Obsessive-Compulsive Disorder (OCD)
Inositol is a natural chemical compound common in many foods, and it is also present in relatively high concentrations in the brain, where it plays an important role in cellular communication (Levine 1997; Camfield 2011). Inositol’s therapeutic mechanism of action is not firmly established, but is believed to involve modulation of serotonin activity in the brain (Harvey 2002; Camfield 2011).
In a six-week, double-blind, controlled, crossover trial of 13 patients with OCD, administration of 18 g per day of oral inositol resulted in an average 4-point reduction in Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores, while placebo treatment resulted in average Y-BOCS score reductions of less than 1 point (Fux 1996). In an unblinded study of 14 untreated OCD patients, a 12-week treatment with 18 g daily inositol resulted in an average reduction in Y-BOCS score of 10.7 points—a nearly 50% reduction from baseline values—and a clinical response, defined as a reduction of baseline Y-BOCS score by half, was achieved in 57% of study participants (Carey 2004).
N-acetylcysteine (NAC), an amino acid derivative, can inhibit glutamate release from brain cells, aid in cellular and metabolic detoxification, lower homocysteine levels, and boost levels of glutathione, an important neutralizer of potentially damaging cellular metabolic byproducts (De Flora 1995; van Zandwijk 1995; Kasperczyk 2015; Sarris 2012). In a randomized controlled trial, 48 patients with OCD (Y-BOCS score greater than 16) who had not responded to a 12-week course of high-dose SRI medication received either additive NAC or placebo while continuing SRI medication for an additional 12 weeks. Twenty-four patients received NAC (starting at 600 mg per day and increasing to 2400 mg per day by week 3) and twenty-four control subjects received a placebo. In the NAC group, 53% had a full clinical response (defined as a decrease in Y-BOCS score of more than 35%), while only 15% in the placebo group achieved a full clinical response. Total average reductions in Y-BOCS score were 10.9 points for the NAC group and 5.7 points for the control group (Afshar 2012).
A case study of a 58-year old woman with OCD who did not respond to SRI therapy reported that the addition of NAC (beginning with 600 mg daily, and increasing to 3000 mg per day over six weeks, and then continuing at that dose for an additional seven weeks) to fluvoxamine treatment resulted in a clinically significant improvement in OCD symptoms (Lafleur 2005). In this case, a reduction of 8 points on the Y-BOCS scale was noticed after only one week of treatment, which is indicative of a much more rapid treatment response compared with SSRI treatment alone (Camfield 2011).
Glycine is an amino acid capable of modifying the activity of some neurotransmitter systems in the brain. Along with glutamate, glycine binds and activates N-methyl-D-aspartate receptors in the brain; activation of these receptors has an anti-compulsive effect in animal models of OCD (Camfield 2011). In a randomized controlled trial in 24 OCD patients with a Y-BOCS score greater than or equal to 18, very high-dose glycine (60 g/day) or placebo was added to ongoing pharmaceutical or behavioral therapy. Patients in the glycine group experienced an average decrease of over six points in Y-BOCS score compared with an average one point decrease for those receiving placebo. Eight of twelve participants in the glycine group dropped out of the study due to side effects from the large dose of glycine, though two patients who responded to glycine treatment continued to take glycine for over a year (Greenberg 2009).
In a case report of a 22-year old male patient with severe, debilitating OCD and no satisfactory response to SSRIs, five years of glycine treatment led to a large reduction in OCD symptoms, and resumption of education and social life (Cleveland 2009).
Milk thistle has been shown in experimental studies to inhibit monoamine oxidase enzymes, and may increase serotonin levels in the cerebral cortex; both of these properties are similar to mechanisms occurring in prescription antidepressants. A double-blind randomized trial in 35 participants with OCD and Y-BOCS scores greater than 20 compared 600 mg of milk thistle extract to 30 mg daily of fluoxetine. Judged on the basis of change in Y-BOCS scores, milk thistle extract and fluoxetine were similarly effective (Camfield 2011; Sayyah 2010; Mazzio 1998).
Valerian root (Valeriana officinalis L.) has historically been used as a sedative, pain reliever, anxiolytic, and migraine treatment; it is thought to act on the GABA neurotransmitter system in the brain. In a placebo-controlled trial of valerian root extract in 31 patients with OCD and Y-BOCS scores greater than 21, those taking 750 mg/day of valerian showed statistically significant reductions in Y-BOCS scores at four, six, and eight weeks compared with those taking placebo (Pakseresht 2011).
St. John’s wort
St. John’s wort (Hypericum perforatum) has been shown to inhibit monoamine reuptake, increase serotonin binding to its cellular receptors, and modulate activity of the hypothalamic-pituitary axis. St. John’s wort has been extensively studied for depression (Sarris 2012). In an open-label uncontrolled trial, 12 OCD patients were given 450 mg of St. John’s wort extract standardized to 0.3% hypericin twice daily for 12 weeks, which produced a significant 7.4 point average reduction in Y-BOCS score (Taylor 2000).
Vitamin B12 and Folate
Vitamin B12 and folate are cofactors in the synthesis of the neurotransmitters serotonin and dopamine (Valizadeh 2011; Atmaca 2005), and vitamin B12 deficiency may be associated with psychiatric disorders (Valizadeh 2011; Upadhyaya 2012; Sahoo 2011). One study found a significantly higher incidence of serum B12 deficiency in OCD patients compared with healthy controls, with 20% of OCD patients showing low B12 levels (Hermesh 1988). Case reports have also described vitamin B12 deficiency in OCD patients (Valizadeh 2011; Sharma 2012).
Two studies identified low levels of folate and significantly higher levels of the amino acid homocysteine in OCD patients compared with healthy controls. One of these studies found that lower folate levels and higher homocysteine levels were associated with higher Y-BOCS scores. The other study found that vitamin B12 levels were lower and homocysteine levels higher in 35 OCD patients compared with healthy controls (Atmaca 2005; Türksoy 2014). Folate and vitamin B12, along with vitamin B6, are able to lower homocysteine levels (Smith 2010).
Some evidence suggests that, compared with healthy individuals, people with OCD may have lower blood levels of zinc, iron, magnesium, and selenium (Shohag 2012; Ozdemir 2009). Studies investigating the role of mineral supplementation in individuals with OCD are needed as available evidence is currently limited. Nevertheless, one small randomized controlled trial did show that supplementation with very high doses of zinc (440 mg/day) plus fluoxetine led to greater reductions in Y-BOCS scores compared to fluoxetine plus placebo in OCD patients (Sayyah 2012). The dosage of zinc used in this study was extremely high, and should not be attempted without close physician supervision.
Several additional natural agents have shown promise in modulating OCD-like behavior in preclinical research, but studies in humans with OCD are needed before the role of these interventions can be clarified.
Probiotics. A rodent model found that the probiotic strain Lactobacillus rhamnosus GG was able to alleviate chemically induced OCD-like behavior, with an effect similar to the SSRI medication fluoxetine (Kantak 2014). The mechanisms by which the gastrointestinal microbiota may influence the central nervous system are not completely understood, but rodent models have shown that an absence of intestinal bacteria can affect the expression of N-methyl-D-aspartate receptors and the production of stress hormones. Additionally, some bacteria and yeast synthesize neurotransmitters and neuromodulators, including dopamine and serotonin; and in mice, a reduction in anxiety-like behavior in response to probiotic administration was demonstrated to be mediated by activity of the vagus nerve, which communicates directly between the gastrointestinal tract and the brain (Bravo 2012; Cryan 2012; Bercik 2011). More studies are needed to clarify the potential of probiotic microorganisms in individuals with OCD.
Ashwagandha (Withania somnifera). Ashwagandha is an Ayurvedic herb with historical usage as an adaptogen that increases resiliency to physical and mental stress (Singh 2011). It has been investigated for its anxiolytic and antidepressant activities in human and animal models (Pratte 2014; Bhattacharya 2000). In a mouse model of OCD-like behavior induced by a neurotoxin, injection of 50 mg/kg of ashwagandha extract reduced this behavior with an efficacy similar to the SSRI fluoxetine (Kaurav 2012).
Saffron. Saffron, a spice derived from the dried stigmas of Crocus sativus L., contains neuroactive compounds that have demonstrated anxiolytic and antidepressant activities in animal models. In multiple randomized controlled trials, saffron extract has shown superior antidepressant effects compared to placebo and efficacy similar to antidepressant medication (Ghasemi 2014; Lopresti 2014; Pitsikas 2008; Hosseinzadeh 2009; Hausenblas 2013; Shahmansouri 2014). In a rodent model of chemically induced OCD, unique water-soluble carotenoids from saffron, called crocins, prevented OCD-like behavior when given as an injection into the abdominal cavity at daily doses ranging from 30‒50 mg/kg (Georgiadou 2012).
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