Psilocybin targets a common molecular mechanism for cognitive impairment and increased craving in alcoholism

Meinhardt, Marcus W.; Pfarr, Simone; Fouquet, Grégory; Rohleder, Cathrin; Meinhardt, Manuela L.; Barroso-Flores, Janet; Hoffmann, Rebecca; Jeanblanc, Jérôme; Paul, Elisabeth; Wagner, Konstantin; Hansson, Anita C.; Köhr, Georg; Meier, Nils; Halbach, Oliver von Bohlen und; Bell, Richard L.; Endepols, Heike; Neumaier, Bernd; Shi, Kai; Bartsch, Dušan; Naassïla, Mickaël; Spanagel, Rainer; Sommer, Wolfgang

doi:10.1126/sciadv.abh2399

Cited by 65 publications

(66 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Only sub-chronic treatment with psilocybin produced a short-lasting anti-relapse effect (220). A recent study showed that psilocybin restored alcohol dependence-induced metabotropic glutamate receptor (mGluR2) down-regulation and reduced alcohol-seeking behavior in rats (221). Interestingly, in a rodent food reward model, low dose psilocybin and ketamine failed to positively affect motivation or attention, though subtle improvements in attention and impulsive behavior were noted in "low performing" rats (222).…”

Section: Addictionmentioning

confidence: 99%

Psychedelic Therapy's Transdiagnostic Effects: A Research Domain Criteria (RDoC) Perspective

et al. 2021

View full text Add to dashboard Cite

Accumulating clinical evidence shows that psychedelic therapy, by synergistically combining psychopharmacology and psychological support, offers a promising transdiagnostic treatment strategy for a range of disorders with restricted and/or maladaptive habitual patterns of emotion, cognition and behavior, notably, depression (MDD), treatment resistant depression (TRD) and addiction disorders, but perhaps also anxiety disorders, obsessive-compulsive disorder (OCD), Post-Traumatic Stress Disorder (PTSD) and eating disorders. Despite the emergent transdiagnostic evidence, the specific clinical dimensions that psychedelics are efficacious for, and associated underlying neurobiological pathways, remain to be well-characterized. To this end, this review focuses on pre-clinical and clinical evidence of the acute and sustained therapeutic potential of psychedelic therapy in the context of a transdiagnostic dimensional systems framework. Focusing on the Research Domain Criteria (RDoC) as a template, we will describe the multimodal mechanisms underlying the transdiagnostic therapeutic effects of psychedelic therapy, traversing molecular, cellular and network levels. These levels will be mapped to the RDoC constructs of negative and positive valence systems, arousal regulation, social processing, cognitive and sensorimotor systems. In summarizing this literature and framing it transdiagnostically, we hope we can assist the field in moving toward a mechanistic understanding of how psychedelics work for patients and eventually toward a precise-personalized psychedelic therapy paradigm.

show abstract

Section: Addictionmentioning

confidence: 99%

Psychedelic Therapy's Transdiagnostic Effects: A Research Domain Criteria (RDoC) Perspective

et al. 2021

View full text Add to dashboard Cite

show abstract

“…The psychedelic is, therefore, able to activate 5HT receptors as mentioned, ultimately leading to their downregulation [4]. In such instances, there is a compensatory upregulation in the metabotropic glutamate receptors (mGluR2/3) due to the inverse relationship between mGluR2/3 and 5HT-2A receptors [5]. The stimulation of 5HT-2A receptors on pyramidal cells in levels V and VI in the cortex by psilocin, a metabolite, leads to the release of glutamate in the prefrontal cortex [6].…”

Section: Review Mechanism Of Actionmentioning

confidence: 98%

“…A group of compounds that have recently sparked interest for their treatment potential is psychedelic drugs including psilocybin, dimethyltryptamine (DMT), mescaline, and lysergic acid diethylamide (LSD), among others [4]. These drugs are currently controversial for their hallucinogenic effects and recreational use; however, their resemblance to tryptophan enables them to act as serotonin agonists and activate 5HT receptors, mainly the 5HT-2A receptor [5]. This effect makes them promising candidates in the treatment of substance abuse disorders as well as mood disorders [6].…”

Section: Review Mechanism Of Actionmentioning

confidence: 99%

“…The significance of the upregulation of the mGluR2/3 pathway is the result of the receptor's abundance in the route from the medial prefrontal cortex to the nucleus accumbens where these receptors play a role in the mediation of craving and addiction, as well as cognitive function [5]. It has been found that persons with an alcohol addiction have a deficiency or downregulation in their mGluR2 pathway in the infralimbic region of the medial prefrontal cortex [5].…”

Section: Review Mechanism Of Actionmentioning

confidence: 99%

See 1 more Smart Citation

Analysis of Psilocybin-Assisted Therapy in Medicine: A Narrative Review

Ziff¹,

Stern²,

Lewis³

et al. 2022

Cureus

View full text Add to dashboard Cite

Psilocybin-containing mushrooms have been consumed by various cultures in many different parts of the world for thousands of years. Psilocybin, a classic psychedelic, contains unique psychoactive properties and has been incorporated into religious ceremonies and investigated for its medicinal value. In the mid-20th century, psilocybin, along with most other classic psychedelics (5HT-2A agonists), was classified as a Schedule I substance, bringing a halt to research on its medicinal utility. The resurgence of clinical trials involving psilocybin in the 21st century has produced promising results concerning the treatment of addiction, depression, and end-of-life mood disorders. Results from these trials have shown significant reductions in depression and anxiety when compared with a placebo, and one trial found no significant difference when compared to a routinely prescribed selective serotonin reuptake inhibitor (SSRI). Studies conducted with patients with advanced-stage cancer have demonstrated that psilocybin may also be beneficial at reducing depression and anxiety associated with psychological crises due to a terminal diagnosis. Psilocybin therapy in the treatment of addiction, which is notoriously difficult to treat, has shown encouraging results. Due to its low toxicity and low risk of overuse, psilocybin has the potential to have a significant influence in the field of addiction medicine. Psilocybin addiction research has been primarily focused on nicotine and alcohol and, in a few small, open-label trials, has shown superiority over traditional therapies. Psilocybin has a relatively unique and incompletely understood mechanism of action, which allows it to be given at several isolated periods. This infrequent dosing regimen has been shown to produce durable effects with minimal toxicity. This review analyzes the potential of psilocybin in the treatment of addiction, depression, and end-of-life mood disorders. In addition, it will discuss the difficulties involved with conducting scientific research on psychedelic compounds, adverse effects, and the therapeutic measures that are necessary to accompany the safe and effective administration of these psychoactive chemicals.

show abstract

“…G*Power analysis (two-tailed unpaired t test; α = 0.05; power = 0.80) conducted in previous CIE rats (Hirth et al, 2016;Meinhardt et al, 2021;Sommer et al, 2008;Uhrig et al, 2017) suggested a total of 16 rats (N = 8/group) with an effect size of Cohen's d = 1.5.…”

Section: Induction Of Alcohol Dependencementioning

confidence: 99%

Disrupted circadian expression of β‐arrestin 2 affects reward‐related µ‐opioid receptor function in alcohol dependence

Meinhardt

Giannone

Hirth

et al. 2022

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

There is increasing evidence for a daily rhythm of µ‐opioid receptor (MOR) efficacy and the development of alcohol dependence. Previous studies show that β‐arrestin 2 (bArr2) has an impact on alcohol intake, at least partially mediated via modulation of MOR signaling, which in turn mediates the alcohol rewarding effects. Considering the interplay of circadian rhythms on MOR and alcohol dependence, we aimed to investigate bArr2 in alcohol dependence at different time points of the day/light cycle on the level of bArr2 mRNA (in situ hybridization), MOR availability (receptor autoradiography), and MOR signaling (Damgo‐stimulated G‐protein coupling) in the nucleus accumbens of alcohol‐dependent and non‐dependent Wistar rats. Using a microarray data set we found that bArr2, but not bArr1, shows a diurnal transcription pattern in the accumbens of naïve rats with higher expression levels during the active cycle. In 3‐week abstinent rats, bArr2 is up‐regulated in the accumbens at the beginning of the active cycle (ZT15), whereas no differences were found at the beginning of the inactive cycle (ZT3) compared with controls. This effect was accompanied by a specific down‐regulation of MOR binding in the active cycle. Additionally, we detect a higher receptor coupling during the inactive cycle compared with the active cycle in alcohol‐dependent animals. Together, we report daily rhythmicity for bArr2 expression linked to an inverse pattern of MOR, suggesting an involvement for bArr2 on circadian regulation of G‐protein coupled receptors in alcohol dependence. The presented data may have implications for the development of novel bArr2‐related treatment targets for alcoholism.

show abstract

Psilocybin targets a common molecular mechanism for cognitive impairment and increased craving in alcoholism

Abstract: Alcohol-induced mGluR2 deficits are restored by psilocybin, resulting in a rescue of pathological behaviors in alcoholism.

Cited by 65 publications

References 82 publications

Psychedelic Therapy's Transdiagnostic Effects: A Research Domain Criteria (RDoC) Perspective

Psychedelic Therapy's Transdiagnostic Effects: A Research Domain Criteria (RDoC) Perspective

Analysis of Psilocybin-Assisted Therapy in Medicine: A Narrative Review

Disrupted circadian expression of β‐arrestin 2 affects reward‐related µ‐opioid receptor function in alcohol dependence

Contact Info

Product

Resources

About