Rhodiola rosea ancient medicinal herb for stress, mild to moderate depression and neuro-protection Patricia L. Gerbarg, MD Assistant Clinical Professor in Psychiatry New York Medical College and Richard P. Brown, MD Associate Clinical Professor in Psychiatry Columbia University College of physicians and Surgeons

Presenter Disclosures The following personal financial relationships with commercial interests relevant to this presentation existed during the past 12 months: No relationships to disclose. Patricia L. Gerbarg, MD Richard P. Brown, MD

Defining Adaptogens Adaptogens are herbal preparations used to: Protect against physical, toxic, chemical, hypoxic, heat, cold, radiation Increase attention and endurance under stress Reduce stress-induced impairments/disorders through actions on the neuro-endocrine- immune system. (A Panossian & G Wikman. Curr Clin Pharmacol (3): ; AG Panossian. Psychiatric Clinics of North America. March (1):39-64).

Molecular Mechanisms of Adaptogens Metabolic Regulators Rich in antioxidants Cellular repair: mitochondria, heat shock proteins, neuropeptide Y, glucocorticoid receptors Epigenetic effects

Rhodiola Rosea

Clinical Uses for Rhodiola rosea Antidepressant solo treatment Enhance effects of prescription antidepressants Relieve fatigue in medically ill patients Improve age-related decline in memory and cognitive function Relieve fatigue and cognitive dysfunction caused by antidepressants and other medications Increase energy, motivation Improve mental and physical and endurance

Additional Benefits of Rhodiola rosea Improve stress tolerance and resiliency for physical and emotional stress Prevent/Treat Post-traumatic Stress Disorder ADHD – helps improve mental focus Improve cognitive recovery from neuro-lyme disease Prevent/relieve: high altitude sickness, jet lag Used for sexual enhancement Antibacterial

SHR-5 Rhodiola rosea for Depression DBRPC 6-wk trial mild-mod depression A - 340mg/d B – 680mg/d C – placebo Mean drop in Scores A B C HAMD 25    23  self-esteem DBRPC = double-blind randomized placebo-controlled HAMD = Hamilton Depression Scale (Darbinyan et al. Nordic J of Psychiatry. 2007; 61(5):343-8)

Rhodiola and Intellect Increases production of energy (ATP and Creatine) in mitochondria in cells of the brain, muscles, and other organs. Enables brain cells to function well for longer periods of time Fuels cellular repair mechanisms (Saratikov AS, Krasnov EA (1987) Rhodiola rosea is a valuable medicinal plant. Tomsk. Russia Pp )

R. Rosea Improves Mental Work Capacity Under Stress: randomized controlled studies Improved: mental fatigue, memory, attention, errors over time, coordination, eye fatigue, well- being, physical work capacity, final exam marks Russian cosmonauts given exhausting mental tasks reading monitors for long hours Cadets at Russian Military Academy Foreign high school students Exam period fatigue/stress in college students (Baranov VM et al. 1994; Shevtsov et al. Phytomedicine 10:95-105, 2003; Spasov AA et al. 2000, Panossian 2013; Brown, Gerbarg. The Rhodiola Revolution. Rodale. 2004)

What is the # 1 Misconception about Rhodiola rosea? “Rhodiola acts as an MAOI and should not be combined with antidepressants.” True False X

Monoamine Oxidase Inhibitors (MAOIs) One in vitro study: a solution from a R. rosea extract, in far greater concentration that would occur with oral doses, had MAOI activity R. rosea extracts in therapeutic doses contain such small amounts of MAOIs that they have no clinical significance when taken by mouth R. rosea has been combined with all classes of antidepressants (except MAOIs) with no adverse effects. (van Diermen D, et al. J Ethnopharmacology Mar 18;122(2): ; A)

Rhodiola in Menopause  energy and mood  memory  mental focus, “sharpness” 3 women who had been without menses for < 12 months resumed regular menstruation

Rhodiola & Estrogenicity Selective Estrogen Receptor Modulator (SERM) Tested ovariectomized rats Strong estrogen receptor binding but not activation of estrogen receptors No  in circulating estradiol or LH No change in uterine size R. rosea  d excess estradiol levels from estrogen implants ( Eagon PK, et al Evaluation of the medicinal botanical Rhodiola rosea for estrogenicity [Abstract]. In American Association of Cancer Research.)

What is the # 2 Misconception about Rhodiola rosea? “Rhodiola rosea induces P450 enzymes and can interfere with the metabolism of certain prescription drugs.” True False X

R. rosea root extract showed in vitro inhibition of CYP3A4 isozyme and P-glycoprotein. R. rosea (SHR-5) extract fed to rats (in vivo) showed no significant effect on 2 CYP450 substrates or on warfarin anticoagulant activity. Adverse interactions of R. rosea with prescription medications have not been reported in humans. (Hellum et al., Planta Med (4):331-8; Panossian, et al. Planta Med ; Kennedy, DA, and D Seely Expert Opin Drug Saf; Francis Brinker Herbal Contraindications and Drug interactions.) In Vitro, In Vivo, or In Human?

R. Rosea helps kill cancer cells and protect against side effects of chemotherapy Rodents with transplants of human cancers: Lewis lung sarcoma, Pliss lymphosarcoma, Ehrlich’s sarcoma, NKY/LY tumor, and melanoma B16 Given adriamycin or cyclophosphamide R. rosea increased chemotherapy effectiveness Protected liver and bone marrow stem cells from toxic effects of the chemotherapy (Brown, Gerbarg, Muskin. How to Use Herbs, Nutrients, and Yoga in Mental Health. NY: WW Norton, 2009)

Breast Cancer and Ovarian Cancer Human Breast Cancer grafts in mice. Rhodiola crenulata slowed growth, prevented metastasis, induced death of breast cancer cells but not normal human mammary epithelial cells. 28 women stage III-IV ovarian cancer after surgery and 1 st Rx cisplatin + cyclophosphamide. 9 pts given AdMax (L.carthemoides, R.rosea, E.senticosus, S.chinesis) had:  CD3,4,5,8 lymphocytes,  IgG, IgM  fatigue and depression 2 R. rosea compounds killed prostate cancer cells (Y. Tu et al. J Med food. 2008; Vinalathan et al. Phytotherapy Res 2005; Kormosh et al Phytother Res 2006)

Rhodiola rosea Potential Side Effects Stimulative effects can be additive – Caffeine in coffee, sports drinks – Mild anti-platelet at higher doses (above 800 mg/day) in some people can cause increased bruising Patients susceptible to stimulative effects – Anxiety disorder, Bipolar disorder, Elderly – Patients with underlying cardiac arrhythmia (Panossian AG. Adaptogens in mental and behavioral disorders. Psych Clin NA. 2013:49-64; Gerbarg & Brown. Phytomedicines for prevention and treatment of mental health disorders. Psych Clin NA. 2013:37-47)

R. Rosea Daily Dosages Healthy people to  physical and cognitive function: mg/day Augment antidepressants: mg/day Elderly, medically ill, anxious: start mg, titrate slowly as tolerated Response may take 1 week to 2 months Take most of the dose in the morning on an empty stomach at least 20 min before a meal for best absorption. A second dose can be taken midday as needed Do not take in late afternoon or evening, as it may impair sleep

Quality is Important R. rosea extracts contain hundreds of bioactive compounds that can be destroyed or volatilized during extraction. The quality of cultivated R. rosea varies depending on climate and soil conditions The quality of supplements varies greatly. It is particularly important to use highest quality brands to get the full benefits and minimize side effects

Alaska Rhodiola rosea 3-Year-Old Plant

Summary and Future Directions Educate consumers and doctors regarding benefits, HDIs, side effects, and quality products  interest and support for human studies: – firmer evidence base of safety and efficacy – Enable clinicians to extend therapeutic benefits to patients – new treatments for depression, fatigue, stress, mental and physical performance, cognitive and memory decline, cancer, space exploration – Possible selective estrogen receptor modulator (SERM)

“We consider ourselves phytopharmaceuticals!” BIG PHARMA

Key References -1 Alexander Panossian. Adaptogens in Mental and Behavioural Disorders. Psych Clin NA. 2013, 36(1): Brown RP, Gerbarg PL. The Rhodiola Revolution. Rodale press Gerbarg PL, Brown RP. Phytomedicines for Prevention and Treatment of Mental Health Disorders. Psych Clin NA. 2013, 36(1): A Panossian & G Wikman. Evidence-based efficacy of adaptogens in fatigue and molecular mechanisms related to their stress-protective activity. Curr Clin Pharmacol (3):

Francis Brinker Herbal Contraindications and Drug Interactions plus Herbal Adjuncts with Medicines. 4th ed. Sandy, Oregon: Eclectic Medical Publications. Kennedy DA, Seely D Clinically based evidence of drug-herb interactions: a systematic review. Expert Opin Drug Saf. 9 (1): Jerome Sarris, Panossian A, Schweitzer I, et al. Herbal medicine for depression, anxiety and insomnia: a review of psychopharmacology and clinical evidence. Eur Neuropsychopharmacol. 2011,21(12): Gurley BJ. Pharmacokinetic herb-drug interactions (Part 1): origins, mechanisms, and the impact of botanical dietary supplements. Planta Med. 2012; 78: