ARC Blog

Calming the Brain Circuitry: How Supplements Might Help

Anxiety can be difficult to treat at the best of times. Unfortunately, rates of depression and anxiety have been increasing throughout the world. Recently, included with all the normal stressors of life, are all the additional challenges from a global pandemic combined with significant political and social upheaval. The data appears to indicate that women and youth have been impacted the hardest. Cases of depression have risen by 27.6% while cases of anxiety have increased by 25.6% overall (CMDC 2021). 

Stress and anxiety go hand in hand. When stress becomes excessive, it can lead to changes in the brain, including excessive worry and hypervigilance. In some cases, even after the external stressor has passed, the underlying emotional reactions continue resulting in an anxiety disorder (McEven 2012). To reverse this process, it becomes necessary to raise an individual’s stress tolerance and damp down the overactive fear circuitry in the brain.

Over the course of my career, having treated thousands of patients struggling with anxiety, a few treatments are worth highlighting. While every case of anxiety is unique and needs to be treated as such, the consistency of benefits from magnesium, vitamin B3, and ashwagandha should not be overlooked. Often these supplements can make a significant difference in helping to raise an individual’s tolerance to stress along with helping to calm fear circuitry throughout the brain. 

Treating deficiencies of magnesium is crucial when addressing anxiety. By far, the most common nutrient deficiency I encounter in my practice is magnesium. Some of the latest research suggests that half of the individuals in the United States don’t consume enough of the mineral to meet their minimum requirements (Blumberg 2017). It is also worth noting that a study on early humans suggests that we used to consume around four times more magnesium than we do now (Eaton 2000). 

Foods containing natural Magnesium by Nataliia Mysak from Getty Images.


Magnesium is crucial for normal function. The mineral is needed for over 300 different biochemical reactions (Long 2015). In fact, it is the second most abundant electrolyte found within the body’s cells. Most functions are influenced by magnesium and the mineral has key roles in muscle contraction and relaxation along with energy production. Of interest, magnesium also has a role in balancing the stress response. Stress increases demands for the nutrient, as magnesium is lost in the urine during stressful events. Stress resilience is decreased if magnesium becomes deficient (Seelig 1994).

Not surprisingly, magnesium is also crucial for normal brain function. Magnesium helps to block excitatory signaling, slowing overactive brain circuitry. It also helps protect brain cells from damage or death (Kirkland 2018). As such, magnesium has a neuroprotective role, helping to maintain balance. 

Yet that’s not all that magnesium can do. The mineral also has anti-inflammatory activity. Due to increased inflammation, magnesium deficiency can worsen many common conditions, including heart disease, arthritis, asthma, high blood pressure, diabetes, and stroke (Shahi 2019, Nielsen 2018). 

It should come as no surprise that magnesium deficiency has been associated with mental health. Anxiety, irritability, depression, agitation, and even psychosis have all been linked to low levels of the mineral (Wacker 1968, Seelig 1975). While the quality of the evidence is poor, a recent review on magnesium still concluded that the published research suggests benefits for anxiety in those more vulnerable to anxiety states (Boyle 2017). 

Animal models also lend credence to the idea that magnesium has anti-anxiety effects. Magnesium deficiency has been shown to worsen anxiety and alter normal gut flora in mice (Pyndt 2015). Other research has confirmed an anxiety-induced state in mice due to magnesium deficiency that appears to be rooted in a disruption of the normal stress response (Sartori 2012). 

Most individuals struggling with an anxiety disorder will likely benefit from supplemental magnesium. Magnesium supplementation makes sense considering the frequency of deficiency and the increased need for magnesium in stressed individuals. Generally, reasonable doses of magnesium around 400-600 mg per day in individuals without kidney dysfunction are quite safe. The most common side effect is diarrhea, which often can be addressed by using a different form of the nutrient. 

Nutritional foods as source minerals of Vitamin B3 by Getty Images Pro.

Vitamin B3

Vitamin B3, or niacin, has two common forms: nicotinic acid and niacinamide (sometimes called nicotinamide). The vitamin has research going back to the 1950s exploring its effects on treating mental health conditions. Clinical trials initially examined the effects of niacin combined with vitamin C on new-onset schizophrenia, with benefits found for higher doses of the vitamins (Hoffer 2008). However, later studies failed to confirm the findings, and niacin as a treatment for schizophrenia became somewhat controversial (Ban 1971). 

At the same time, in parallel, research exploring the effects of high-dose niacin on animals started to show tranquilizing effects. An early study from 1958 found that mice given large doses of niacinamide became sedated (Woolley 1958).

As research continued, receptors in the brain for benzodiazepines, commonly used for treating anxiety, were discovered. A quest began to understand how the body naturally activated these receptors to decrease anxiety states. Data started to accumulate suggesting that vitamin B3 played a role. By 1980 it had been established that niacinamide had some similarities to sedative medications that act through benzodiazepine receptors (Tallman 1980). A smattering of reports afterward continued to support the idea, but research into the clinical benefits of vitamin B3 for anxiety was never seriously pursued (Möhler 1979, Kennedy 1980, Fomenko 1978, Akhundov 1992).

While more evidence is needed, recent case studies suggest that some individuals may have reduced anxiety with high-dose supplementation of niacinamide (Wright 1992, Prousky 2004, Prousky 2005). However, not all cases were found to respond (Prousky 2010). 

In my own clinical experience, niacinamide is helpful for a significant percentage of individuals with diagnosed anxiety disorders. The anti-anxiety effects are only achieved through higher doses. Fortunately, research has shown niacinamide to be safe up to 3000 mg per day, and is the preferred form, since nicotinic acid has more side effects. Additional research has also found significant anti-inflammatory effects from niacinamide. As a side benefit, these effects may be helpful in cases of arthritis (Cunningham 1998, Jonas 1996). 

Ashwagandha superfood powder and root on cutting board by Getty Images Pro.


Ayurvedic medicine has been around for thousands of years. And one of the most revered herbs in Ayurvedic medicine is ashwagandha. Ashwagandha is generally seen as a tonic herb for improving stamina and overall health. More recently, some of the latest research suggests that ashwagandha may have a place in mental health care. 

One of the main effects of ashwagandha is the normalization of the hypothalamic-pituitary-adrenal (HPA) axis. These glands work together as key players in the stress response. When stressed, signals from the brain activate the HPA axis which increases the production of the stress hormone cortisol. Too much exposure to elevated cortisol is associated with health risks from excessive stress. 

Ashwagandha appears to target and reduce the overactive stress response effectively. While magnesium is also crucial, ashwagandha has been shown to modulate stress: reducing stress hormone levels and increasing stress tolerance. 

Studies in mice have found that ashwagandha increases physical stamina. In addition, the herb was able to prevent stress-induced changes, including gastric ulcers, reductions in adrenal cortisol levels, and adrenal gland enlargement. The authors concluded that ashwagandha produces a nonspecific increased resistance to stress (Singh 1982). 

Other animal research has confirmed the stress-resilient state produced from ashwagandha supplementation. Random foot shocks are often used as a technique to induce a state of chronic stress. In rats, this stress causes major dysregulation, leading to blood sugar problems, increased stress hormones, depression, reduced mental function, stomach ulcers, and immune system deficits. In high doses, ashwagandha appears to almost completely reverse these stress-induced changes (Bhattacharya 2003).

Clinical studies in humans have shown similar benefits. A recent two-month clinical trial found that just 240 mg of ashwagandha extract per day reduced anxiety significantly with strong trends towards reductions in stress as well. Morning cortisol levels were decreased and in men, but not women, testosterone levels improved (Lopresti 2019). A review of the research from 2014 found five studies that, in total, were suggestive of reduced anxiety and stress with ashwagandha supplementation (Pratte 2014). 

While more evidence is needed to identify optimal dosing parameters, ashwagandha has a very long history of safe use. And through its ability to reduce or normalize the stress response, it’s likely that many patients can benefit from the herb’s effects. Used alone or in combination with niacinamide and magnesium, it’s not unusual for patients to note a significant reduction in anxiety levels with supplementation.  


Rates of depression and anxiety have been increasing, reaching epidemic levels throughout the world. However, by addressing the underlying physiology of anxiety, including overactive brain circuitry and the elevated stress response, it is often possible to reduce, if not eliminate, symptoms of anxiety. Magnesium, niacinamide, and ashwagandha are three approaches that often help improve anxiety symptoms. When used correctly, all three treatments are usually well tolerated.

View Dr. Greenblatt’s list of references.

A pioneer in the field of functional and integrative medicine, board-certified child and adult psychiatrist, James M. Greenblatt, MD, has treated patients since 1988. After receiving his medical degree and completing his psychiatry residency at George Washington University, Dr. Greenblatt completed a fellowship in child and adolescent psychiatry at Johns Hopkins Medical School. He currently serves as the Chief Medical Officer at Walden Behavioral Care in Waltham, MA and an Assistant Clinical Professor of Psychiatry at Tufts University School of Medicine and Dartmouth College Geisel School of Medicine. Dr. Greenblatt has lectured internationally on the scientific evidence for nutritional interventions in psychiatry and mental illness. He is the author of seven books, including best-seller, Finally Focused: The Breakthrough Natural Treatment Plan for ADHD. His latest book, Answers to Anorexia, was released in October 2021 and his new book, Functional & Integrative Medicine for Antidepressant Withdrawal, will be available in March 2022. He is the founder of Psychiatry Redefined, an educational platform dedicated to the transformation of psychiatry, which offers online courses, conferences, and fellowship programs for professionals. Please visit or for more information.
Subscribe To Our Newsletter

Subscribe To Our Newsletter

Join our mailing list to receive the latest news and happenings around ARC.

You have Successfully Subscribed!