Herbal remedies and supplements may come in many different forms and formulations. Since they are currently not subject to the same regulatory requirements as conventional medicines they can vary substantially in contents and dose even if they purport to contain the same ingredients. The pharmacological properties of an extract or a supplement may depend on many different factors (Table 6.2.9.1).

Cognitive enhancers are either used in the treatment of dementia to enhance mental performance or prevent cognitive decline in healthy people. One strategy aims at increasing choline availability, e.g. by inhibiting acetylcholine esterase. Alternative non-cholinergic neuroprotective strategies have been postulated. These rely on antioxidants scavenging free radicals thereby reducing neurotoxicity or anti-coagulants and increasing cerebral blood flow.⁽⁴⁾ Suggested herbal cognitive enhancers for which some positive trial evidence has been collated include ginkgo (Ginkgo biloba), panax
ginseng (Panax ginseng), hydergine (Claviceps purpurea), sage (Salvia officinalis), and vitamin E. The potential side effects can be derived from the purported mechanisms of action. For example, remedies increasing the cerebral blood flow such as ginkgo may increase the risk of cerebral haemorrhage. Panax ginseng has been associated with manic episodes and hydergine can lead to ergot poisoning unless dosed carefully. Some sage species can lower the seizure threshold. Others contain camphor, which can be toxic in high doses.⁽²⁾ Also, evidence is emerging that taking vitamin E above the recommended level may increase all-cause mortality.⁽⁵⁾

Drugs considered to be either anxiolytics or sedatives essentially have the same underlying mechanisms of action. The stronger an agent the more sedating it will be, leading to coma in extreme cases. Four mechanisms of action have been implicated; binding to γ-aminobutyric acid (GABA) receptors leading to hyperpolarization of the cell membrane through increased influx of chlorine anions; inhibition of excitatory amino acids (EAA) thereby also impairing the ability to form new memories; sodium channel blockade, reducing depolarization of the cell membrane; and calcium channel blockade, reducing the release of neurotransmitters into the synaptic cleft.⁽⁴⁾ The most commonly used CAMs for anxiolysis and sedation, such as valerian (Valeriana officinalis), passion flower (Passiflora incarnata), kava (Piper methysticum), and German chamomile (Matricaria recutita) are GABAergic. Lemon balm (Melissa officinalis) has cholinergic and GABAergic properties. For other plant remedies, including hops (Humulus lupulus), oats (Avena sativa), lavender (Lavendula angustifolia), and starflower also known as borage (Borago officinalis), the actual mechanism of action remains unknown. Melatonin regulates the circadian rhythm and also has some GABAergic properties although trial evidence remains inconclusive. Some of these remedies can potentially have serious side effects. For instance, kava extracts have been associated with significant and potentially fatal hepatotoxicity. Starflower contains γ-linolenic acid that may lower the seizure threshold. Some passion flower extracts may contain cyanide components. As expected, all remedies in this class can lead to drowsiness when taken in high doses and can potentiate the effect of synthetic sedatives.

Most complementary antidepressants are thought to work through serotonergic and noradrenergic pathways. The most robust clinical data are available for St John’s wort (Hypericum perforatum), having been extensively reviewed in meta-analyses.⁽¹⁾ Hyperforin, inhibiting the reuptake of monoamines, is thought to be the most likely active component. Supplements, such as S-adenosylmethionine (SAMe), folic acid, l-tryptophan, and 5-hydroxytryptophan are components or co-factors in the serotonin synthesis. For SAMe, equivalence to tricyclic antidepressants has been demonstrated. However, SAMe is very expensive and a suitable oral formulation may be difficult to obtain. Selenium has also been suggested but the mechanism of action, albeit still unclear, seems to be different. Its antioxidant properties may reduce nerve cell damage. Selenium also facilitates conversion from thyroxin (T4) to thyronine (T3), and T3 substitution is one possible augmentation strategy for antidepressants. As for lithium, the therapeutic index is narrow. Omega-3 fatty acids are known to stabilize membranes and to facilitate monoaminergic, serotonergic, and cholinergic neurotransmission. The currently available evidence supports the use of eicosapentaeonic acid on its own or in combination with docosahexaonic acid as adjunctive treatment.⁽⁶⁾ Serotonergic remedies should not be combined with each other or with conventional antidepressants because of the increased risk of serotonin syndrome. Equally, herbal antidepressants may induce mania in vulnerable patients although current evidence relies on case reports only. Finally l-tryptophan and 5-hydroxytryptophan should be avoided until the associated risk of eosinophilic myalgic syndrome is fully explained.