Novel psychoactive substances (designer drugs): overview and pharmacology of modulators of monoamine signalling

Novel psychoactive substances, often sold as 'legal highs' or 'research chemicals', pose health risks similar to classic illicit drugs. They are chemically diverse, including phenethylamines, synthetic cathinones, and tryptamines, and act on monoamine neurotransmitter systems. Stimulants like pipradrols and pyrovalerone cathinones block dopamine and noradrenaline reuptake, while entactogens such as MDMA-like cathinones enhance serotonin release. Hallucinogens, including tryptamines, directly activate 5-HT2A serotonin receptors. Synthetic cannabinoids act on CB1 receptors like THC. The ratio of serotonergic to dopaminergic activity helps predict a substance's psychotropic effects, toxicity, and addiction potential. Most poisonings are mild to moderate, but serotonergic drugs can cause serotonin syndrome, hyperthermia, and seizures; dopaminergic drugs are highly addictive and linked to psychosis; synthetic cannabinoids may cause agitation, hypertension, and renal failure. Treatment is supportive.

Study at a glance

Abstract

Novel psychoactive substances are newly used designer drugs ("internet drugs", "research chemicals", "legal highs") potentially posing similar health risks to classic illicit substances. Chemically, many novel psychoactive substances can be classified as phenethylamines, amphetamines, synthetic cathinones, piperazines, pipradrols/piperidines, aminoindanes benzofurans, and tryptamines. Pharmacologically, these substances interact with various monoaminergic targets. Typically, stimulants inhibit the transport of dopamine and noradrenaline (pipradrols, pyrovalerone cathinones) or induce the release of these monoamines (amphetamines and methamphetamine-like cathinones), entactogens predominantly enhance serotonin release (phenylpiperazines, aminoindanes, para-substituted amphetamines, and MDMA-like cathinones) similar to MDMA (ecstasy), and hallucinogens (tryptamines, hallucinogenic phenethylamines) are direct agonists at serotonergic 5-HT2A receptors. Synthetic cannabinoids are another group of novel substances which all act as agonists at the cannabinoid CB1 receptor similar to THC but are chemically diverse. In particular, the relative serotonergic vs dopaminergic activity (determined by the dopamine/serotonin transporter inhibition ratio in vitro) can be helpful to predict the desired psychotropic but also the toxic effects of novel substances as well as their potential for addiction. Although the use of novel psychoactive substances mostly produces minor or moderate poisonings, serious complications occur. Serotonergic drugs (entactogens and hallucinogens) are associated with acute serotonin syndrome, hyperthermia, seizures, and hyponatremia. Dopaminergic drugs are highly addictive and acute toxicity includes prolonged stimulation, insomnia, agitation, and psychosis. Agitation, anxiety, paranoia, hypertension, and rarely myocardial infarction and renal failure are seen with synthetic cannabinoids. Treatment is supportive.