Metabolism of m-CPP, trazodone, nefazodone and etoperidone: Clinical and Forensic Aspects

Abstract

Abstract: Trazodone, Nefazodone, and Etoperidone are classified as atypical antidepressants belonging to the phenylpiperazine class. These antidepressants metabolize into mchlorophenylpiperazine (mCPP), which was initially employed in veterinary medicine but has gained widespread use as a recreational drug globally, despite legal restrictions in numerous countries. The active metabolite, mCPP, exerts various neuropsychiatric effects through its interaction with serotonin receptors, primarily exhibiting nonselective agonistic properties with some antagonistic effects, and also influencing temperature, behavior, and hormone release via central 5-HT receptors. The surge in mCPP's popularity can be attributed to its MDMA-like effects, and its initial misidentification as an MDMA substitute facilitated its unregulated distribution worldwide. This systematic review aims to comprehensively explore the pharmacokinetics and pharmacodynamics of these compounds, with a specific focus on the forensic challenges posed by mCPP being a metabolite of antidepressants. The primary objective is to delineate the consumption patterns of these compounds in laboratory settings, making this review crucial for understanding the intricate nuances of these drugs in forensic contexts. GRAPHICAL ABSTRACT Atypical Antidepressants Trazodone Nefazodone Etoperidone m-CPP Piperazine Designer Drug m-CPP * Major Mood Depression * Insomnia * Anxiety Disorders * Chronic Pain * Frontal Cognitive Dysfunction * Sexual Dysfunction Low abuse potential Fatalities overdoses are rare Typically involve coingestion of others CNS depressants But side effects are rare No sexual function impartment No anxiety No insomnia No anticholinergic effects The most commun adverse effects include: * Gastrointestin al effects * Xerostomia * Orthostatic hypotension * Headache * Sedation * Wight changes Capsules Tablets Pills Powder Liquid Adverse Effects: * Headache * Anorexia * Nausea * Potentially cardiotoxic, hepatotoxic, neurotoxic, nephrotoxic and endocrine disrupting * Hallucinogenic * Alcohol-euphoric symptoms like * MDMA symptoms like * Panic * Anxiety * Dysphoria * Psychosis * Sleep disruption * Weakness * Dizziness mCPP is frequently found in Ecstasy pills as a replacement for MDMA Pre and postsynaptic serotonin effects Serotonin release (SERT) Dopamine release Cortisol and prolactin release acting at 5- HT central receptors Antagonize 5-HT1A, 5-HT1B, 5-HT1D and 5-HT2C receptors Start as anti-helminthic agent in the 1950s VS Nowadays as a recreational drug, sold at party pill or adulterant of MDMA and cocaine Dose Dependent Inhibits SERT Antagonize 5-HT1A, 5-HT2A, 5-HT2B and 5-HT2C Antagonize H1 and ⍺1 receptors Inhibits GABA release Blocks T-type calcium channels Inhibits 5-HT1A and 5-HT2A receptors Potent reversal inhibition of SERT Inhibits the reuptake of norepinephrine Antagonizes 5-HT2 and ⍺1-adrenergic Abuse Potential 3 Figure 1: Pharmacokinetics and pharmacodynamics aspects of trazodone, nefazodone, etoperidone and m-chlorophenylpiperazine (mCPP).