Safety and Tolerability of the Anxiolytic and Nootropic Drug Phenibut: A Systematic Review of Clinical Trials and Case Reports.

Phenibut is a nootropic drug that exerts anxiolytic and antinociceptive effects by acting on the GABAB receptor and the α2-δ subunit of voltage-dependent calcium channels. An increased number of reports of dependence to and intoxication by phenibut purchased online on the one hand and the wide prescription of phenibut in Eastern Europe for more than half a century on the other hand have resulted in a number of controversies regarding its use. In this review, we have summarized currently available information from case reports of phenibut dependence and intoxication and safety data from clinical trials. We included 14 dependence and intoxication case reports (16 patients) and reviewed 11 phenibut clinical trials (583 patients). The clinical symptoms in the case reports included cardiovascular effects, insomnia, anxiety and agitation, hallucinations, and depressed level of consciousness. In addition, the doses used (0.5-100 g/day) were much higher than the recommended daily dose (0.25-2 g/day). An analysis of phenibut side effects described in the clinical trials showed adverse events in only 5.66% of patients, and the most reported side effect was somnolence (1.89%). There are discrepancies in the reported side effects of phenibut in clinical trials compared to those reported in cases of online-purchased phenibut dependence and intoxication. The current systematic review provides evidence that, at therapeutic doses, phenibut is safe and well tolerated with minor adverse effects, but questions regarding the quality of phenibut obtained online and the contribution of alcohol and other drug abuse to phenibut dependence and intoxication remain open.

Use of cognitive enhancers: methylphenidate and analogs.

OBJECTIVE: In the last decades, several cognitive-enhancing drugs have been sold onto the drug market. Methylphenidate and analogs represent a sub-class of these new psychoactive substances (NPS). We aimed to review the use and misuse of methylphenidate and analogs, and the risk associated. Moreover, we exhaustively reviewed the scientific data on the most recent methylphenidate analogs (methylphenidate and ethylphenidate excluded). MATERIALS AND METHODS: Literature search was performed on methylphenidate and analogs, using specialized search engines accessing scientific databases. Additional reports were retrieved from international agencies, institutional websites, and drug user forums. RESULTS: Methylphenidate/Ritalin has been used for decades to treat attention deficit disorders and narcolepsy. More recently, it has been used as a cognitive enhancer and a recreational drug. Acute intoxications and fatalities involving methylphenidate were reported. Methylphenidate was scheduled as an illegal drug in many countries, but NPS circumventing the ban and mimicking the psychostimulant effects of methylphenidate started being available: ethylphenidate, 3,4-dichloromethylphenidate, 3,4-dichloroethylphenidate, 4-fluoromethylphenidate, 4-fluoroethylphenidate, methylnaphthidate, ethylnaphthidate, isopropylphenidate, propylphenidate, 4-methylmethylphenidate, and N-benzylethylphenidate have been available in the past few years. Only little data is currently available for these substances. Many intoxications involving methylphenidate analogs were reported. To date, ethylphenidate was involved in 28 fatalities, although it was reportedly directly related to the cause of death in only 7 cases; 3,4-dichloroethylphenidate was involved in 1 death. CONCLUSIONS: The rapid expansion of methylphenidate analogs onto the drug market in the past few years makes likely the occurrence of intoxications and fatalities in the next years. Careful monitoring and systematic control of methylphenidate analogs should be undertaken to reduce the uprising threat, and education efforts should be made among high-risk populations.

Dietary supplement for energy and reduced appetite containing the ß-agonist isopropyloctopamine leads to heart problems and hospitalisations.

In 2013 the Dutch authorities issued a warning against a dietary supplement that was linked to 11 reported adverse reactions, including heart problems and in one case even a cardiac arrest. In the UK a 20-year-old woman, said to have overdosed on this supplement, died. Since according to the label the product was a herbal mixture, initial LC-MS/MS analysis focused on the detection of plant toxins. Yohimbe alkaloids, which are not allowed to be present in herbal preparations according to Dutch legislation, were found at relatively high levels (400-900 mg kg(-1)). However, their presence did not explain the adverse health effects reported. Based on these effects the supplement was screened for the presence of a ß-agonist, using three different biosensor assays, i.e. the validated competitive radioligand ß2-adrenergic receptor binding assay, a validated ß-agonists ELISA and a newly developed multiplex microsphere (bead)-based ß-agonist assay with imaging detection (MAGPIX(®)). The high responses obtained in these three biosensors suggested strongly the presence of a ß-agonist. Inspection of the label indicated the presence of N-isopropyloctopamine. A pure standard of this compound was bought and shown to have a strong activity in the three biosensor assays. Analysis by LC-full-scan high-resolution MS confirmed the presence of this 'unknown known' ß3-agonist N-isopropyloctopamine, reported to lead to heart problems at high doses. A confirmatory quantitative analysis revealed that one dose of the preparation resulted in an intake of 40-60 mg, which is within the therapeutic range of this compound. The case shows the strength of combining bioassays with chemical analytical techniques for identification of illegal pharmacologically active substances in food supplements.

Prolonged altered mental status and bradycardia following pediatric donepezil ingestion.

CONTEXT: Donepezil is a centrally-acting, reversible acetylcholinesterase inhibitor that is used in the treatment of Alzheimer disease. Altered mental status, nausea, vomiting, and bradycardia have been reported in therapeutic and supratherapeutic ingestions of donepezil, though pediatric exposures have not been well-described. We report a case of prolonged altered mental status and recurrent bradycardia in a child with a single-pill ingestion of donepezil. CASE DETAILS: A 14-month-old boy was brought to the Emergency Department 3 hours after ingesting one of his grandfather's donepezil tablets (10 mg). Upon arrival, he was somnolent and drooling, with multiple episodes of vomiting and diarrhea. Pupils were normal. Initial vitals: temperature, 36.8°C; blood pressure, 103/56 mmHg; heart rate, 140/min; respiratory rate, 36/min; oxygen saturation, 97%. His drooling, vomiting, and diarrhea resolved, but he remained intermittently agitated. Over the course of the following four days, he had intermittent, episodes of asymptomatic bradycardia to a low of 55/min, primarily when sleeping. A transient episode of junctional rhythm was observed. Serum donepezil level 97 hours post-ingestion was 10 ng/ml. He did not require atropine treatment, and was discharged in stable condition on hospital day 5. DISCUSSION: Donepezil has a prolonged elimination of half-life in adults of approximately 70 hours. Despite its relative specificity for central AChEs, peripheral cholinergic symptoms have been described. We report a case of a symptomatic ingestion of donepezil in a child. CONCLUSIONS: Even after a single-tablet ingestion, donepezil may cause prolonged altered mental status and bradycardia in young children.