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Serotonin syndrome (SS) (also referred to as serotonin toxicity) is a potentially life-threatening drug-induced toxidrome associated with increased serotonergic activity in both the peripheral (PNS) and central nervous systems (CNS). It is characterised by a dose-relevant spectrum of clinical findings related to the level of free serotonin (5-hydroxytryptamine [5-HT]), or 5-HT receptor activation (predominantly the 5-HT1Aand 5-HT2Asubtypes), which include neuromuscular abnormalities, autonomic hyperactivity, and mental state changes. Severe SS is only usually precipitated by the simultaneous initiation of 2 or more serotonergic drugs, but the syndrome can also occur after the initiation of a single serotonergic drug in a susceptible individual, the addition of a second or third agent to long-standing doses of a maintenance serotonergic drug, or after an overdose. The combination of a monoamine oxidase inhibitor (MAOI), in particular MAO-A inhibitors that preferentially inhibit the metabolism of 5-HT, with serotonergic drugs is especially dangerous, and may lead to the most severe form of the syndrome, and occasionally death. This review describes our current understanding of the pathophysiology, clinical presentation and management of SS, and summarises some of the drugs and interactions that may precipitate the condition. We also discuss the newer novel psychoactive substances (NPSs), a growing public health concern due to their increased availability and use, and their potential risk to evoke the syndrome. Finally, we discuss whether the inhibition of tryptophan hydroxylase (TPH), in particular the neuronal isoform (TPH2), may provide an opportunity to pharmacologically target central 5-HT synthesis, and so develop new treatments for severe, life-threatening SS.

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Nicotinamide N-methyltransferase (NNMT) has been proposed as a link between the environmental and genetic factors of Parkinson disease (PD). Therefore, we explored the hypothesis that high levels of NNMT expression may predispose to the development of PD. Regions of high mRNA expression were shown in the spinal cord, medulla, and temporal lobe, with lowest expression in the cerebellum, subthalamic nucleus, and caudate nucleus. Using 2 NNMT antibodies, the protein was shown to be expressed in multipolar neurons in the temporal lobe, caudate nucleus, and spinal cord, granular neurons of the cerebellum, dopaminergic neurons in the substantia nigra, and in the axons of the third nerve. Expression of NNMT was compared in PD and non-PD control cerebella and caudate nucleus. PD tissue exhibited significantly increased levels of NNMT protein and activity. PD disease duration was inversely correlated with the level of expression in cerebellum. This is the first demonstration that patients with PD have higher levels of NNMT activity and protein in brain tissue than those without PD and that NNMT expression is associated with neurons that degenerate in PD.

A series of terpenes has been assessed as skin penetration enhancers towards the model polar penetrant 5-fluorouracil (5-FU). Cyclic terpenes were selected from the chemical classes of hydrocarbons (e.g., alpha-pinene), alcohols (e.g., alpha-terpineol), ketones (e.g., carvone), and oxides (e.g., 1.8-cineole, ascaridole). Permeation experiments were performed on excised human epidermal membranes and the terpenes varied in their activities; alpha-pinene only doubled the permeability coefficient of aqueous 5-FU, whereas 1.8-cineole caused a near 95-fold increase. Essential oils, e.g., chenopodium (70% ascaridole), were less effective than the corresponding isolated terpenes, 5-FU is less soluble in the terpenes than in water, and the terpenes did not exert their action by increasing partitioning of the drug into the membranes as illustrated by stratum corneum:water partitioning studies. The penetration enhancers increased drug diffusivity through the membranes, an effect which correlated empirically with the enhancer activities. The principal mode of action of these accelerants may be described by the lipid-protein-partitioning theory: the terpenes interacted with intercellular stratum corneum lipids to increase diffusivity, and the accelerant effects were not due to partitioning phenomena. Keratin interaction was assumed negligible.

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