Special Report: Complementary Alternative and Integrative Medicine Can Help Meet Challenges of COVID-19

More physicians are taking the time to study CAIM; however, the number who are qualified and available for expert consultations is quite limited. Consequently, psychiatrists cannot rely on referring patients to CAIM specialists, but instead they need to educate themselves regarding how to use these treatments safely and effectively (see Table 1). Those who do will be rewarded with a new set of skills for improving patient outcomes; reducing the burden of medication side effects; and maintaining their own capacities, including their will to serve patients during these challenging times.

Breath in the Time of COVID-19

The COVID-19 epidemic has spawned secondary epidemics of stress, anxiety, depression, and posttraumatic stress disorder (PTSD). Voluntarily Regulated Breathing Practices (VRBPs), particularly when combined with gentle movement, have been shown to improve anxiety, mood, trauma, attention, cognitive function, energy, and social engagement. While intense breath practices tend to increase energy, slow breath practices, such as Coherent Breathing (also called Resonant Breathing) at 4.5 to 6.0 breaths a minute, rapidly reduce anxiety, hyperarousal, and defensiveness. Coherent Breathing promotes autonomic balance by downregulating overactivity of the sympathetic nervous system and upregulating the parasympathetic system, which is underactive in anxiety disorders, depression, PTSD, and chronic fatigue.

In addition to balancing the activity of the autonomic system, preliminary evidence suggests that Coherent Breathing may increase levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in circuits involved in emotion regulation. For example, in a trial of patients with major depressive disorder who practiced yoga and Coherent Breathing for 12 weeks, Chris Streeter, M.D., and colleagues reported significant improvement in depression and suicidal ideation, as well as a significant increase in thalamic GABA levels on mass resonance spectroscopy. The study appeared in the March 2020 Journal of Alternative and Complementary Medicine.

Interoception is the perception of feelings from inside the body. With each breath, millions of sensors throughout the respiratory system send afferent messages to central regulatory structures involved in emotion regulation, stress response, cognitive function, and behavior. These include the amygdala, hypothalamus, thalamus, insular cortex, prefrontal cortex, and anterior cingulate cortex. In contrast to automatic breathing, intracranial iEEG recordings of VRBPs showed increased “breath coherence,” entrainment of electrical activity with the breath pattern in critical brain areas: insula; amygdala; and premotor, olfactory, and caudal-medial frontal (executive function) and temporal cortices. Furthermore, when subjects focused attention on breathing, iEEG-breath coherence increased in anterior cingulate premotor, insular, and hippocampal cortices. In a magnetoencephalography study in humans, mental regulation of slow VRBPs modulated cortical alpha activity in a well-structured patten of alpha waves over wide areas of the brain.

In accord with the Polyvagal Theory, slow VRBPs can activate afferent myelinated vagal parasympathetic pathways, which may reduce defensive reactions; facilitate a psychophysiological state of feeling safe; activate the social engagement network; and increase feelings of love, connectedness, empathy, and cooperation.

Breath practices can be taught efficiently to individuals, families, or groups in any clinical setting or remotely online. Learning how to teach the practices and how to observe the patient’s breath pattern is important to assure the optimal performance of breath techniques. The usual “dose” for coherent breathing is 20 minutes a day and as needed for anxiety, sleep, or pain. For severe anxiety or PTSD, 20 minutes twice daily and as needed for stress/anxiety are advised.

Breath-Based Program for Pandemic-Related Stress in Staff Working With Special Needs Children

Agencies responsible for children, especially those with special needs, have been under severe, prolonged COVID-19-related stress in the United States and other countries. Contributing factors include disrupted treatment, staff shortages, family dysfunction, and emotional/behavioral deterioration among the children. Worsening of the child’s symptoms and family strain create increased demand for services.

In a December 2020 pilot study conducted by two of the authors (Dr. Gerbarg and Dr. Brown), 24 members of the staff of the Regional Integrative Support for Northern Ireland (RISE NI) completed a live 12-hour online program (4 hours a day for three consecutive days) of breathing, movement, and awareness practices called Breath-Body-Mind (BBM). The researchers were encouraged to do the practices at home 20 minutes a day and attend a weekly 45-minute group practice. Standardized measures of anxiety and stress were obtained before the program, immediately after, and at week 6. The group mean score on the Stress Overload Scale-Short was well above the normative level at baseline, declined significantly immediately after BBM, and fell significantly below the norm after six weeks of practice. A large proportion of the participants reported moderate to very strong improvements, including less worry (70%), clearer mind (79%), more energy (78%), and more empathy (62%).

Breath-Based Programs for Maternal, Fetal, and Newborn Stress

Maternal distress can adversely affect children’s development before as well as after birth. The rates of anxiety and depression during the COVID-19 epidemic among pregnant women are estimated to have doubled or tripled. Maternal depression and anxiety are associated with increased risk of preterm birth, lower birth weight, postpartum depression, and behavioral difficulties in children.

Slow, gentle breath practices, such as Coherent Breathing at 5 to 6 breaths a minute with equal inhalation and exhalation, are a safe way to reduce anxiety and increase maternal heart rate variability (HRV), which is associated with increased fetal HRV. Coherent Breathing with visualization has been used to calm anxious high-risk mothers and agitated premature infants in a neonatal care setting, facilitating positive coregulation and mother-infant bonding. This can also reduce regurgitation during feedings, which is essential for weight gain and eventual discharge.

Herbal Adaptogens: Best in Show

Among the adaptogenic herbs, Rhodiola rosea (R. rosea) has the greatest potential for use in psychiatric practice. A substantial evidence base of safety and efficacy supports the use of this phytomedicinal to enhance mood, energy, and cognitive function. Adaptogens contain numerous bioactive substances that protect organisms from damage by infections, chemical toxins, free radicals, radiation, cancer, stress, extreme heat and cold, low oxygen conditions, and other hazards. As a metabolic regulator, R. rosea increases mitochondrial production of energy transport adenosine triphosphate (ATP) and supports repair of cellular components. These fundamental cellular effects contribute to numerous benefits in chronic fatigue, depression, perimenopausal depression, attention-deficit/hyperactivity disorder, PTSD, and cognitive dysfunction.

A review of 11 randomized, controlled trials (RCTs) concluded that R. rosea may have beneficial effects on physical performance, mental performance, and mental illness. A pharmacological review noted that R. rosea extracts and one of the constituents, salidroside, demonstrated anti-aging, anti-inflammatory, immunostimulant, DNA reparative, and anti-cancer effects.

The R. rosea root contains compounds with multiple mechanisms of action throughout the body. The methods of cultivation and extraction of these compounds are critical to the quality of products. Clinicians can identify high-quality products by using those proven to be effective in published studies and those recommended by experienced CAIM practitioners. (See the book How to Use Herbs, Nutrients, and Yoga in Mental Health Care by the authors of this article.)

R. rosea for Chronic Fatigue

R. rosea can improve mental and physical energy in patients with chronic fatigue syndrome following infections (for example, Lyme disease and “long” COVID-19); medication-induced fatigue; and fatigue associated with cancer, medical illnesses, or depression. For example, in an open-label multicenter clinical trial, 100 subjects with prolonged or chronic fatigue syndrome symptoms were administered an ethanol extract of R. rosea. The greatest change was observed after one week of treatment. Fatigue continued to decline with statistically significant improvement at week 8. The safety assessment was favorable, most adverse events being mild and unrelated to the extract.

R. rosea for Mental Fatigue

Mental fatigue causes a decline of mental functioning, often with an increased error rate. This has been associated with reduced “top-down” resources and decreased attention. Studies have shown that R. rosea can reduce mental fatigue, reaction time, and errors on tasks. A 12-week study of 50 healthy adults given 200 mg twice daily of R. rosea demonstrated significant improvements on a battery of attentional tasks at weeks 6 and 12 in indicators of processing resources, decreased reaction time, and reduced rate of errors.

R. rosea for Depression

R. rosea can be used to treat patients with mild-to-moderate depression. In a placebo-controlled study of 128 mild to moderately depressed patients, 150 mg TID of Arctic root (another name for R. rosea) was associated with significantly improved depression in two-thirds of subjects compared with placebo. A double-blind, randomized, controlled study using Arctic root SHR-5 as a monotherapy for 89 adults with mild to moderate depression (baseline score on the Hamilton Depression Rating Scale [HAM-D] ranging from 12 to 31) found that those given Arctic root SHR-5 (340 mg/day or 680 mg/day) for six weeks showed significantly greater improvements in mean HAM-D scores compared with the placebo group.

R. rosea Augmentation of Antidepressants

The relative safety and efficacy of R. rosea capsules in combination with sertraline for mild to moderate major depressive disorder was confirmed in a 12-week double-blind, placebo-controlled trial published in 2020. One hundred patients were randomized to three groups, and all three showed significant improvements on measures of depression. Post-treatment declines in HAM-D, Beck Depression Inventory (BDI), and Clinical Global Improvement (CGI) scores were greater for group B (sertraline + Rhodiola at 600 mg/day) than for group A (sertraline + placebo) and group C (sertraline + Rhodiola 300 mg/day + placebo).

Two of the authors of this report (Drs. Gerbarg and Brown) find R. rosea particularly beneficial for depression in perimenopausal women with fatigue, “brain fog,” mild memory retrieval difficulties, and loss of libido. The observed improvements in energy, mood, mental sharpness, memory, and sexual desire may be related to activating effects and increased mitochondrial energy as well as its effects as a possible selective estrogen receptor modulator (SERM). SERMs are of interest because they may affect estrogen receptors differently, depending on the organ. The ideal SERM would activate estrogen receptors in the brain and bones but not in the breast, ovaries, or uterus. The net result would be preservation of brain function and bone structure without increased risk of cancer.

Attention-Deficit Disorder With or Without Hyperactivity

For patients with mild attention-deficit disorder with or without hyperactivity and those who cannot tolerate the side effects of stimulant medications at therapeutic doses, R. rosea is worth a trial. Prescription stimulants, whose pharmacological activity peaks and falls rapidly, can cause withdrawal symptoms (restlessness, jitteriness, anxiety, and insomnia) and may contribute to addiction. In patients whose stimulant medication wears off late in the day, a moderate midday dose of R. rosea can maintain attentional focus without disturbing sleep because the effect fades after 6 to 8 hours.

Stimulant abuse can lead to increased blood pressure and heart rate, blood vessel constriction, increased blood glucose, rapid or irregular heartbeat, delirium, panic, psychosis, paranoia, myocardial infarction, heart failure, or seizures. In contrast, the use of R. rosea causes no withdrawal symptoms or addiction, no loss of appetite, no cardiac disease, and no abnormal mental states. We find in clinical practice that R. rosea is generally safe in therapeutic doses and does not lead to abuse or withdrawal syndromes.

Effective Dosing of R. rosea

In clinical practice, R. rosea has been found to be an effective augmentation to antidepressant drugs, particularly for symptoms of fatigue, apathy, psychomotor retardation, anhedonia, memory impairment, and poor concentration. Best effects occur when taken on an empty stomach 30 minutes before breakfast and lunch, with total daily doses ranging from 300 mg/day to 900 mg/day. The use of best-quality R. rosea as monotherapy or augmentation for moderate to severe depression warrants further study.

Risks, Adverse Effects, and Potential Medication Interactions

In rat toxicity studies, the median lethal dose was calculated to be 28.6 ml/kg, approximately 3,360 mg/kg. Since the usual clinical doses are 200 mg/day to 900 mg/day, there is a considerable margin of safety. A randomized crossover study of 13 healthy volunteers found no effects on cytochrome P (CYP) enzymes except for modest inhibition of CYP2C9 (possibly significant for substrates with a narrow therapeutic index, such as phenytoin and warfarin).

As with prescription antidepressants, R. rosea may increase the risk of mania in bipolar patients. It can occasionally cause jitteriness, agitation, or insomnia in patients who are sensitive to stimulating agents and may have additive effects when combined with caffeine. Uncommon side effects include anxiety, headache, bruising (with doses of 900 mg or more a day), palpitations, increased blood pressure, and chest pain. Animal studies show no teratogenic effects.

Neutraceutical SAMe Acts as Natural Antidepressant

S-adenosylmethionine (SAMe), a central metabolite in animal cells, provides methyl groups and other moieties for production of neurotransmitters, lipid membranes, proteins, and glutathione. SAMe donates methyl groups (CH3) involved in activation and deactivation of histones that turn on and off the genes in DNA. It has been used to treat depression, osteoarthritis, liver toxicity, gallstones of pregnancy, Parkinson’s disease, and other medical conditions for over 30 years, mainly in Europe.

Extensive research and clinical experience confirm that SAMe has very few side effects and virtually no drug interactions. The adverse effects of prescription antidepressants, particularly weight gain and sexual dysfunction, contribute to patient discontinuation. Because SAMe does not cause sexual side effects, sedation, weight gain, or cognitive interference, it is more acceptable to patients.

An APA work group of the Council on Research reviewed 17 open-label trials; 19 double-blind, randomized, controlled trials; and 21 trials comparing SAMe with prescription antidepressants. The review, by Anup Sharma, M.D., Ph.D., et al., was published June 2017 in the Journal of Clinical Psychiatry. The researchers reported encouraging evidence of the efficacy and safety of SAMe as a monotherapy and as an augmentation for other antidepressants. Their review also identified “supportive early evidence for SAMe in certain neurocognitive, substance use, and psychotic disorders.” Additional clinical studies are needed to further delineate the role of SAMe in neuropsychiatric conditions.

Unsolved Mysteries of SAMe Research

SAMe is one of the most useful treatments available for children, and adults, including older people, pregnant women, and medically ill patients. We have used SAMe in our clinical practices for over 20 years to treat patients with depression, cognitive impairment, mental and physical fatigue, attention-deficit disorder, arthritis, and liver dysfunction. Nevertheless, several recent three-armed, well-designed, double-blind, randomized, controlled studies of patients with mild to moderate major depressive disorder found no significant differences in improvement among placebo, SAMe, and prescription antidepressants. Considering these reports, why do we continue to recommend SAMe for treatment of depression?

SAMe was approved for marketing as a nutraceutical for depression in the United States in 1999. Based on its review of SAMe studies, the U.S. Department of Health and Human Services Agency for Healthcare Research and Quality concluded that SAMe was equivalent to standard pharmacotherapy for depression and osteoarthritis with fewer side effects.

Prior to 2005, most studies used intramuscular SAMe or 800 mg of 1,4-butanedisulfonate SAMe twice daily by mouth in patients with moderate to severe depression. Eventually, a large pharmaceutical company bought the European company that manufactured high-quality butanedisulfonate SAMe and discontinued sales in the United States, but continued to sell it in other countries. Subsequently, American researchers studying SAMe for major depression used the tosylate or toluenate forms. Since then, several trials of SAMe for mild to moderate depression in this country have reported inconclusive results and large placebo-response rates, and some have used doses below the recommended dose of 1,600 mg/day.

Nonconclusive results from these three-armed, well-designed studies may be due to patient selection or heterogeneity (especially using patients with mild or nonbiological depression), the use of less potent forms of SAMe, or other unknown factors. Reanalysis of data from these studies has not yet identified the reasons for the high placebo-response rates and inconclusive data. The authors of one of these studies—David Mischoulon, M.D., Ph.D., et al.—deserve credit for writing that they continue to prescribe SAMe to their patients with good results, thereby acknowledging the discrepancy between the study data and their own clinical observations.

An independent manufacturer, ExtremeV, is now selling high-quality 1,4-butanedisulfonate SAMe in the United States under the brand name Azendus. In our clinical practices, we have found Azendus to be more potent and to require lower doses compared with other SAMe brands.