The consequences of functional selectivity suggest that the inherent activity and toxicity profile of each individual agonist might be different and relevant to deducing what could result from idiosyncratic responses or overdose,73 but toxicity data are not usually published. Functional selectivity means that drugs that are equipotent ligands at the 5-HT2A receptor can have different

“downstream” effects.40,74 Some clinically used dopamine agonists are also agonists at the 5-HT2A receptor, eg, lisuride and pergolide. LSD and pergolide are hallucinogenic, but lisuride is not.74 There appear to be no reports of complications involving hyperthermia with these drugs. Is it just luck that they happen to exhibit the “functional selectivity” that avoids this? One might assume Panobinostat that if experimental compounds did precipitate hyperthermic toxicity they would rapidly be screened out; however, without published toxicity data doubt remains. Be that as it may, the triptans are inactive at the 2A receptor, HDAC cancer and the evidence indicates that their very weak activity at the 1A receptor is almost certainly of no relevance or consequence. Indeed, if there were to be a convincing report of definite severe hyperthermic SS with a triptan, it would be a valuable

report deserving critical evaluation. Such a case might provide insights about functional selectivity and genetic variants of receptors.75,76 It is therefore clear, in my opinion, that triptans do not pose a risk of causing severe SS for 2 reasons: (1) they do not show serotonergic side effects or toxicity by themselves or with other serotonergic drugs; (2) they do not posses the

pharmacological properties that we are confident are required to mediate SS. It is important to note that there have been clear precedents of many false-positive reports with other drugs that we know are not serotonergic and cannot precipitate SS, eg, amitriptyline, trazodone, nefazodone, and mirtazapine. These have all been analysed in detail elsewhere9,10,14,15: but there are numerous incorrect reports of supposed SS from them, so they serve to remind us of the importance of establishing the pharmacology of the drug and its ability to raise serotonin, which constitute the sine qua non for SS, and of using our knowledge of the spectrum concept of SS to Staurosporine mouse predict the serotonergic potency of drugs in humans from data about their propensity to induce SS.9 There is a great contradiction between the estimate of risk, and the conclusions and recommendations, of the USA FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA) in their respective assessments of methylene blue,77 an MAOI, see Stanford,22 and triptans. On the one hand, the MHRA fail to warn of SS despite strong evidence of severe SS, whereas the FDA does warn of “fatal” SS where no substantive evidence exists.