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R. Horsley

Psilocin and ketamine microdosing: effects of subchronic intermittent microdoses in the elevated plus-maze in male Wistar rats

March 13, 2018 / Anxiety disorders / PTSD, Ketamine, Mushrooms / Psilocybin, Papers, Psychology, Psychopharmacology, Publications / By / , , ,

Abstract

Short-term moderate doses of serotonergic and dissociative hallucinogens can be useful in the treatment of anxiety. Recently, a trend has developed for long-term intermittent ‘microdosing’ (usually one-tenth of a ‘full’ active dose), with reports of long-lasting relief from anxiety and related disorders; however, there is no scientific evidence for the efficacy of therapeutic microdosing nor to show its lasting effects. The objective of this study was to test for lasting effects on anxiety in rats after microdosing with ketamine or psilocin. Over 6 days, Wistar rats (N=40) were administered ketamine (0.5 or 3 mg/kg), psilocin (0.05 or 0.075 mg/kg), or saline on three occasions. A 5-min elevated plus-maze test was conducted 48 h after the final drug treatment (n=8). Dependent variables were entries (frequency), spent time (%), and distance traveled (cm) in each zone, as well as total frequency of rears, stretch-attend postures, and head dips. Statistical analyses of drug effects used separate independent one-way analysis of variance and pair-wise comparisons using independent t-tests. Statistical effects were modest or borderline and were most consistent with a mildly anxiogenic profile, which was significant at lower doses; however, this conclusion remains tentative. The lower doses of ketamine and psilocin produced comparable effects (to one another) across each variable, as did the higher doses. This pattern of effects may suggest a common (e.g. neurotransmitter/receptor) mechanism. We conclude that microdosing with hallucinogens for therapeutic purposes might be counter-productive; however, more research is needed to confirm our findings and to establish their translational relevance to clinical ‘psychedelic’ therapy.
Horsley, R. R., Páleníček, T., Kolin, J., & Valeš, K. (2018). Psilocin and ketamine microdosing: effects of subchronic intermittent microdoses in the elevated plus-maze in male Wistar rats. Behavioural pharmacology. 10.1097/FBP.0000000000000394
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Detailed pharmacological evaluation of methoxetamine (MXE), a novel psychoactive ketamine analogue—Behavioural, pharmacokinetic and metabolic studies in the Wistar rat

May 4, 2016 / Neuroscience, New substances, Other substances, Papers, Psychopharmacology, Publications, Safety, Toxicology / By / , , , , ,

Abstract

Methoxetamine (MXE) is a novel psychoactive compound (NPS) that emerged in 2010 as a substitute for the dissociative anaesthetic ketamine. MXE has a reputation of carrying a lower risk of harm than ketamine, however a number of deaths have been reported. Currently very little is known about the psychopharmacological effects of this compound or its toxicity; therefore we tested, in Wistar rats, the effects of MXE in a series of behavioural tasks, measured its pharmacokinetics and urinary metabolites.

Locomotor activity and its spatial characteristics (in the open field) and sensorimotor gating (prepulse inhibition; PPI) were evaluated after 5, 10 and 40 mg/kg subcutaneous (sc.) MXE. Pharmacokinetics and brain: serum ratios were evaluated after 10 mg/kg sc. MXE so that peak drug concentration data could be used to complement interpretation of maximal behavioural effects. Finally, quantification of metabolites in rat urine collected over 24 h was performed after single bolus of MXE 40 mg/kg sc.

5 and 10 mg/kg MXE induced significant locomotor stimulation, in addition it increased thigmotaxis and decreased time spent in the centre of the open field (indicative of anxiogenesis). By contrast, 40 mg/kg reduced locomotion and increased time spent in the centre of the arena, suggesting sedation/anaesthesia or stereotypy. The duration of effects was present for at least 60–90 min, although for 5 mg/kg, locomotion diminished after 60 min. MXE decreased baseline acoustic startle response (ASR) and disrupted PPI, irrespective of testing-onset. MXE (all doses) reduced habituation but only at 60 min. Maximal brain levels of MXE were observed 30 min after administration, remained high at 60 min and progressively declined to around zero after six hours. MXE accumulated in the brain; the brain: serum ratio was between 2.06 and 2.93 throughout the whole observation. The most abundant urinary metabolite was O-desmethylmethoxetamine followed by normethoxetamine.

To conclude, MXE acts behaviourally as a typical dissociative anaesthetic with stimulant and anxiogenic effects at lower doses, sedative/anaesthetic effects at higher doses, and as a disruptor of sensorimotor gating. Its duration of action exceeds that of ketamine which is consistent with reports from MXE users. The accumulation of the drug in brain tissue might reflect MXE’s stronger potency compared to ketamine and indicate increased toxicity.

Horsley, R. R., Lhotkova, E., Hajkova, K., Jurasek, B., Kuchar, M., & Palenicek, T. (2016). Detailed pharmacological evaluation of methoxetamine (MXE), a novel psychoactive ketamine analogue—Behavioural, pharmacokinetic and metabolic studies in the Wistar rat. Brain Research Bulletin. http://dx.doi.org/10.1016/j.brainresbull.2016.05.002
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30 April - Q&A with Rick Strassman

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