus on potential risks of (multiple) administrations of a psychedelic in low doses. To that end, (pre)clinical studies including biological (e.g. heart rate, receptor turnover and occupancy) as well as cognitive (e.g. memory, attention) parameters have to be conducted and will shed light on the potential negative consequences microdosing could have.
Kuypers, K. P., Ng, L., Erritzoe, D., Knudsen, G. M., Nichols, C. D., Nichols, D. E., … & Nutt, D. (2019). Microdosing psychedelics: More questions than answers? An overview and suggestions for future research. Journal of Psychopharmacology, 0269881119857204., https://doi.org/10.1177/0269881119857204
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Psychedelics and Acceptance and Commitment Therapy (ACT): A Process-Based Approach - September 15th

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