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Although these findings have been promising, small sample sizes and short duration are noted as being limitations in all research to date. Safety Can be used long-term and is well tolerated, with low toxicity. Safety in pregnancy and breast-feeding is not sufficiently proven to recommend its use. Medicine interactions • Benzodiazepines: Theoretical additive effect to drug due to GABAergic activity. • Chemotherapeutic agents (doxorubicin, cyclophosphamide, epirubicin, fluorouracil): May improve chemotherapy- induced fatigue via unknown mechanism. • Psychotropic drugs (olanzapine, typical antipsychotics, antidepressants, mood stabilisers, antianxiety, hypnotic): May improve neurotransmitter dysfunctions due to GABAergic and NMDA potentiating activity.13 Kava (piper methysticum) Kava is the most researched herbal medicine for treatment of generalised anxiety. A group of compounds called kavalactones are believed to direct its anxiolytic actions. They appear to have targeted actions on the gamma-aminobutyric acid (GABA) pathway via alteration of lipid membrane structure and sodium channel function, noradrenaline and dopamine reuptake inhibition, among other possible mechanisms.5 Evidence A number of clinical trials and meta- analyses suggest that kava is a non- addictive, non-hypnotic anxiolytic with potential to treat generalised anxiety.5,14 • A 2003 Cochrane review (12 RCTs; n=645) reported that compared with placebo, kava extract appears to be an effective symptomatic treatment option for anxiety. Adverse events were mild, transient and infrequent.15 • A 2010 review of efficacy and safety (six RCTs) also supported the use of kava for generalised anxiety.16 • A 2013 six-week RCT (n=75) involving patients with clinically diagnosed generalised anxiety disorder showed a significant reduction in anxiety for the kava group compared with placebo. An even greater effect in anxiety reduction was seen in patients with moderate to severe generalised anxiety disorder (GAD). A dose of 120mg of kavalactones was used for the first three weeks and dose was doubled for non-responders after three weeks.17 Safety Previous safety concerns about any hepatotoxicity risk with kava have not been supported by recent research. Short-term use up to 24 weeks has been reported to be relatively safe. However, further research for extended periods is warranted to determine long-term safety on the liver versus established pharmaceutical options.15 Kava products manufactured in Australia are governed by the code of Pharmaceutical Good Manufacturing Practice, which ensures that the kava material is screened for contaminants, a potential source of earlier toxicity issues. Medicine interactions Kavalactones have been identified as inhibitors of several enzymes of the CYP450 system. Due to possible additive effects, concomitant use with benzodiazepines and antidepressants is not recommended. Cautionary avoidance of alcohol is also recommended. There is insufficient research to support safe use during pregnancy or breastfeeding. Rhodiola (rhodiola rosea) Rhodiola is a medicinal plant also described as an adaptogen. It’s endorsed by the European Medicines Agency for temporary relief of mental stress, exhaustion and fatigue, based on a long history of traditional use.18 Rhodiola normalises the release of stress hormones while simultaneously boosting energy metabolism via activation of ATP synthesis in mitochondria.7 A clinical picture for rhodiola could be a patient who needs to boost physical and mental stamina, reduce mental fatigue and improve concentration, particularly during times of stress. Evidence Clinical trials have been largely lacking, although smaller studies show promising results. • A 2007 six-week RCT evaluated efficacy and safety for subjects with mild/ moderate depression (n=89) taking either 340mg or 680mg/day. Overall depression and emotional instability improved significantly with both doses compared with placebo, with no serious side effects noted at either dose.19 • A 2008 pilot study of 10 participants with diagnosed GAD received 340mg of rhodiola extract for 10 weeks. Results showed that those treated with the rhodiola extract showed significant improvement in anxiety symptoms with a reduction in HARS scores similar to those found in clinical trials.20 • A 2009 RCT (n=60) assessed efficacy for subjects suffering from stress-related fatigue using a dose of 576mg daily of the HEALTH VITAMINS MINERALS AND SUPPLEMENTS 83 rhodiola extract. Rhodiola was associated with a significant anti-fatigue effect and improved mental performance scores when compared with placebo.21 • A 2015 12-week proof of concept RCT (n=57) evaluated relative safety and efficacy of rhodiola compared with the SSRI sertraline for mild to moderate depression. The decline in Hamilton Depression Rating scores was greater for sertraline, compared with rhodiola and placebo. However, rhodiola resulted in significantly fewer adverse events and was better tolerated. By week 12 there were clinically meaningful improvements with rhodiola compared with placebo. Authors concluded that rhodiola appears less effective than sertraline but may present a more favourable risk-to- benefit ratio for people with mild to moderate depression.22 • A comprehensive 2018 review of trials to date concluded that based on accumulated evidence, rhodiola is appropriate treatment for clinically relevant stress symptoms and signs of burnout. Burnout is a risk factor for anxiety and depression, as well as for a range of somatic diseases. The ability of rhodiola to increase resistance to persistent stress makes it a useful evidence-based option for mental health support in a vulnerable population.23 Overall, trials to date have been limited in subject numbers and often exploratory in design, so further RCTs are needed to confirm results. Safety It is well tolerated and may be suitable for long-term use with a favourable safety profile in clinical trials. Safety during pregnancy and lactation has not been established. Medicine interactions Concomitant use with benzodiazepines and antidepressants is not recommended due to possible additive effects. Caution is advised with drugs involving CYP2C9 enzyme substrates.13 St John’s wort (hypericum perforatum) Evidence St John’s wort (SJW) has been evaluated over several decades for its antidepressant actions. Earlier meta-analyses have recommended it as first line treatment for mild to moderate depression, suggesting it may be therapeutically equivalent to imipramine with better patient adherence.5,24 • A 2008 Cochrane review of patients with TO PAGE 84 RETAIL PHARMACY • MAY 2021