Psychedelics are emerging as potential treatments for a range of mental health conditions, including anxiety and depression, treatment-resistant depression, and substance use disorders. Recent studies have also suggested that the psychedelic psilocybin may be able to treat obsessive–compulsive disorder (OCD). Since the 1960s, case studies have reported improvements to obsessive and compulsive behaviors in patients taking psychedelics recreationally. The effects of psilocybin were then systematically assessed in a small, open-label trial in 2006, which found that psilocybin significantly reduced the symptoms of OCD. Reduced compulsive behaviors have also been seen in rodent models of OCD after administration of psilocybin. Nonetheless, the mechanisms underlying the effects of psychedelics for OCD are unclear, with hypotheses including their acute pharmacological effects, changes in neuroplasticity and resting state neural networks, and their psychological effects. This review will evaluate the evidence supporting the theory that psychedelics can be used for the treatment of OCD, as well as the data regarding claims about their mechanisms. It will also discuss issues with the current evidence and the ongoing trials of psilocybin that aim to address these knowledge gaps.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with no effective treatments, not least due to the lack of authentic animal models. Typically, rodent models recapitulate the effects but not causes of AD, such as cholinergic neuron loss: lesioning of cholinergic neurons mimics the cognitive decline reminiscent of AD but not its neuropathology. Alternative models rely on the overexpression of genes associated with familial AD, such as amyloid precursor protein, or have genetically amplified expression of mutant tau. Yet transgenic rodent models poorly replicate the neuropathogenesis and protein overexpression patterns of sporadic AD. Seeding rodents with amyloid or tau facilitates the formation of these pathologies but cannot account for their initial accumulation. Intracerebral infusion of proinflammatory agents offer an alternative model, but these fail to replicate the cause of AD. A novel model is therefore needed, perhaps similar to those used for Parkinson’s disease, namely adult wildtype rodents with neuron-specific (dopaminergic) lesions within the same vulnerable brainstem nuclei, ‘the isodendritic core’, which are the first to degenerate in AD. Site-selective targeting of these nuclei in adult rodents may recapitulate the initial neurodegenerative processes in AD to faithfully mimic its pathogenesis and progression, ultimately leading to presymptomatic biomarkers and preventative therapies.

Background: Abrupt cessation of therapy with a selective serotonin reuptake inhibitor (SSRI) is associated with a discontinuation syndrome, typified by numerous disabling symptoms, including anxiety. Surprisingly, little is known of the behavioural effect of SSRI discontinuation in animals. Aim: Here, the effect of SSRI discontinuation on anxiety-like behaviour was systematically investigated in mice. Methods: Experiments were based on a three-arm experimental design comprising saline, continued SSRI and discontinued SSRI. Mice were assessed 2 days after SSRI discontinuation over a 5-day period using the elevated plus maze (EPM) and other anxiety tests. Results: An exploratory experiment found cessation of paroxetine (12 days) was associated with decreased open-arm exploration and reduced total distance travelled, in male but not female mice. Follow-up studies confirmed a discontinuation effect on the EPM in male mice after paroxetine (12 days) and also citalopram (12 days). Mice receiving continued paroxetine (but not citalopram) also showed decreased open-arm exploration but this was dissociable from the effects of discontinuation. The discontinuation response to paroxetine did not strengthen after 28 days of treatment but was absent after 7 days of treatment. A discontinuation response was not discernible in other anxiety and fear-learning tests applied 3–5 days after treatment cessation. Finally, discontinuation effects on the EPM were typically associated with decreased locomotion on the test. However, separate locomotor testing implicated anxiety-provoked behavioural inhibition rather than a general reduction in motor activity. Conclusion: Overall, this study provides evidence for a short-lasting behavioural discontinuation response to cessation of SSRI treatment in mice.

Selective serotonin reuptake inhibitor (SSRI) therapy cessation often induces a disabling discontinuation syndrome, including increased anxiety. We recently reported that SSRI discontinuation induced behavioural changes in mice, which we hypothesise arose from activated anxiety circuitry. Here, we investigated the effect of discontinuation from the SSRI paroxetine on the expression of the activity-dependent gene c-fos in selected anxiety-related midbrain and forebrain regions. Male mice were injected daily with paroxetine (10 mg/kg) or saline for 12 days, then treatment was either continued or discontinued for two or five days. Mice were then tested on the elevated plus maze (EPM) and tissue collected 90 min later. Brain sections including the dorsal (DRN) and median raphe nucleus, periaqueductal grey, hippocampus, prefrontal cortex, and amygdala were processed for c-Fos immunoreactivity. Two days after paroxetine discontinuation, when mice showed elevated anxiety-like behaviour on the EPM, increased c-Fos immunoreactivity was evident in the DRN and ventral hippocampus, but not in any other region examined, compared to saline-treated controls. Increased c-Fos in the DRN was evident in TPH2-immunopositive neurons as well as neurons doubled-labelled for TPH2 and VGLUT3, suggesting activation of 5-HT-glutamate co-releasing neurons. Five days after paroxetine discontinuation, increased c-Fos immunoreactivity was evident in the DRN, but mice no longer exhibited increased anxiety. These findings suggest that, under the current conditions, paroxetine discontinuation is associated with a short-lasting activation of anxiety-promoting circuitry limited to DRN 5-HT neurons and the hippocampus. This circuitry may contribute to symptoms such as anxiety that are a feature of SSRI discontinuation syndrome.

Cessation of therapy with a selective serotonin (5-HT) reuptake inhibitor (SSRI) is often associated with an early onset, disabling discontinuation syndrome the mechanism of which is surprisingly little investigated. Here we determined the effect on 5-HT neurochemistry of discontinuation from the SSRI paroxetine. Paroxetine was administered repeatedly to mice (once daily, 12 days versus saline controls) and then either continued or discontinued for up to 5 days. Whereas tissue levels of 5-HT and/or its metabolite 5-HIAA tended to decrease during continuous paroxetine, levels increased above controls after discontinuation, notably in hippocampus. In microdialysis experiments continuous paroxetine elevated hippocampal extracellular 5-HT and this effect fell to saline control levels on discontinuation. However, depolarisation (high potassium)-evoked 5-HT release was reduced by continuous paroxetine but increased above controls post-discontinuation. Extracellular hippocampal 5-HIAA also decreased during continuous paroxetine and increased above controls post-discontinuation. Next, immunohistochemistry experiments found that paroxetine discontinuation increased Fos expression in midbrain 5-HT neurons, adding further evidence for a hyperexcitable 5-HT system. The latter effect was recapitulated by 5-HT _1A receptor antagonist administration although gene expression analysis could not confirm altered expression of 5-HT _1A autoreceptors following paroxetine discontinuation. Finally, in behavioural experiments paroxetine discontinuation increased anxiety-like behaviour, which partially correlated in time with the measures of increased 5-HT function. In summary, this study finds that SSRI discontinuation triggers a rebound activation of 5-HT neurons across a range of experiments. This effect is reminiscent of neural changes associated with various psychotropic drug withdrawal states, suggesting a common unifying mechanism.

Background Abrupt cessation of therapy with a selective serotonin reuptake inhibitor (SSRI) is often associated with a discontinuation syndrome, typified by numerous disabling symptoms including elevated anxiety, which is of unknown cause. Aim Here, the effect of SSRI discontinuation on anxiety-like behaviour was investigated in mice. Methods Mice were treated repeatedly with paroxetine, citalopram or saline using a 3-arm experimental design comprising saline, continued SSRI and discontinued SSRI. Mice were assessed over 5 days after SSRI discontinuation using the elevated plus maze (EPM) and other anxiety tests. Results In an exploratory experiment mice discontinued (2 days) from paroxetine (12 days) showed evidence of increased anxiety on the EPM, although this effect was observed in male and not female mice. Follow-up studies confirmed the EPM findings in male mice discontinued (2 days) from paroxetine (12 or 28 days) or citalopram (12 days) compared to saline controls. Continued treatment with paroxetine was also anxiogenic on the EPM but this was not the case for citalopram. Paroxetine exposure for more than a week was required to elicit evidence of a discontinuation response, which did not obviously strengthen with increased frequency or duration of dose. Finally, SSRI discontinuation effects were not resolvable from continued treatment in other anxiety tests applied between 3 and 5 days post-discontinuation. Conclusion Overall, the current study provides evidence for a short-lasting increase in anxiety-like behaviour in mice following SSRI discontinuation, and offers a means for the investigation of the neurobiological mechanisms involved.