Recently, the abuse of ketamine has soared. Therefore, it is of great importance to study its potential risks. The effects of prolonged ketamine on the brain can be observationally studied in chronic recreational users. We performed a systematic review of studies reporting functional and structural brain changes after repeated ketamine abuse. We searched the following electronic databases: Medline, Embase and PsycINFO We screened 11,438 records and 16 met inclusion criteria, totaling 440 chronic recreational ketamine users (2–9.7 years; mean use 2.4 g/day), 259 drug-free controls and 44 poly-drug controls. Long-term recreational ketamine use was associated with lower gray matter volume and less white matter integrity, lower functional thalamocortical and corticocortical connectivity. The observed differences in both structural and functional neuroanatomy between ketamine users and controls may explain some of its long-term cognitive and psychiatric side effects, such as memory impairment and executive functioning. Given the effect that long-term ketamine exposure may yield, an effort should be made to curb its abuse.

Key PointsQuestion: Do psychotropic drug concentrations in surface water pose a risk for the environment?Findings: In this in-depth study examining over a thousand water samples collected across the Netherlands we found that surface water concentrations of oxazepam and carbamazepine are above acceptable limits in some locations. Households were estimated to be the largest contributor, even in an area with a large community hospital.Meaning: To ensure safe wildlife habitats and prevent further decline of vulnerable species, reducing surface water concentrations of psychotropic drugs is needed. This likely requires changes in waste management as well as in prescription and use behaviors. AbstractImportance: For most countries it is currently unknown to what degree concentrations of psychotropic drugs in surface water exceed environmental threshold concentrations (ETCs) for ecosystems and what risk mitigation could be applied. ETCs are defined as per-compound threshold concentrations above which detrimental effects on reproduction, growth, and mortality of aquatic organisms cannot be excluded.Objective: To quantify concentrations of antidepressants, antipsychotics, mood stabilizers, and benzodiazepines in surface water, investigate their sources and assess whether these levels exceed ETCs. Design: Cross-sectional analysis of measured and modeled data. Environmental levels were compared to ETCs to evaluate their risks for the aquatic environment. Finally, sources of psychotropic drugs were investigated. Setting: All available Dutch water monitoring data from all regional and national monitoring campaigns of 2019, the last year before the COVID-19 pandemic.Exposures: Concentrations of aripiprazole, carbamazepine and its metabolites, clozapine, diazepam, (es)citalopram, fluoxetine, haloperidol, nortriptyline, olanzapine, oxazepam, temazepam, quetiapine, sertraline, valproic acid, and venlafaxine. Main outcomes and measures: The main outcomes were measured and modeled concentrations of the aforementioned agents in surface water. As a secondary outcome, where possible, average risk quotients (RQs) were calculated by dividing the measured or modeled concentrations by the ETC. An RQ > 1 was interpreted as a risk to the environment.Results: Psychotropic drug samples (n=1201; 14-520 measurements per drug) showed the highest average concentrations for oxazepam (0.91 µg/L; RQ = 1.89) and carbamazepine (0.74 µg/L; RQ = 1.48), with individual measurements exceeding ETCs. For other drugs, measured concentrations did not reach the detection limit (amisulpride, (es)citalopram, quetiapine, and venlafaxine) or did not exceed the ETC (fluoxetine). Furthermore, households contributed most to psychotropics in surface water. Finally, psychotropics were cleared less efficiently from a wastewater treatment plant than other medications.Conclusions and Relevance: Psychotropic drugs are present in surface water, are primarily emitted by households, and may put organisms at risk. We signal a need to reduce concentrations of several psychotropic agents in the environment. Our findings set the stage for policies and research aimed at curtailing emissions of psychotropic drugs into the environment and highlight a need for responsible prescribing and waste measures.

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