With regard to SAMe, there is fairly strong evidence that oral or intravenous SAMe is effective for treatment of major depression, and may even have a faster onset of action than conventional antidepressants. It may be used as monotherapy or in combination with other antidepressants and anxiolytics, and may even accelerate the effect of conventional antidepressants. SAMe has demonstrated good tolerability, no toxicity, lack of drug–drug interactions, and a relatively benign side-effect profile, with minor gastrointestinal complaints (such as dyspepsia, nausea, or stool changes) or stimulation/agitation being the most commonly reported [65]. It may be especially good for elderly and/or medically ill patients in whom side effects and interactions may be a significant concern. There have been some reports of SAMe causing increased anxiety and mania in bipolar patients with depression [81], so caution needs to be taken with bipolar individuals. SAMe is among the more expensive of psychotropic nutraceuticals (costing approximately US$25–$50 per week based on an 800 mg or 1600 mg daily dose), and the instability of the pure compound requires costly manufacturing procedures (e.g., tosylation) and storage elements (e.g., blister packs). Doses reported in the literature range from 400 to 3200 mg/day, though some individuals may require even higher doses for symptomatic relief. SAMe augmentation of conventional antidepressants in cases of partial response, appears to be a viable niche for this compound.

An overarching issue concerning clinicians prescribing SJW is the marked difference in preparation quality and standardization among products [82]; thus, the results of high-quality European pharmaceutical grade extracts cannot be generalized to inferior extracts. Clinicians are advised to use standardized SJW products (such as LI-160, Ze-117, or WS-5570 extracts) which have proven efficacy in clinical trials, to better ensure replication of results. The common daily dosage of concentrated SJW is 900 mg, often given in two to three doses per day in tablet form, amounting to about 1mcg of hypericin (one active component) and/or 0.5–5 % of hyperforin (depending on whether the extract is standardized to reduce hyperforin). However, more severely depressed patients may need up to 1800 mg/day. If needing to avoid drug interactions, the low hyperforin extract ZE-117 may be advised; however, it should be noted that hyperforin crosses the blood–brain barrier, whereas hypericin does not [15]. SJW has not been studied in treatment-resistant depression, and it is unlikely in many cases to exert a potent enough thymoleptic effect required.

While concerns exist over interactions between SJW and various pharmaceuticals, this issue centers on extracts containing higher amounts of hyperforin, which is responsible for inducing cytochrome (CYP) P450 pathways and the P-glycoprotein drug efflux pump, thereby reducing drug serum levels [83]. For this reason, clinicians are advised to only prescribe low-hyperforin SJW products if the patient is taking other medication. Products standardized for higher levels of hypericin and flavonoids should not induce CYP pathways [84]. While SJW has a sound safety profile, case reports have reported possible SJW-induced mania, psychosis, and serotonin syndrome [8]. While many of these mania cases detail concomitant use of other medications and/or recreational drugs, and a background of cyclothymia, a clear temporal association appears to exist between SJW use and induction of hypomania or mania. Therefore, caution is advised in people with a personal or family history of bipolar disorder. Several case reports of serotonin syndrome have been documented by drug surveillance agencies, and this is likely due to use of high-dose SJW and/or concomitant use with synthetic antidepressants, particularly serotonergic agents. Considering this risk, SJW should not be co-prescribed with antidepressants; although there may a role for low-dose SJW when a patient is withdrawing from an antidepressant, or potentially in pregnancy (with appropriate clinical judgment and supervision).

In respect to saffron, while the stigma is fairly expensive, the less expensive petals have still been found to be effective in MDD. The daily doses of up to 1.5 g have been found to be safe [30], with a “Generally Recognized as Safe” (GRAS) status in the United States [85]. In clinical studies, only rare minor adverse effects have been found, for example, digestive upsets, insomnia, irritability, and tachycardia [30]. A 1-week double-blind RCT in humans evaluated saffron stigma tablets (200–400 mg) for short-term safety and tolerability in 10 healthy adults [86]. Clinical examination showed no gross biological or clinical changes in all volunteers after intervention, with no major adverse events reported during the small pilot trial. Finally, regarding zinc prescription, no major adverse effects should occur. It should, however, be advised for consumers to avoid consumption on an empty stomach (may cause nausea), and not exceeding the recommended dosage to prevent an imbalance between other minerals consumed (due to competitive absorption).