Psychedelics Promote Structural and Functional Neural Plasticity
TL;DR: It is reported that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo.
About: This article is published in Cell Reports.The article was published on 2018-06-12 and is currently open access. It has received 436 citations till now.
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TL;DR: A leading model of global brain function, hierarchical predictive coding, is integrated with an often-cited model of the acute action of psychedelics, the entropic brain hypothesis, which states that psychedelics work to relax high-level priors, sensitising them to liberated bottom-up information flow, which can help guide and cultivate the revision of entrenched pathological priors.
Abstract: This paper formulates the action of psychedelics by integrating the free-energy principle and entropic brain hypothesis. We call this formulation relaxed beliefs under psychedelics (REBUS) and the anarchic brain, founded on the principle that—via their entropic effect on spontaneous cortical activity—psychedelics work to relax the precision of high-level priors or beliefs, thereby liberating bottom-up information flow, particularly via intrinsic sources such as the limbic system. We assemble evidence for this model and show how it can explain a broad range of phenomena associated with the psychedelic experience. With regard to their potential therapeutic use, we propose that psychedelics work to relax the precision weighting of pathologically overweighted priors underpinning various expressions of mental illness. We propose that this process entails an increased sensitization of high-level priors to bottom-up signaling (stemming from intrinsic sources), and that this heightened sensitivity enables the potential revision and deweighting of overweighted priors. We end by discussing further implications of the model, such as that psychedelics can bring about the revision of other heavily weighted high-level priors, not directly related to mental health, such as those underlying partisan and/or overly-confident political, religious, and/or philosophical perspectives. Significance Statement Psychedelics are capturing interest, with efforts underway to bring psilocybin therapy to marketing authorisation and legal access within a decade, spearheaded by the findings of a series of phase 2 trials. In this climate, a compelling unified model of how psychedelics alter brain function to alter consciousness would have appeal. Towards this end, we have sought to integrate a leading model of global brain function, hierarchical predictive coding, with an often-cited model of the acute action of psychedelics, the entropic brain hypothesis. The resulting synthesis states that psychedelics work to relax high-level priors, sensitising them to liberated bottom-up information flow, which, with the right intention, care provision and context, can help guide and cultivate the revision of entrenched pathological priors.
361 citations
Cites background from "Psychedelics Promote Structural and..."
...Taken together, the above-cited findings speak to the notion that the brain enters an entropic hot state under psychedelics in which synaptic efficacy and plasticity are elevated (Ly et al., 2018)....
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...Recent (Berthoux et al., 2018; Ly et al., 2018) and older work (Vaidya et al....
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...The result of this window of exceptionally high plasticity may be to leave a legacy of potentially enduring functional and perhaps anatomic change (Ly et al., 2018)....
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...Our empirically informed theoretical treatment of psychedelics begins with a review of their pharmacology and associated behavioral research, both in animals and humans, making special reference to synaptic efficacy-enhancing effects (Ly et al., 2018)....
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TL;DR: State-of-the art studies have recently begun to close important knowledge gaps by elucidating the mechanisms of action of psychedelics with regard to their effects on receptor subsystems, systems-level brain activity and connectivity, and cognitive and emotional processing.
Abstract: Renewed interest in the use of psychedelics in the treatment of psychiatric disorders warrants a better understanding of the neurobiological mechanisms underlying the effects of these substances. After a hiatus of about 50 years, state-of-the art studies have recently begun to close important knowledge gaps by elucidating the mechanisms of action of psychedelics with regard to their effects on receptor subsystems, systems-level brain activity and connectivity, and cognitive and emotional processing. In addition, functional studies have shown that changes in self-experience, emotional processing and social cognition may contribute to the potential therapeutic effects of psychedelics. These discoveries provide a scientific road map for the investigation and application of psychedelic substances in psychiatry.
180 citations
09 Apr 2021
TL;DR: It is proposed that the subjective effects of psychedelics are necessary for their enduring beneficial effects and that these subjective effects account for the majority of their benefit.
Abstract: Classic psychedelics produce altered states of consciousness that individuals often interpret as meaningful experiences. Across a number of human studies, when the participant-rated intensity of the overall drug effects are statistically controlled for, certain subjective effects predict therapeutic and other desirable outcomes. Underlying neurobiological mechanisms are likely necessary but not sufficient to confer full and enduring beneficial effects. We propose that the subjective effects of psychedelics are necessary for their enduring beneficial effects and that these subjective effects account for the majority of their benefit.
163 citations
TL;DR: This work demonstrates that, through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant that has therapeutic potential.
Abstract: The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals1. Unlike most medications for the treatment of substance use disorders, anecdotal reports suggest that ibogaine has the potential to treat addiction to various substances, including opiates, alcohol and psychostimulants. The effects of ibogaine-like those of other psychedelic compounds-are long-lasting2, which has been attributed to its ability to modify addiction-related neural circuitry through the activation of neurotrophic factor signalling3,4. However, several safety concerns have hindered the clinical development of ibogaine, including its toxicity, hallucinogenic potential and tendency to induce cardiac arrhythmias. Here we apply the principles of function-oriented synthesis to identify the key structural elements of the potential therapeutic pharmacophore of ibogaine, and we use this information to engineer tabernanthalog-a water-soluble, non-hallucinogenic, non-toxic analogue of ibogaine that can be prepared in a single step. In rodents, tabernanthalog was found to promote structural neural plasticity, reduce alcohol- and heroin-seeking behaviour, and produce antidepressant-like effects. This work demonstrates that, through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant that has therapeutic potential.
134 citations
TL;DR: In this paper, a randomized controlled trial compared single-dose psilocybin with singledose niacin in conjunction with psychotherapy in participants with cancer-related psychiatric disorders.
Abstract: Background:A recently published randomized controlled trial compared single-dose psilocybin with single-dose niacin in conjunction with psychotherapy in participants with cancer-related psychiatric...
134 citations
Cites background from "Psychedelics Promote Structural and..."
...…increased entropy in the brain (Carhart-Harris, 2018), and disruption of activity within the default mode network, a brain system that is associated with self-referential information processing and mindwandering (Carhart-Harris and Nutt, 2017; Carhart-Harris and Goodwin, 2017; Ly et al., 2018)....
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..., 2019), increased entropy in the brain (Carhart-Harris, 2018), and disruption of activity within the default mode network, a brain system that is associated with self-referential information processing and mindwandering (Carhart-Harris and Nutt, 2017; Carhart-Harris and Goodwin, 2017; Ly et al., 2018)....
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References
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TL;DR: The Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) as discussed by the authors was used to estimate the burden of disease attributable to mental and substance use disorders in terms of disability-adjusted life years (DALYs), years of life lost to premature mortality (YLLs), and years lived with disability (YLDs).
4,753 citations
TL;DR: The acute and longer-term treatment outcomes associated with each of four successive steps in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial are described and compared.
Abstract: Objective: This report describes the participants and compares the acute and longer-term treatment outcomes associated with each of four successive steps in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. Method: A broadly representative adult outpatient sample with nonpsychotic major depressive disorder received one (N=3,671) to four (N=123) successive acute treatment steps. Those not achieving remission with or unable to tolerate a treatment step were encouraged to move to the next step. Those with an acceptable benefit, preferably symptom remission, from any particular step could enter a 12-month naturalistic follow-up phase. A score of ≤5 on the Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR 16 ) (equivalent to ≤7 on the 17-item Hamilton Rating Scale for Depression [HRSD 17 ]) defined remission; a QIDS-SR 16 total score of ≥11 (HRSD 17 ≥14) defined relapse. Results: The QIDS-SR 16 remission rates were 36.8%, 30.6%, 13.7%, and 13.0% for the first, second, t...
3,768 citations
"Psychedelics Promote Structural and..." refers background in this paper
...…antidepressant drugs, and those who do will usually require at least 2–4 weeks of treatment before they experience any beneficial effects 3170 Cell Reports 23, 3170–3182, June 12, 2018 ª 2018 The Author( This is an open access article under the CC BY-NC-ND license (http:// (Rush et al., 2006)....
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...3170 Cell Reports 23, 3170–3182, June 12, 2018 a 2018 The Author( This is an open access article under the CC BY-NC-ND license (http:// (Rush et al., 2006)....
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TL;DR: This review provides basic information about translation of doses between species and estimation of starting dose for clinical trials using allometric scaling and the method of calculation of injection volume for parenteral formulation based on human equivalent dose.
Abstract: Understanding the concept of extrapolation of dose between species is important for pharmaceutical researchers when initiating new animal or human experiments. Interspecies allometric scaling for dose conversion from animal to human studies is one of the most controversial areas in clinical pharmacology. Allometric approach considers the differences in body surface area, which is associated with animal weight while extrapolating the doses of therapeutic agents among the species. This review provides basic information about translation of doses between species and estimation of starting dose for clinical trials using allometric scaling. The method of calculation of injection volume for parenteral formulation based on human equivalent dose is also briefed.
3,148 citations
"Psychedelics Promote Structural and..." refers background in this paper
...Interestingly, 10 mg/kg and 1 mg/kg doses produced similar responses despite the fact that they are predicted to be hallucinogenic and subhallucinogenic, respectively (Strassman et al., 1994; Nair and Jacob, 2016)....
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...First, all available data suggested that this dose would produce hallucinogenic effects in rats with minimal safety risks (Glennon et al., 1980, 1983; Glennon, 1999; Gatch et al., 2009; Smith et al., 1998; Appel et al., 1999; Winter et al., 2007; Carbonaro et al., 2015; Helsley et al., 1998; Strassman et al., 1994; Nair and Jacob, 2016)....
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TL;DR: A first placebo-controlled, double-blinded trial to assess the treatment effects of a single dose of an N-methyl-D-aspartate (NMDA) receptor antagonist in patients with depression suggests a potential role for NMDA receptor-modulating drugs in the treatment of depression.
3,039 citations
"Psychedelics Promote Structural and..." refers background in this paper
...Ketamine has demonstrated remarkable clinical potential as a fast-acting antidepressant (Berman et al., 2000; Ionescu et al., 2016; Zarate et al., 2012), even exhibiting efficacy in treatmentresistant populations (DiazGranados et al....
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TL;DR: Robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week.
Abstract: Context Existing therapies for major depression have a lag of onset of action of several weeks, resulting in considerable morbidity. Exploring pharmacological strategies that have rapid onset of antidepressant effects within a few days and that are sustained would have an enormous impact on patient care. Converging lines of evidence suggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders. Objective To determine whether a rapid antidepressant effect can be achieved with an antagonist at theN-methyl-D-aspartate receptor in subjects with major depression. Design A randomized, placebo-controlled, double-blind crossover study from November 2004 to September 2005. Setting Mood Disorders Research Unit at the National Institute of Mental Health. Patients Eighteen subjects withDSM-IVmajor depression (treatment resistant). Interventions After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days postinfusion. Main Outcome Measure Changes in scores on the primary efficacy measure, the 21-item Hamilton Depression Rating Scale. Results Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week. Conclusions Robust and rapid antidepressant effects resulted from a single intravenous dose of anN-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week. Trial Registration clinicaltrials.gov Identifier:NCT00088699.
2,965 citations