Key Nutraceuticals in Mental Health, Part 2

In Part 1 of this series, we defined nutraceutical as a wide variety of products derived from foods or other biological substances that are marketed for health benefits beyond basic nutrition.

In functional psychiatry we prioritize identification of nutrient deficiencies through testing and at the same time or later in treatment, we may also consider targeted nutraceuticals that have evidence for particular psychiatric conditions or that appear relevant based on insights gained through genomic or other functional testing. These interventions are intended to provide benefits beyond simply correcting deficiencies and may help address more specific biological or clinical concerns.

In this article we will look at the use of Omega 3 fatty acids, Curcumin/OPCs, Rhodiola and folate and the evidence for their use as nutraceuticals in mental health. 

1. Omega-3 Fatty Acids (EPA ± DHA)

Omega-3 fatty acids, often referred to as “fish oil,” have long been promoted in functional medicine for their potential benefits on inflammation, cellular membrane function, mitochondrial health, and overall brain health. Modern dietary patterns characterized by increased consumption of ultra-processed foods have dramatically increased omega-6 intake, potentially creating an imbalance in the ideal omega 3/omega 6 ratio that may contribute to inflammatory and psychiatric vulnerability in genetically susceptible individuals.

Although the most robust clinical effects may be specific to those with deficiencies, low omega-3 levels appear to be disproportionately common in psychiatric populations, including individuals with ADHD.^{1, 2} These findings highlight an important principle in functional psychiatry: testing may improve treatment precision and clinical outcomes. A 2023 narrative review synthesized the available data on omega-3 index and psychiatric disease and proposed a risk threshold of ≤4% omega-3 index across multiple psychiatric conditions including psychosis transition.³

Omega-3 fatty acids have one of the most extensively studied evidence bases among nutraceuticals for depression. Omega-3 polyunsaturated fatty acid (PUFA) supplementation is currently recommended as a preventive intervention in high-risk adults, as a second-line monotherapy for mild to moderate major depressive disorder, and as an adjunctive treatment alongside antidepressants in moderate to severe depression.^{4, 5} The best-supported dosing for omega-3 fatty acids in depression centers on EPA-predominant formulations at 1–2 g/day of total omega-3, with EPA comprising ≥60% of the EPA+DHA content. However, if a deficiency is present, higher levels may be indicated.

The scientific evidence for benefit  in ADHD is more modest but we know that Omega 3’s are essential for neurodevelopment and children with deficiencies improve with supplementation.^{6, 7}

In contrast to the depression literature — where EPA is consistently favored — DHA appears more effective in conditions involving neurodevelopment, neurodegeneration, and structural brain health, where its role as the predominant omega-3 in neuronal membranes is most relevant. International consensus guidelines (World Association of Perinatal Medicine, FAO) specifically recommend adequate maternal DHA intake during pregnancy and lactation for optimal visual and cognitive development. Supplementation with n–3 PUFA during pregnancy or breastfeeding in mothers increased language abilities and supplementation in term infants improved intelligence in later childhood.⁸

And finally, it is important to highlight the landmark study demonstrating that 12 weeks of omega-3 supplementation (1.2 g/day) in individuals at high risk for psychosis significantly reduced transition rates. Only 4.9% of participants in the omega-3 group transitioned to psychosis, compared with 27.5% in the placebo group. The omega-3 group also showed significant improvements in positive symptoms, negative symptoms, and global functioning, with benefits persisting throughout the 40-week monitoring period.⁹ Remarkably, at a median 6.7-year follow-up, the protective effect remained, with transition rates of approximately 10% in the omega-3 group versus 33% in placebo. Although several subsequent replication studies were negative overall, individuals with lower baseline omega-3 status and those who achieved greater increases in tissue omega-3 levels appeared to derive the greatest clinical benefit.

2. Rhodiola

Rhodiola is a Siberian herb known as an adaptogen. Adaptogens typically increase resistance to stress, help restore balance or homeostasis with broad non-specific effects. Rhodiola has wide-spread effects on the HPA axis, serotonin modulation, and anti-oxidant and anti-inflammatory effects.

The evidence base for Rhodiola rosea is strongest for stress-related fatigue and burnout, with emerging but limited evidence for mild-to-moderate depression, cognitive performance under stress, and exercise performance.¹⁰

Even though there are no randomized controlled trials specifically in ADHD populations, clinically it has been useful in ADHD- particularly for inattentive symptoms in patients who do not want to use stimulant medication. The main caveat is to avoid its use in someone with Bipolar Disorder and be aware it may be overstimulating for a very energetic child. Common clinical dosing ranges are 100–400 mg/day standardized extract usually standardized to rosavins and salidroside content.

3. Methylfolate (L-methylfolate) and Folinic Acid

The use of folate in functional psychiatry is foundational but nuanced. Standard blood testing is rarely helpful since it measures folate and what we need to know is whether the patient can methylate it so it can cross the blood brain barrier where it is vital for a wide range of brain functions including: neurotransmitter synthesis, methylation reactions, DNA and RNA synthesis, neurodevelopment, myelin formation and maintenance, homocysteine regulation, BH4 (tetrahydrobiopterin) support, mitochondrial and cellular energy function, neuroplasticity and synaptic function,mood regulation, inflammation and immune modulation and antioxidant and oxidative stress protection!

We have strong RCT evidence for the use of  high dose L-methylfolate (15 mg) as adjunctive treatment for MDD, particularly in patients with MTHFR polymorphisms or low folate status⁴ but clinical experience shows that rarely do patients need doses at that level and starting with doses of 1 or 2 mg is a good place to start. Some individuals experience anxiety, over-stimulation, insomnia, emotional lability or even hypomanic symptoms which is why many experienced clinicians start low and titrate cautiously.

Some clinicians report benefits in ADHD , particularly those with low folate status, elevated homocysteine, or relevant genomic findings, but controlled trials are sparse and results inconsistent.

And beyond methylation capacity, some individuals require a different form of folate called Folinic acid to effectively reach the brain through an alternative pathway or “back door,” due to problems with the primary folate receptor system. Detecting this issue often requires more sophisticated, non-routine testing such as genomics or folate receptor autoantibody testing (FRAT). This has generated particular interest in autism, where folinic acid has shown benefit for language, communication, attention, and irritability.

Because folinic acid is generally well tolerated—with the same “start low and go slow” approach often recommended for L-methylfolate—many clinicians now begin with supplements that contain both methylfolate and low-dose folinic acid, typically in the 2–3 mg range.

4. OPCs (Oligomeric Proanthocyanidins) & Curcumin

OPCs and curcumin are both plant-derived polyphenolic compounds with antioxidant, neuroprotective and anti-inflammatory properties. Common sources of OPCs are found in pine bark extract, grapeseed extract, cocoa, green tea, and blueberries.

Curcumin has additional effects beyond anti-inflammatory properties that would predict a beneficial effect in depression (i.e.positive effects on serotonin and dopamine through MAO inhibition, regulation of the HPA axis and reductions in cortisol and increase in BDNF to promote neuroplasticity).

Indeed curcumin showed strong clinical  performance in the 2025 network meta-analysis both as monotherapy and as an adjunct to antidepressants). (11) The largest individual RCT (n=123) found curcumin (250–500 mg twice daily) and curcumin/saffron combinations significantly improved depressive and anxiety symptoms over 12 weeks, with particular benefit in atypical depression (65% response rate).¹²

The quality and formulation of curcumin are important considerations when selecting a supplement, as standard curcumin has relatively poor absorption. Several proprietary formulations, including Meriva® and Theracurmin®, have published data supporting improved bioavailability and GI absorption.

OPCs are a diverse group and the strongest  psychiatric signal is for Pycnogenol®, a French maritime pine bark extract rich in procyanidins/OPCs. A small randomized placebo-controlled trial in children with ADHD found improvements in attention, hyperactivity, and oxidative stress markers.¹³

As a group, polyphenols have been shown to improve abnormal EEG theta/beta ratios in ADHD¹⁴, with laboratory evidence also suggesting they may help lower blood copper levels and reduce copper-related oxidative stress, both of which may be relevant to hyperactivity, irritability, and impulsivity across multiple diagnoses. In addition, polyphenol-rich compounds have shown promise for improving memory and executive functioning in older adults with mild cognitive impairment.¹⁵

From a functional psychiatry perspective, OPC-rich compounds are generally viewed as neuroprotective and brain-supportive interventions rather than primary psychiatric treatments. However, clinical experience has supported superior efficacy when used together rather than as isolates particularly in ADHD.

Summary

In functional psychiatry, nutraceuticals are used as targeted treatments for mental health conditions that extend beyond simply correcting nutritional deficiencies. They may be used alone or integrated with conventional psychiatric care as part of a personalized, systems-based approach to supporting brain health and emotional functioning. No doubt the evidence base will continue to expand as interest grows in the use of more natural and biologically based interventions for mental health. However, advancing this research will require greater financial support, as many nutraceuticals and naturally occurring compounds offer limited commercial profit potential compared with pharmaceutical products.