Saint John's wort, an herbal inducer of the cytochrome P4503A4 isoform, may alleviate symptoms of Willis-Ekbom's disease

Abstract

OBJECTIVE:Certain drug classes alleviate the symptoms of Willis-Ekbom's disease, whereas others aggravate them. The pharmacological profiles of these drugs suggest that drugs that alleviate Willis-Ekbom's disease inhibit thyroid hormone activity, whereas drugs that aggravate Willis-Ekbom's disease increase thyroid hormone activity. These different effects may be secondary to the opposing actions that drugs have on the CYP4503A4 enzyme isoform. Drugs that worsen the symptoms of the Willis-Ekbom's disease inhibit the CYP4503A4 isoform, and drugs that ameliorate the symptoms induce CYP4503A4. The aim of this study is to determine whether Saint John's wort, as an inducer of the CYP4503A4 isoform, diminishes the severity of Willis-Ekbom's disease symptoms by increasing the metabolism of thyroid hormone in treated patients.METHODS:In an open-label pilot trial, we treated 21 Willis-Ekbom's disease patients with a concentrated extract of Saint John's wort at a daily dose of 300 mg over the course of three months.RESULTS:Saint John's wort reduced the severity of Willis-Ekbom's disease symptoms in 17 of the 21 patients.CONCLUSION:Results of this trial suggest that Saint John's wort may benefit some Willis-Ekbom's disease patients. However, as this trial was not placebo-controlled, the extent to which Saint John's wort is effective as a Willis-Ekbom's disease treatment will depend on future, blinded placebo-controlled studies.

Willis-Ekbomdisease (Restless Legs Syndrome) Pathophysiology: The Imbalance Between Dopamine and Thyroid Hormone Theory

“…As such, it is reasonable to assume that the lack of iron will impair the balance between TH and DA in two ways: (1) by decreasing DA synthesis and (2) by diminishing TH metabolism [20]. Many MRI and ultrasound observations have documented decreased brain iron in the substantia nigra [37]; however, it may be misleading to suggest that the DA dysfunction that causes WED exists in the dopaminergic system of the substantia nigra.…”

“…These facts imply that iron plays a central role in WED pathophysiology. These clinical and therapeutic observations may also be explained in terms of the IMBTH/DA as the main cause of WED [20].…”

“…A study of pharmacological profiles suggests that drugs that alleviate WED tend to reduce TH activity, whereas drugs that aggravate WED tend to augment TH. One of these effects may actually be secondary to the diverse actions these drugs have on the Cytochrome P450 system (CYP450): the first induces the system (e.g., dopamine agonists), and the second inhibits it (e.g., SSRIs) [20].…”

“…Iron is a cofactor of many enzymatic systems [26], and it is reasonable to assume that when it is lacking in the enzymes of which it is part, these enzymes will experience a reduction in their activity, with the intensity correlating with the severity is the iron deficiency [20]. In the chain of reactions ending in the synthesis of DA, iron acts as a cofactor of the enzyme tyrosine hydroxylase (Thy) that catalyzes the conversion of tyrosine into L-DOPA.…”

“…Adding more plausibility to the IMBDA/TH, it is known that WED symptoms appear (or worsen) in the evening and night [6,8], a time when thyrotropin levels are increased compared to daytime levels [19]. Additionally, from clinical practice, it is known that many drugs that worsen WED symptoms increase TH activity by inhibiting the 3A4 isoform of cytochrome P450 where part of TH is degraded (e.g., calcium channel blockers; SSRIs) [8,12]; some drugs that relieve WED symptoms diminish TH activity by inducing the 3A4 isoform of cytochrome P450 (e.g., Saint John's Wort) [20]. Notably, it has been observed that the tuberoinfundibular and mesolimbic DA pathways in the brain regulate the expression of the cytochrome P450 system of enzymes in rats.…”