Anxiety Disorders: Supplements With Likely Efficacy

2015

Like depression, anxiety is an area of psychopharmacology where many naturopathic compounds have been studied. While kava has established efficacy with adults and consistently has been shown to be effective in decreasing symptoms of anxiety, no studies thus far have been performed with children and adolescents, and some risk of hepatotoxicity may be present, and consequently the supplement is included in this section. In addition, some other compounds have also revealed at least some efficacy, but research has primarily been done with adult patients, and clinicians must use caution when applying results of these studies to pediatric patients.

Anxiolytic medications work by increasing the amount of activity in the serotonergic pathways, as well as altering the glutamate-GABA balance in favor of inhibitory effects. Supplements that accomplish similar changes in the brain have been shown to be effective in managing symptoms of anxiety.

Kava

Kava (Piper methysticum), alsto referred to as kava kava, is a tall bush indigenous to the South Pacific, especially Hawaii, Fiji, Samoa, Tonga, Tahiti, New Guinea, and New Zealand. Its root is typically ground, and indigenous cultures have also chewed it, prepared it as an infusion, or brewed it to use for celebratory and ceremonial occasions for thousands of years. In addition, it has been used as a gift to symbolize the resolution of a social conflict, and ‘partaken as an after-work drink to relax’. It has peen prized because, unlike many herbal herbs that cause sleepiness, kava’s relaxant effects seem to occur without significant drowsiness.

Kava has been used in the west at least since the eighteenth century, and is approved by Germany’s Commission E as a treatment for nervous anxiety and stress (Medical Economics, 2007). In addition to its anxiolytic effects, kava is also known for its analgesic, antibacterial, antifungal, anti-inflammatory, antithrombotic, and muscle relaxant properties (Medical Economics, 2007). Kava supplements are generally available in capsules that range from 100-500 mg, a liquid, and tea bags for brewing. As with all supplements, capsules and tablets are preferred because the exact dosage is easier to control, although those who do not like to swallow pills may prefer to use the liquid.

Evidence of Efficacy

Although case reports of the benefits of kava as an anxiolytic date back some 200 years, controlled research is more recent and seems to have started in the late 1980s. Controlled studies in Europe have revealed that clinical effects are usually evident after 4 weeks of treatment, but in some cases, treatment for 8 weeks was necessary before significant symptom reduction was noted. Symptoms of various anxiety disorders seem to respond well to treatment with kava, including agoraphobia, specific phobia, generalized anxiety disorder, and adjustment disorder with anxiety. By the end of the 1990s, some 14 randomized clinical trials were conducted around the world and results revealed that kava was far superior to placebo and safe when used at 60-240 mg/day for up to 25 weeks of treatment. An update reviewed 11 controlled trials with a total of 645 participants and revealed similar results.

Head-to-head studies comparing kava and prescription anti-anxiety medications have also been performed. Kava has been shown to be equally effective as oxazepam (a benzodiazepine anxiolytic) with fewer side effects, and other studies similarly compared kava with other benzodiazepines and buspirone, and find comparable efficacy. In the largest, multicenter, randomized, placebo-controlled trial, 129 patients were given kava, buspirone (a serotonergic anxiolytic) or opipramol (a tricyclic anxiolytic primarily used in Germany) and found that 70 percent of patients given kava responded well (at least a 50 percent reduction in symptoms), and 60 percent attained symptom remission. In another study, patients who were originally on a benzodiazepine were started on kava and gradually the dose of kava was increased while the benzodiazepines were tapered and eventually discontinued. Results revealed that after 3 weeks on kava as monotherapy, the anxiolytic effects were similar to that previously seen with the benzodiazepine, and far superior to placebo.

Very few studies have investigated the use of kava with children or adolescents, although case reports, primarily published on naturopathically oriented websites, suggest that kava is effective in adolescents. In addition, in rare cases, serious hepatotoxicity has been reported, but remains controversial (as further discussed below). Clinicians and parents should weigh these factors very carefully. If a trial of kava is undertaken, regular medical monitoring of liver function should be performed, and the American Botanical Council recommends that any use of kava for more than 1 month should be done under medical supervision.

Pharmacodynamics

Kava contains dozens, if not hundreds, of constituents. Psychoactive ingredients are presumed to be the many kavapyrones and kavalactones, including kavain, dihydrokavain, yangonin, methysticin, and dihydromethysticin. Kavain and dihydrokavain are presumed to be the most permeable to the blood-brain barrier.

Kavalactones facilitate the functioning of GABA A receptors, in a manner that is similar to benzodiazepines, but kavalactones do not appear to bind to benzodiazepine receptors. The overall effect involves positive allosteric modulation of chloride channels, increasing the influx of chloride and hyperpolarizing the cell. The increase in GABA activity may also be secondary to kavain’s suppression of thromboxane, which further enhances GABA activity. In addition, kavalactones inhibit calcium channels, and various kavalactones may do so additively, producing a reduction of calcium influx by as much as 70 percent. Thus, the psychoactive effect involves broad inhibition of neuronal firing. Several kavalactones have also been found to inhibit sodium channels, further contributing to the inhibitory effect.

Kavalactones may have other psychoactive properties. Kavain and methysticin weakly block the reuptake of norepinephrine, but seem to have no effect on serotonin. The effect on dopamine is inconsistent, with levels rising in some parts of the brain and dropping in others. Kavalactones may also reversibly block platelet MAO B enzymes, and this effect does not seem evident until at least 3 or 4 weeks of treatment. This may be responsible for some of the latency of clinical response observed in research trials.

Pharmacokinetics

Kava lactones are rapidly absorbed in the small intestine and transported to the liver, where they undergo metabolism via the CYP 450 system of enzymes. Although the specific pathways have not yet been identified, 2D6 may be the primary pathway (see further discussion of adverse effects). Importantly, however, kava constituents seem to inhibit 1A2, 2C9, 2C19, 2D6, 3A4, and 4A9/11 enzymes, thus making the use of kava problematic with most prescription medications (Medical Economics, 2007). After the first pass effect, kava enters systemic circulation and is absorbed by various tissues in the body. Several kavalactones cross the blood-brain barrier, but may do so competitively, making it difficult to predict which ones are most psychoactive. Peak levels of kavalactones in the plasma occur about 2 hours after oral administration, and metabolites of kava are excreted in the urine, while unabsorbed portions are excreted in the feces.

Dosing

In research, typical dose for adults is 70-240 mg/day (0.8-2.8 mg/kg/ day) of kava, or 60-120 mg/day (0.7-1.4mg/kg/day) of a standardized preparation of 30 percent kavalactones. Dose with children and adolescents should start at the low end of the range and gradually titrate upwards, and clinicians should keep in mind that 4 weeks or more may be necessary before therapeutic effect is evident, and therefore a few weeks at each dose level may be needed before it will be apparent whether the dose is effective. The supplement may be administered in divided doses, although it is usually given in the evening.

Adverse Effects

Most regard kava to be safe and effective, especially in low doses, and that fears of adverse effects have caused many to use kava at doses that are unnecessarily low. Mild reactions include gastrointestinal upset, dizziness, headache, and dermatological reactions, including ‘kava dermopathy’ after prolonged heavy use, a yellowing of the skin. Changes in vision, mydriasis, and disturbances in eye tracking have also been reported, as well as impaired motor reflexes and rare difficulties in motor coordination, including choreoathetosis, all of which reversed upon discontinuation (Medical Economics, 2007).

The greatest concern surrounds the risk of liver damage. Over 60 cases of hepatotoxicity have been reported around the world, and many of these required liver transplants, including a 14-year-old girl who had been taking kava supplements (at unspecified dose) for 3 months. Concern over hepatotoxicity has caused some countries to restrict the use of kava and require a prescription. In some cases, it is apparent that adulterants added to kava may have been responsible for the liver damage, and methods of extraction may also be involved. In addition, some of those with liver damage have been found to exhibit low levels of endogenous CYP 2D6 enzyme, which may be responsible for most of kava’s metabolism. This is further confirmed by data that suggests that in many cultures, heavy use of kava (at doses hundreds of times greater than doses used during supplementation) reveal no history of hepatic damage. Waller (2002) performed a high-level review of all available data and concluded that serious adverse hepatic effects that can be traced to kava use are extremely rare, and involve very few individuals who may be hypersensitive to it or reveal an idiosyncratic reaction. Another published report estimated that of approximately 250 million daily doses of kava administered in the 1990s, only two individuals revealed hepatotoxicity secondary to kava, and in both cases the supplement was used far above the recommended dose. Consequently, most regard kava as safe when used at the doses recommended above, although patients who take kava should have their liver function monitored regularly, especially if the supplement will be used for more than 1 month.

The use of alcohol is contraindicated when kava supplementation is utilized. Kava and alcohol may have additive, if not synergistic, effects because they both increase GABA transmission and exert similar inhibitory effects. Even more importantly, both kava and alcohol induce liver enzymes, and the combination of the two may further predispose patients for liver damage. This is very important to consider in adolescents, since many teenagers tend to experiment with alcohol, especially if they also have a history of symptoms of anxiety.

Additional factors should also be considered. In some cases, patients who used kava started to exhibit symptoms of depression, especially with long-term use. Generally, patients with a history of depression should avoid using kava. Because depression and anxiety often coexist, the supplement may not be appropriate for that group of patients.

Because of kava’s extensive inhibition of liver enzymes, the use of kava should be avoided with the vast majority of medications, including anticoagulants, antiplatelet medications, heparins, thrombotic agents, amantidine, muscle relaxants, and most psychoactive agents (antidepressants, anxiolytics, mood stabilizers, etc.). Patients need to remember that even over-the-counter medications should be avoided with kava. For example, acetaminophen (sold in the US as Tylenol), poses some risk of hepatotoxicity, especially when used regularly, and using kava with Tylenol may increase the risk of liver damage. Parents of patients who take kava must be advised against using any medications concurrently with the supplement unless the combination is cleared (and monitored) by a medical professional.

Use of kava is contraindicated during pregnancy. Female adolescents who take kava and are suspected of being sexually active must be advised of this risk, and should use contraception to prevent pregnancy. If oral contraceptives are used, since they are metabolized by a CYP 3A4 pathway that is inhibited by kava, their plasma levels may increase, potentially causing unpredictable results. Once again, medical professionals prescribing the contraceptives must be aware that kava will be used concurrently and must approve (and monitor) the combination.

Inositol

Inositol is an isomer of glucose and is present in high concentrations in the brain. It was once classified as part of the B vitamin group and was designated vitamin B8, but was then found to be synthesized by the human body and was declassified as a vitamin. Inositol is found in many foods, including high-bran cereals, fruit, nuts, and beans. Inositol is available in several forms, and only some of these are appropriate for psychiatric use. These include inositol and myo-inositol. Other forms, such as inositol hexaphosphate, inositol nicotinae, and D-chiroinositol have not been shown to have mental health effects and are used to treat cancer, vascular diseases, and insulin resistance. Supplemental inositol is available in capsules of various strengths, generally ranging from 500-1000 mg. Inositol powder is also available.

Evidence of Efficacy

As discussed in Chapter 6, supplementation with inositol may offer some benefits in treating depression. In addition, a number of small studies reported that inositol has been found effective in reducing symptoms of anxiety. In a double-blind, placebo-controlled, cross-over study, 25 patients with panic disorder exhibited decreases in anxiety that were significantly greater than responses to placebo, even though the placebo effect in the study was reported to be quite large. In addition, Fux et al. (1996) investigated the use of inositol to treat symptoms of obsessive compulsive disorder and found that a dose of 18g/day was effective in reducing symptoms of obsessive compulsive disorder over a 3 month trial. Although a head-to-head comparison with prescription medications was not performed, the authors noted that the degree of improvement was comparable to that seen with SSRIs. Another study also found inositol to be effective in obsessive compulsive disorder-spectrum disorders, including trichotillomania. After reviewing several studies as well as the pharmacology of the nutrient, Levine (1997) concluded that inositol appears effective for the same conditions commonly treated by SSRIs, including depression, anxiety, and obsessive compulsive disorder. At this time, although results of research studies are still preliminary, reference resources on child and adolescent psychopharmacology list inositol as a safe and potentially effective ‘natural’ treatment alternative.

Pharmacodynamics

The mechanism of action of inositol is not fully understood. Inositol may be involved in neurotransmitter synthesis and is a precursor to the phosphatidylinositol (PI) cycle, an important intracellular second messenger system. By changing the PI cycle, inositol may exert intracellular changes that are similar to those seen when a post-synaptic receptor is activated, but without the need to activate that receptor. Thus, it may ‘fool’ the cell into thinking that it is activated. Consequently, it may be involved in regulating the activity of mono-amines (especially serotonin, with possible action on dopamine and norepinephrine) as well as other neurotransmitters. This serotonergic activity may be involved in inositol’s anxiolytic properties.

Pharmacokinetics

Inositol is absorbed from the small intestine. It is hypothesized that inositol is metabolized to phosphatidylinositol and then converted to phos-phatylinositol-4,5-bisphosphate, which is a precursor to second-messenger molecules. Unfortunately, little else is known about the pharmacokinetics of inositol, and time to peak and elimination half-life have not been established. Thus far, no effect on liver metabolism has been identified.

Dosing

Although there is no recommended daily intake for inositol, the average daily dietary intake is estimated to be about 1g/day (Medical Economics, 2008). Inositol is dosed at much higher levels than other supplements. Therapeutic doses usually range from 12-18g/day, taken in divided doses (usually two to three times per day). Inositol is also available as a powder that dissolves easily in water or juice. This may be a good option for those who have difficulties swallowing pills. Dosing usually starts at 2g twice per day, increasing to up to 6g three times per day. Inositol can be taken with or without food. Onset of clinical effect is usually observed in 2-4 weeks.

Adverse Reactions

Inositol is generally well tolerated at doses of up to 20g/day. In children, the studied dose (for attention deficit hyperactivity disorder (ADHD) was 50mg/kg/day. Common adverse effects are mild and may include gastrointestinal upset, such as nausea, diarrhea, and flatulence. Rarely, an increase in blood glucose levels has been observed. At high doses, there are rare reports of decreased peripheral nerve conduction. The supplement is considered safe to use with other medications, but few studies have investigated such combinations.

Inositol is contraindicated during pregnancy because it may induce uterine contractions. Female adolescents who take inositol and are suspected of being sexually active must be advised of this risk, and should use contraception to prevent pregnancy.

Because of its antidepressant effects, inositol may be associated with a small increase in suicidal tendencies in those patients who present with symptoms of depression. Clinicians should carefully monitor patient response and intervene if an increase in suicidal thoughts or plans becomes evident. In addition, inositol is also associated with a small risk of inducing hypomanic or manic symptoms, and case reports exist of patients ‘switching’ from depressive to manic symptoms. Careful monitoring of dose/response and adverse effects is necessary.