The stress-reducing effects of B vitamins may be attributable to modulation of HCy accumulation, as well as glucocorticoid production, and possible modulatory effects on the HPA axis. Preliminary evidence also suggests that MV supplementation containing B vitamins may modulate cortisol levels, as indicated by elevation of the cortisol awakening response [15]. In a large randomised-controlled trial (RCT) by Schlebusch et al. [16], 300 adults reporting high levels of stress were administered a vitamin B complex (Berocca Calmag; including 8.25 mg B6, and 10 μg B12) for 30 days, with reduced psychological distress (as measured by the Berocca® Stress Index, Hamilton Anxiety Rating Scale and Psychological General Well-Being Scale) reported in comparison to placebo. Another study by Carroll et al. (2000) found reductions in stress levels (measured by the perceived stress scale; PSS), in psychological distress (according to the General Health Questionnaire; GHQ-28) and in anxiety symptoms (measured by the Hospital Anxiety and Depression Scale; HADS). The reduction in these symptoms occurred following 4 weeks of supplementation with a MV containing B vitamins (Berocca® including 10 mg B6, 400 μg B9 and 10 μg B12) in 80 healthy males. Similarly, Stough et al. [17] also reported that 3-month supplementation with a high-dose vitamin B complex (including 20.63 mg B6, 150 μg B9 and 30 μg B12) in 60 participants reporting chronic work-related stress was associated with lowered ratings of personal strain as measured by the Occupational Stress Inventory.

A number of studies have demonstrated similar findings regarding stress, fatigue and other mood measures [18–24]. A meta-analysis by Long and Benton [25] reported that chronic MV supplementation in non-clinical samples was associated with reduced levels of perceived stress (Standardized Mean Difference; SMD = 0.35), anxiety (SMD = 0.32), fatigue (SMD = 0.27), confusion (SMD = 0.23) and mild psychiatric symptoms (SMD = 0.30). No evidence for a reduction in depressive symptoms was found in the non-clinical samples, although the supplements containing higher doses of B vitamins were found to be more effective in improving mood states.

In regards to clinically significant depression, a number of large epidemiological studies have linked deficiencies in B9 and B12, together with elevated HCy levels with a higher incidence of depressive disorders [26–30]. Similarly, an animal study by Botez et al. [31] found an association between folate deficiency and reduced brain serotonin synthesis. A few intervention studies have also been published in relation to folate in depressed samples. An early placebo-controlled trial by Godfrey et al. [32] in 43 patients with folate deficiency (<200 μg/l red-cell folate) and a DSM III diagnosis of major depression or schizophrenia reported that 15 mg/day of folic acid (in addition to standard psychotropic treatments) for 6 months was associated with improved clinical and social outcomes.

In a randomized study by Passeri et al. [33], 50 mg/day of 5′-Methyltetrahydrofolic acid (5′-MTHF) for 8 weeks was found to be equally effective as 100 mg/day trazodone in reducing depressive symptoms in 96 elderly participants with dementia and depression, as measured using the Hamilton Depression Rating Scale (HDRS). In an augmentation study with 0.5 mg folic acid/day in addition to fluoxetine (20 mg/day) in 127 patients with a DSM III-R diagnosis of major depression, Coppen and Bailey [34] reported a greater proportion of female treatment responders (>50 % reduction in HDRS score) in the folic acid group in comparison to placebo augmentation (93.3 % versus 61.1 %, respectively). Plasma HCy levels were also significantly reduced in women (20.6 %). Interestingly, no significant clinical effects or HCy effects were found in men, with the authors suggesting that the effective dose may have been insufficient to observe treatment effects in males. In a smaller open-label study by Alpert et al. [35], 15–30 mg/day of folinic acid (Leucovorin) was added to existing selective serotonin reuptake inhibitor (SSRI) treatment over an 8-week period in 22 adults with a DSM-IV diagnosis of major depressive disorder (MDD). Significant reductions in the HDRS scores were observed for treatment completers (n = 17), although only 27 % of the intention-to-treat sample achieved a treatment response (<50 % reduction in HDRS scores). In a meta-analysis of the findings from these three folate intervention studies, Taylor et al. [36] found that adding folate to existing treatments (e.g. SSRIs) resulted in an average reduction of an extra 2.65 points on the HDRS. In a subsequent narrative review of folic acid and B12 in the treatment of depression, Coppen et al. [37] recommended that 800 μg/day of folic acid (B9) and 1 mg/day of vitamin B12 be utilized in future intervention studies.

In relation to the effects of B vitamin supplementation in addressing clinically significant anxiety symptoms, there is currently a paucity of published findings. However, an intriguing study by Rucklidge and colleagues [38, 39] provided evidence of MV supplementation with B vitamins providing beneficial effects in the aftermath of a 6.3 earthquake in Christchurch New Zealand, 2011. Ninety-one adults reporting heightened anxiety or stress 2 to 3 months following the earthquake were randomized to 28 days of Berocca™ (including 10 mg B6, 400 μg B9 and 10 μg B12) or varying doses of a MV (CNE) containing B vitamins (maximum doses of 19.2 mg B6, 768 μg B9 and 480 μg B12). However, it should be noted that a large range of other nutraceutical substances were also included in the CNE supplements. All groups were found to have significant reductions in symptoms of psychological distress, as measured by the Depression and Anxiety Scale (DASS), Impact of Event Scale (IES-R) and Perceived Stress Scale (PSS), with greater improvements in mood, anxiety and energy observed in the high-dose CME group when compared to Berocca™. Whilst these findings are encouraging, they need be interpreted conservatively in consideration of the lack of a placebo comparator group. It is also noteworthy that the broad range MV demonstrated greater efficacy than the Berooca™ high-dose vitamin B complex, suggesting that other substances may have been responsible for the effect (see section on magnesium below). In a 1-year follow-up study, Rucklidge et al. [39] reported that participants who were involved in the study and received Berocca™ or CME treatment (n = 64) had better long-term outcomes compared with controls who had not received the treatment (n = 21).

In summary, further research is required in regards to the efficacy of supplementation with MV and B vitamins in the amelioration of clinical depression, anxiety and stress symptoms. B vitamins, in particular folate (B9) and B12, appear to have efficacy in reducing stress and improving mood in non-clinical adult samples. There is evidence to suggest that folate (B9) may be effective as an adjunct treatment for participants with depression, particularly in cases of folate deficiency. In regards to the effects of MV and B vitamin supplementation in anxiety, the studies by Rucklidge et al. [38, 39] provide intriguing preliminary data regarding the potential efficacy of these substances in ameliorating the effects of trauma and stressor-related anxiety and stress. Further research in clinical samples is warranted, together with a more detailed analysis of the relative contribution of each substance to reductions in clinical symptoms. MTHFR genotyping would also be informative, regarding whether supplementation with B vitamins is more effective for individuals with the 677 TT polymorphism.

MI has been found to have acute effects on mood within 6 h post-dose [77], and the antidepressant effects of MI in clinical samples, including MDD and premenstrual dysphoric disorder (PMDD), have been well supported across a number of studies [78]. In regards to the efficacy of MI as an anxiolytic, there has been some preliminary research conducted in regards to panic disorder, post-traumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD).

Benefits associated with chronic MI consumption have been reported for panic disorder in two studies. In the first study, Benjamin et al. [79] administered 12 g/day MI (6 g/day BID, dissolved in juice) versus placebo to 21 individuals with a DSM III-R diagnosis of panic disorder (16 with agoraphobia), in a 4-week double-blind cross-over trial. The frequency and severity of panic attacks as well as agoraphobic symptoms declined significantly more following MI treatment than placebo. In a subsequent double-blind cross-over comparator study, 20 patients with a DSM-IV diagnosis of panic disorder (with or without agoraphobia) were administered a maximum dose of 18 g/day of MI versus 150 mg/day fluvoxamine for 4 weeks. Improvements on Hamilton Rating Scale for Anxiety, agoraphobia scores and Clinical Global Impression (CGI) of change were similar for both treatments. Further, MI was found to reduce the number of panic attacks (4.0/week) to a greater extent than fluvoxamine (2.4/week), and side effects of nausea and tiredness were also more common with fluvoxamine. In regards to acute effects of MI in ameliorating the effects of panic symptoms, Benjamin et al. [80] reported no effect when a single 20 g dose of MI or placebo was administered to seven patients who met DSM-IV criteria for panic disorder. Panic symptoms were pharmaceutically induced using a known panicogen, meta-chlorophenylpiperazine (intravenous m-CPP), with DSM-IV panic symptom scores together with cortisol and pupil sizes not found to be differentially effected by MI. However, it should be noted that this study was underpowered, and the authors note that the study’s findings do not preclude the possibility that chronic MI administration may ameliorate symptoms in the m-CPP challenge test.

In regards to PTSD, there is currently no evidence to support the use of MI as monotherapy in the treatment of this complex disorder. Kaplan et al. [81] administered 12 g/day MI or placebo to 13 patients who met DSM-III-R criteria for PTSD over a 4-week period in a randomized cross-over trial. No significant improvements were found for MI, according to the Impact of Event Scale (IES), including both intrusion and avoidance trauma symptoms.

A series of initial studies were conducted to investigate MI as a possible treatment for OCD. Fux et al. [82] administered 18 g/day MI to 13 OCD patients (DSM-IV diagnosis) over a period of 6 weeks in a double-blind, randomized, placebo-controlled, cross-over design, using glucose as a placebo. Scores on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) were found to be significantly reduced for the MI group compared to placebo at study endpoint. However, in a follow-up augmentation study by the same group in 10 DSM-IV diagnosed OCD patients, MI was found to be ineffective in reducing obsessive-compulsive symptoms when 18 g/day MI was added to an existing SSRI regimen (fluoxetine, fluvoxamine or clomipramine) for 6 weeks [83]. The authors interpreted this lack of significant benefit as indicating that SSRIs and MI have overlapping modes of action (i.e. serotonergic enhancements). Seedat et al. [84] also reported no advantage for MI versus placebo in an open-label augmentation study where 18 g/day MI was administered to treatment-refractory OCD patients in conjunction with high-dose SSRI treatment (fluoxetine, sertraline, clomipramine or citalopram). Whilst it was noteworthy that a small decrease in Y-BOCS scores was observed in the group as a whole, the majority of patients (7/10) did not improve, as measured by the Clinical Global Impression (CGI) scale.

A more recent open-label study by Carey et al. [76] in 14 treatment-free DSM-IV diagnosed OCD patients reported a significant reduction in Y-BOCS scores and Clinical Global Impression of change (CGI) when MI was administered at 18 g/day for 12 weeks. Changes in brain perfusion, as measured by single photon emission computed tomography (SPECT), were also observed across a number of regions at study endpoint. In relation to symptom reduction in the related disorders of trichotillomania (compulsive hair pulling; TTM) and excoriation (compulsive skin picking), Seedat et al. [85] reported clinical responses to MI in three patients. All three cases showed substantial improvement on 18 g/day MI, as measured on the CGI.

It is noteworthy that the use of 18 g/day of MI has not been well justified in the literature. Early studies by Levine [67, 86] suggested that 12 g/day of MI may be an effective dose for the treatment of depression; therefore, it is unclear as to why 18 g/day was decided for subsequent studies of MI in the treatment of OCD. Presumably, the 18 mg dose was arbitrarily determined by the fact that higher doses of SSRIs are typically required for treatment response in OCD compared to depression. However, to date no systematic dose-escalation study has been conducted in order to determine appropriate dose ranges for this disorder. For this reason, it is possible that a higher dose of MI is required for clinically significant effects in OCD patients with more severe presentations.