More than 38% of Americans use complementary and alternative medicine (CAM) yearly, with 12.7% using so-called “natural products” (Barnes PM et al, CDC Nat Health Stat Rep #12, 2008). More than a third of people over age 50 report use of supplements, yet only about half have discussed this with their doctors (AARP/NCCAM Survey of US Adults 50+, 2010). Whether or not you share your patients’ enthusiasm for supplements, their curiosity and participation are thriving, so this is a great opportunity for you to learn together.

In this article I’ll cover the most frequently used over-the-counter agents for depression, anxiety, and insomnia—some of our more common presenting complaints and those for which patients often seek alternative treatments.

Herbal Medications

Two herbal medicines used to treat depression are St. John’s wort and Rhodiola. While the former has been studied throughout the world for many years, the latter is just beginning to receive attention.

Saint John’s wort (SJW; Hypericum perforatum) is licensed in several European countries as a treatment for mild to moderate depression, and for anxiety and sleep disorders. Though the active ingredients hypericin and hyperforin have been isolated, their mechanisms of action remain hypothetical.

In well-designed trials, SJW’s efficacy is questionable; a 26-week National Institutes of Health (NIH) study found the response to SJW, antidepressants, and placebo for moderate to severe major depression to be similar—and poor (23.9%, 24.8%, and 31.9% respectively), although the rate of overall functioning appeared better for those using the antidepressant (Hypericum Depression Trial Study Group, JAMA 2002;287(14):1807–1814).

A more recent meta-analysis of studies comparing SJW with SSRIs showed that the two are equivalent in efficacy (Rahimi R et al, Prog Neuropsychopharm Biol Psychiatry 2009;33:118–127). Similarly to SSRIs, hypericum may induce (hypo)mania and cycling. The FDA also warns against the concomitant use of hypericum with a range of medicines, as it induces CYP3A4 robustly, and the P-glycoprotein transporter to a lesser extent.

Moreover, serotonin syndrome is a risk when taken with SRIs, triptans, sympathomimetics, and cough syrup. I do not use it in my practice and generally talk clients out of it, offering “natural” options I find more effective.

Rhodiola rosea is thought to influence levels of monoamine neurotransmitters and opioid peptides such as beta-endorphins (Kelly GS, Altern Med Rev 2001;6(3):293–302). This Russian folk medicine has been found superior to placebo in a randomized trial for mild to moderate depression (Darbinyan V et al, Nord J Psychiatry 2007;61(6):503) and in an open-label trial for generalized anxiety disorder (Bystritsky A et al, J Altern Complement Med 2008;14(2):175-80). This herb has been touted as an “adaptogen” for its ability to promote resilience under a variety of stressors (Kelly, op.cit, 2001). Purported mechanisms include the suppression of stress-activated protein kinases, as well as anti-inflammatory and antioxidant pathways. A generally safe and effective dosing range is 300–900 mg daily. Side effects include potential tachycardia and (hypo)mania.

Valerian (Valeriana officinalis), a plant native to Europe, has been used for both insomnia and nervous tension since ancient Greece and Rome. It promotes release and blocks reuptake of gamma-aminobutyric acid (GABA). Clinical trials for insomnia and other sleep problems have been mixed; systematic reviews of these studies have found the evidence inconclusive due to publication bias and significant variability among studies in subjects (including small sample sizes), and in sources, preparation, and doses of valerian. Few studies of valerian in anxiety have been undertaken, and in a Cochrane Review only one available study met their strict inclusion criteria.

Despite lack of conclusive evidence, many of my clients find it helpful, mainly for sleep. Valerian rarely causes poor sleep quality or rebound insomnia when discontinued, or next-day impairment of functioning, problems commonly encountered with other sleep and anxiety medications. Typical recommended doses include 450 mg of extract for sleep, taken one hour before bedtime (study doses have ranged 400–900 mg), and 200–300 mg of extract in the morning for anxiety.

Standardized extracts that have been used in clinical trials are available, including Alluna Sleep, Valerian-400, and Sedonium. Sleep improvement may increase with nightly use rather than on an as-needed basis, results peaking after 14 days (Vorbach EU et al, Psychopharmakotherapie 1996;3:109–115).

The extracts of the root of the kava (Piper methysticum) plant have been studied since the 1960s. While used for anxiety, insomnia, and menopausal symptoms, clinical trials show clear efficacy only for anxiety, for which it has been compared to buspirone and low-dose benzodiazepines.

Kava may lead to hepatotoxicity and liver failure in susceptible clients taking relatively normal doses, and acute liver failure resulting in transplant has occurred after as few as four to 12 weeks of use. In 2002, sales of products containing kava were suspended or withdrawn in many countries, although it remains available in the US.

Ginkgo biloba, used medicinally for thousands of years, deserves mention because it’s taken by so many people with mood disorders who seek to improve memory and cognition. Data are mixed, but most do not demonstrate significant support for acute or long-term use. Evidence for ginkgo’s usefulness in other areas of interest to people with depression—including tinnitus and antidepressant-induced sexual dysfunction—is no more promising than the memory research. Side effects and important drug interactions are numerous.

Amino Acids

Among the many supplements of amino acids (and their derivatives), the most effective for depression may be S-adenosylmethionine (SAMe). Others include GABA and N-acetylcysteine (NAC) (see Emily Deans’ article in this issue for a discussion of NAC). In my practice, I use SAMe as an adjunct and in monotherapy; I use NAC for bipolar depression, impulse dyscontrol, tinnitus, and to support substance use recovery; and GABA as an alternate to benzodiazepines and gabapentin.

While not technically an amino acid, SAMe helps to form amino acids like the antioxidant glutathione, is required for catecholamine synthesis, and helps to regulate gene expression and membrane fluidity. SAMe supplementation can, theoretically, result in increased levels of serotonin, dopamine, and phosphatides. SAMe also works synergistically with folate, B6, and B12 in reducing homocysteine levels. Neuropsychiatric uses of SAMe include depression, anxiety, premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD), attention deficit hyperactivity disorder (ADHD), and improving intellectual performance, among many others. Neuroimaging studies indicate that SAMe affects the brain similarly to conventional antidepressants (Arnold O et al, Eur Neuropsychopharmacol 2005;15(5):533–43).

Compared with many other nonpharmaceutical supplements, three decades of literature suggest its efficacy and safety in depression. It’s somewhat more effective intramuscularly than in its oral form; in fact, there’s only preliminary evidence supporting the use of oral SAMe. Doses of 1,600 mg daily have been most commonly studied; in my practice I use 800 mg twice daily. Nausea and vomiting may occur, so start low and go slow with 200 mg twice daily for two days, then 400 mg twice daily on day three, increasing to 800 mg twice daily over the following two weeks. Concomitant use of vitamin B12 and folate may increase the synthesis of SAMe (Bottiglieri T, Psychiatr Clin North Am 2013;36(1):1–13). SAMe has been associated with (hypo)mania in case reports and clinical trials of both oral and parenteral formulations, and may exacerbate anxiety. Caution should be used with concomitant serotonergic drugs and supplements.

GABA is used orally or sublingually for relieving anxiety, elevating mood, relieving PMS, and treating ADHD. There’s little actual evidence on its effectiveness in humans, although anecdotally, a number of my patients with a trauma history find it calms physiologic symptoms of anxiety and can be helpful for sleep. Doses have not been tested, but some manufacturers recommend at least 2 grams daily with 5 grams being more effective, taken in divided doses between meals.

Quality and Effectiveness

Keep in mind that much of the research on herbal medications comes from Europe (Germany standardizes herbal remedies), where supplements have been regularly used for decades, although most studies are not randomized, placebo-controlled double-blind trials with an adequate sample size. Mechanisms of action and bioavailability may be unstudied or unknown, and perhaps dependent on the synergy of other chemicals present in an herb, or cofactors used with an amino acid.

Furthermore, supplements are products, not drugs, and the FDA does not require data on efficacy, safety, or purity for premarket approval, nor do they require a post-market surveillance period. There is no legal definition of terms like “standardized,” “certified,” or “verified,” and the presence of additives, fillers, or contaminants is not regulated in any fashion. Finally, many temperature-sensitive products get baked in a hot truck or warehouse on their way to the sales floor.

TCPR’s Verdict: Be sure to ask about supplement use, and educate patients that “natural” is not necessarily better or harmless. Many studies are methodologically flawed and outcomes equivocal, so conversations with your colleagues and anecdotal evidence about effectiveness and usage tips are valuable.