PP  Vol.5 No.10 , September 2014
Anxiety-Inducing Dietary Supplements: A Review of Herbs and Other Supplements with Anxiogenic Properties
Abstract: Anxiety disorders comprise the most common group of mental disorders to affect the general population in the United States. These disorders are heterogeneous in nature, highly comorbid with one another, and pose a degree of difficulty regarding diagnosis and management. The exact etiology and pathophysiology of anxiety remains to be elucidated; however, it is likely that it is multifactorial, and all potential causes of anxiety must be investigated, including substance-induced anxiety. Among substances that may induce anxiety are dietary supplements. As utilization of these products appears to be high in the US population, it is important to identify which of available supplements may cause anxiety. Objective: To review the scientific literature to identify dietary supplements associated with induction of anxiety and related symptoms. Methods: A search of Natural Medicines Comprehensive Database, MedlinePlus Herbs and Supplements, and Natural Standard was performed to identify dietary supplements with anxiogenic properties. Dietary supplements were included based on product availability, utilization trends, and if there was sufficient evidence that the substance could elicit anxiety via direct pharmacologic effects. Agents were excluded from the review if anxiety was solely due to withdrawal from the substance or only occurred in the setting of intoxication. A search of MEDLINE and PUBMED was performed to identify relevant peer reviewed publications concerning induction of anxiety and/or its associated symptoms by those dietary supplements chosen for review. Conclusions: Dietary supplements can contribute to and cause anxiety and its related symptoms via overstimulation of the Central Nervous System. Healthcare professionals should screen all patients presenting with symptoms consistent with anxiety for recent or current use of all products capable of inducing anxiety, including dietary supplements.
Cite this paper: McCarthy, C. , Candelario, D. and Liu, M. (2014) Anxiety-Inducing Dietary Supplements: A Review of Herbs and Other Supplements with Anxiogenic Properties. Pharmacology & Pharmacy, 5, 966-981. doi: 10.4236/pp.2014.510109.

[1]   National Center for Complementary and Alternative Medicine (US) (2013) Complementary, Alternative, or Integrative Health: What’s in a Name?

[2]   National Center for Complementary and Alternative Medicine (US) (2006) Herbal Supplements: Consider Safety, Too.

[3]   Bent, S. (2008) Herbal Medicine in the United States: Review of Efficacy, Safety, and Regulation: Grand Rounds at University of California, San Francisco Medical Center. Journal of General Internal Medicine, 23, 854-859.

[4]   Cupp, M.J. (1999) Herbal Remedies: Adverse Effects and Drug Interactions. American Family Physician, 59, 1239-1245.

[5]   Wu, C.H., Wang, C.C. and Kennedy, J. (2011) Changes in Herb and Dietary Supplement Use in the US Adult Population: A Comparison of the 2002 and 2007 National Health Interview Surveys. Clinical Therapeutics, 33, 1749-1758.

[6]   American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders. 5th Edition, American Psychiatric Association, Arlington.

[7]   Kessler, R.C., Aguilar-Gaxiola, S., Alonso, J., et al. (2009) The Global Burden of Mental Disorders: An Update from the WHO World Mental Health (WMH) Surveys. Epidemiologia e Psichiatria Sociale, 18, 23-33.

[8]   Haller, C., Kearney, T., Bent, S., Ko, R., Benowitz, N. and Olson, K. (2008) Dietary Supplement Adverse Events: Report of a One-Year Poison Center Surveillance Project. Journal of Medical Toxicology, 4, 84-92.

[9]   Bandelow, B., Sher, L., Bunevicius, R., et al. (2012) Guidelines for the Pharmacological Treatment of Anxiety Disorders, Obsessive-Compulsive Disorder and Posttraumatic Stress Disorder in Primary Care. International Journal of Psychiatry in Clinical Practice, 16, 77-84.

[10]   Sinclair, L.I., Christmas, D.M., Hood, S.D., et al. (2009) Antidepressant-Induced Jitteriness/Anxiety Syndrome: Systematic Review. The British Journal of Psychiatry, 194, 483-490.

[11]   Boyer, E.W. and Shannon, M. (2005) The Serotonin Syndrome. The New England Journal of Medicine, 352, 1112-1120.

[12]   Birmes, P., Coppin, D., Schmitt, L. and Lauque, D. (2003) Serotonin Syndrome: A Brief Review. Canadian Medical Association Journal, 168, 1439-1442.

[13]   Evans, C.E. and Sebastian, J. (2007) Serotonin Syndrome. Emergency Medicine Journal, 24, e20.

[14]   Mills, K.C. (1997) Serotonin Syndrome. A Clinical Update. Critical Care Clinics, 13, 763-783.

[15]   Ables, A.Z. and Nagubilli, R. (2010) Prevention, Diagnosis, and Management of Serotonin Syndrome. American Family Physician, 8, 1139-1142.

[16]   Linde, K. (2009) St. John’s Wort—An Overview. Forschende Komplementärmedizin, 16, 146-155.

[17]   Henderson, L., Yue, Q.Y., Bergquist, C., Gerden, B. and Arlett, P. (2002) St John’s Wort (Hypericum perforatum): Drug Interactions and Clinical Outcomes. British Journal of Clinical Pharmacology, 54, 349-356.

[18]   Hammerness, P., Basch, E., Ulbricht, C., Barrette, E.P., Foppa, I., Basch, S., et al. (2003) St John’s Wort: A Systematic Review of Adverse Effects and Drug Interactions for the Consultation Psychiatrist. Psychosomatics, 44, 271-282.

[19]   Knüppel, L. and Linde, K. (2004) Adverse Effects of St. John’s Wort: A Systematic Review. Journal of Clinical Psychiatry, 65, 1470-1479.

[20]   Dannawi, M. (2002) Possible Serotonin Syndrome after Combination of Buspirone and St. John’s Wort. Journal of Psychopharmacology, 16, 401.

[21]   Bonetto, N., Santelli, L., Battistin, L. and Cagnin, A. (2007) Serotonin Syndrome and Rhabdomyolysis Induced by Concomitant Use of Triptans, Fluoxetine and Hypericum. Cephalalgia, 27, 1421-1423.

[22]   Lantz, M.S., Buchalter, E. and Giambanco, V. (1999) St. John’s Wort and Antidepressant Drug Interactions in the Elderly. Journal of Geriatric Psychiatry and Neurology, 12, 7-10.

[23]   Gordon, J.B. (1998) SSRIs and St. John’s Wort: Possible Toxicity? American Family Physician, 57, 950.

[24]   Bryant, S.M. and Kolodchak, J. (2004) Serotonin Syndrome Resulting from an Herbal Detox Cocktail. The American Journal of Emergency Medicine, 22, 625-626.

[25]   Beckman, S.E., Sommi, R.W. and Switzer, J. (2000) Consumer Use of St. John’s Wort: A Survey on Effectiveness, Safety, and Tolerability. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 20, 568-574.

[26]   Parker, V., Wong, A.H., Boon, H.S. and Seeman, M.V. (2001) Adverse Reactions to St. John’s Wort. Canadian Journal of Psychiatry, 46, 77-79.

[27]   Brown, T.M. (2000) Acute St. John’s Wort Toxicity. The American Journal of Emergency Medicine, 18, 231-232.

[28]   Markowitz, J.S., Donovan, J.L., DeVane, C.L., Taylor, R.M., Ruan, Y., Wang, J.S., et al. (2003) Effect of St. John’s Wort on Drug Metabolism by Induction of Cytochrome P450 3A4 Enzyme. The Journal of the American Medical Association, 290, 1500-1504.

[29]   Johne, A., Schmider, J., Brockmöller, J., Stadelmann, A., Störmer, E., Bauer, S., et al. (2002) Decreased Plasma Levels of Amitriptyline and Its Metabolites on Comedication with an Extract from St. John’s Wort (Hypericum perforatum). Journal of Clinical Psychopharmacology, 22, 46-54.

[30]   Natural Medicine Comprehensive Database (US) (2011) SAMe Full Monograph.

[31]   Mischoulon, D. and Fava, M. (2002) Role of S-Adenosyl-L-Methionine in the Treatment of Depression: A Review of the Evidence. The American Journal of Clinical Nutrition, 76, 1158S-1161S.

[32]   Saletu, B., Anderer, P., Di Padova, C., Assandri, A. and Saletu-Zyhlarz, G.M. (2002) Electrophysiological Neuroimaging of the Central Effects of S-Adenosyl-L-Methionine by Mapping of Electroencephalograms and Event-Related Potentials and Low-Resolution Brain Electromagnetic Tomography. The American Journal of Clinical Nutrition, 76, 1162S-1171S.

[33]   Arnold, O., Saletu, B., Anderer, P., di Padova, C., Corrado, M. and Saletu-Zyhlarz, G.M. (2005) Double-Blind, Placebo-Controlled Pharmacodynamic Studies with a Nutraceutical and a Pharmaceutical Dose of Ademetionine (SAMe) in Elderly Subjects, Utilizing EEG Mapping and Psychometry. European Neuropsychopharmacology, 15, 533-543.

[34]   Di Rocco, A., Rogers, J.D., Brown, R., Werner, P. and Bottiglieri, T. (2000) S-Adenosyl-Methionine Improves Depression in Patients with Parkinson’s Disease in an Open-Label Clinical Trial. Movement Disorders, 15, 1225-1229.

[35]   Papakostas, G.I., Mischoulon, D., Shyu, I., Alpert, J.E. and Fava, M. (2010) S-Adenosyl Methionine (SAMe) Augmentation of Serotonin Reuptake Inhibitors for Antidepressant Nonresponders with Major Depressive Disorder: A Double-Blind, Randomized Clinical Trial. The American Journal of Psychiatry, 167, 942-948.

[36]   Iruela, L.M., Minguez, L., Merino, J. and Monedero, G. (1993) Toxic Interaction of S-Adenosylmethionine and Clomipramine. The American Journal of Psychiatry, 150, 522.

[37]   Birdsall, T.C. (1998) 5-Hydroxytryptophan: A Clinically-Effective Serotonin Precursor. Alternative Medicine Review, 3, 271-280.

[38]   Turner, E.H., Loftis, J.M. and Blackwell, A.D. (2006) Serotonin a la Carte: Supplementation with the Serotonin Precursor 5-Hydroxytryptophan. Pharmacology & Therapeutics, 109, 325-338.

[39]   Natural Medicine Comprehensives Database (US) (2014) L-Tryptophan Full Monograph.

[40]   Natural Medicine Comprehensives Database (US) (2014) 5-HTP Full Monograph.

[41]   Van Woert, M.H. and Sethy, V.H. (1975) Therapy of Intention Myoclonus with L-5-Hydroxytryptophan and a Peripheral Decarboxylase Inhibitor, MK 486. Neurology, 25, 135-140.

[42]   Van Woert, M.H., Rosenbaum, D., Howieson, J. and Bowers Jr., M.B. (1977) Long-Term Therapy of Myoclonus and Other Neurologic Disorders with L-5-Hydroxytryptophan and Carbidopa. The New England Journal of Medicine, 296, 70-75.

[43]   Thal, L.J., Sharpless, N.S., Wolfson, L. and Katzman, R. (1980) Treatment of Myoclonus with L-5-Hydroxytryptophan and Carbidopa: Clinical, Electrophysiological, and Biochemical Observations. Annals of Neurology, 7, 570-576.

[44]   Haskell, C.F., Dodd, F.L., Wightman, E.L. and Kennedy, D.O. (2013) Behavioral Effects of Compounds Co-Consumed in Dietary Forms of Caffeinated Plants. Nutrition Research Review, 26, 49-70.

[45]   Hechman, M.A., Weil, J. and Mejia, E.G. (2010) Caffeine (1,3,7-Trimethylxanthine) in Foods: A Comprehensive Review on Consumption, Functionality, Safety, and Regulatory Matters. Journal of Food Science, 75, R77-R87.

[46]   DRUGDEX System Micromedex 2.0. (2014) Caffeine.

[47]   Lara, D.R. (2010) Caffeine, Mental Health, and Psychiatric Disorders. Journal of Alzheimer’s Disease, 20, S239-248.

[48]   Childs, E. and de Wit, H. (2006) Subjective, Behavioral, and Physiological Effects of Acute Caffeine in Light, Nondependent Caffeine Users. Psychopharmacology(Berlin), 185, 514-523.

[49]   Nardi, A.E., Lopes, F.L., Freire, R.C., Veras, A.B., Nascimento, I., Valença, A.M., et al. (2009) Panic Disorder and Social Anxiety Disorder Subtypes in a Caffeine Challenge Test. Psychiatry Research, 169, 149-153.

[50]   Bergin, J.E. and Kendler, K.S. (2012) Common Psychiatric Disorders and Caffeine Use, Tolerance, and Withdrawal: An Examination of Shared Genetic and Environment Effects. Twin Research and Human Genetics, 15, 473-482.

[51]   Childs, E., Hohoff, C., Deckert, J., Xu, K., Badner, J. and de Wit, H. (2008) Association between ADROA2A and DRD2 Polymorphisms and Caffeine-Induced Anxiety. Neuropsychopharmacology, 33, 2791-2800.

[52]   Bhatti, S.K., O’Keefe, J.H. and Lavie, C.J. (2013) Coffee and Tea: Perks for Health and Longevity? Current Opinion in Clinical Nutrition and Metabolic Care, 16, 688-697.

[53]   Ellam, S. and Williamson, G. (2013) Cocoa and Human Health. Annual Review of Nutrition, 33, 105-128.

[54]   De Araujo, Q.R., Gattward, J.N., Almoosawi. S., Silva, M.D.C., Dantas, P.A. and Araujo Jr., Q.R. (2013) Cacao and Human Health: From Head to Foot—A Review. Critical Reviews in Food Science and Nutrition, In Press.

[55]   Natural Medicine Comprehensives Database (US) (2013) Cocoa Full Monograph.

[56]   Latif, R. (2013) Health Benefits of Cocoa. Current Opinion in Clinical Nutrition and Metabolic Care, 16, 669-674.

[57]   Burdock, G.A., Carabin, I.G. and Crincoli, C.M. (2009) Safety Assessment of Kola Nut Extract as a Food Ingredient. Food and Chemical Toxicology, 47, 1725-1732.

[58]   Natrual Medicine Comprehensive Database (US) (2013) Cola Nut Full Monograph.

[59]   Schimpl, F.C., da Silva, J.F., Goncalves, J.F. and Mazzafera, P. (2013) Guarana: Revisiting a Highly Caffeinated Plant from the Amazon. Journal of Ethnopharmacology, 150, 14-31.

[60]   Natural Medicine Comprehensives Database (US) (2012) Guarana Full Monograph.

[61]   Silvestrini, G.I., Marino, F. and Cosentino, M. (2013) Effects of a Commercial Product Containing Guaraná on Psychological Well-Being, Anxiety and Mood: A Single-Blind, Placebo-Controlled Study in Healthy Subjects. Journal of Negative Results in BioMedicine, 12, 9.

[62]   Berigan, T. (2005) An Anxiety Disorder Secondary to Energy Drinks: A Case Report. Psychiatry, 2, 10.

[63]   Wolk, B.J., Ganetsky, M. and Babu, K.M. (2012) Toxicity of Energy Drinks. Current Opinion in Pediatrics, 24, 243-251.

[64]   Heck, C.I. and De Mejia, E.G. (2007) Yerba Mate Tea (Ilex paraguariensis): A Comprehensive Review on Chemistry, Health Implications, and Technological Considerations. Journal of Food Science, 72, R138-R151.

[65]   Bracesco, N., Sanchez, A.G., Contreras, V., Menini, T. and Gugliucci, A. (2011) Recent Advances on Ilex paraguariensis Research: Mini Review. Journal of Ethnopharmacology, 136, 378-384.

[66]   Natural Medicine Comprehensives Database (US) (2013) Mate Full Monograph.

[67]   Natural Standard: The Authority on Integrative Medicine (US) (2014) Khat.,-herbs-supplements/k/khat/

[68]   Wabe, N.T. (2011) Chemistry, Pharmacology, and Toxicology of Khat (Catha edulis Forsk.): A Review. Addiction of Health, 3, 137-149.

[69]   Kalix, P. (1991) The Pharmacology of Psychoactive Alkaloids from Ephedra and Catha. Journal of Ethnopharmacology, 32, 201-208.

[70]   Patel, N.B. (2000) Mechanism of Action of Cathinone: The Active Ingredient of Khat (Catha edulis). East African Medical Journal, 77, 329-332.

[71]   Kalix, P. (1994) Khat, an Amphetamine-Like Stimulant. Journal of Psychoactive Drugs, 26, 69-74.

[72]   Al-Motarreb, A., Baker, K. and Broadley, K. (2002) Khat: Pharmacological and Medical Aspects and Its Social Use in Yemen. Phytotherapy Research, 16, 403-413.

[73]   Kalix, P. (1992) Cathinone, a Natural Amphetamine. Pharmacology & Toxicology, 70, 77-86.

[74]   Kelly, J.P. (2011) Cathinone Derivatives: A Review of Their Chemistry, Pharmacology and Toxicology. Drug Testing and Analysis, 3, 439-453.

[75]   Geisshusler, S. and Brenneisen, R. (1987) The Content of Psychoactive Phenylpropyl and Phenylpentenyl Khatamines in Catha edulis Forsk. of Different Origin. Journal of Ethnopharmacology, 19, 269-277.

[76]   Brenneisen, R., Fisch, H.U., Koelbing, U., Geisshusler, S. and Kalix, P. (1990) Amphetamine-Like Effects in Humans of the Khat Alkaloid Cathinone. British Journal of Clinical Pharmacology, 30, 825-828.

[77]   Martin, W.R., Sloan, J.W., Sapira, J.D. and Jasinski, D.R. (1971) Physiologic, Subjective, and Behavioral Effects of Amphetamine, Methamphetamine, Ephedrine, Phenmetrazine, and Methylphenidate in Man. Clinical Pharmacology & Therapeutics, 12, 245-258.

[78]   Jager, A.D. and Sireline, L. (1994) Natural History of Khat Psychosis. Australian and New Zealand Journal of Psychiatry, 28, 331-332.

[79]   The WHO Expert Committee on Drug Dependence (ECDD) (2006) Assessment of Khat (Catha edulis Forsk.).

[80]   Hassan, N.A., Gunaid, A.A., El Khally, F.M. and Murray-Lyon, I.M. (2002) The Effect of Chewing Khat Leaves on Human Mood. Saudi Medical Journal, 23, 850-853.

[81]   Eckersley, W., Salmon, R. and Gebru, M. (2010) Khat, Driver Impairment and Road Traffic Injuries: A View from Ethiopia. Bulletin of the World Health Organization, 88, 235-236.

[82]   Randall, T. (1993) Khat Abuse Fuels Somali Conflict, Drains Economy. The Journal of the American Medical Association, 269, 12-15.

[83]   Drug Enforcement Agency (2012) Drug Fact Sheet. Khat.

[84]   Natural Medicine Comprehensives Database (US) (2014) Yohimbe Full Monograph.

[85]   Kunelius, P., Häkkinen, J. and Lukkarinen, O. (1997) Is High-Dose Yohimbine Hydrochloride Effective in the Treatment of Mixed-Type Impotence? A Prospective, Randomized, Controlled Double-Blind Crossover Study. Urology, 49, 441-444.

[86]   Tam, S.W., Worcel, M. and Wyllie, M. (2001) Yohimbine: A Clinical Review. Pharmacology & Therapeutics, 91, 215-243.

[87]   Jacobsen, F.M. (1992) Fluoxetine-Induced Sexual Dysfunction and an Open Trial of Yohimbine. The Journal of Clinical Psychiatry, 53, 119-122.

[88]   Ernst, E. and Pittler, M.H. (1998) Yohimbine for Erectile Dysfunction: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. The Journal of Urology, 159, 433-436.

[89]   Teloken, C., Rhoden, E.L., Sogari, P., Dambros, M. and Souto, C.A. (1998) Therapeutic Effects of High Dose Yohimbine Hydrochloride on Organic Erectile Dysfunction. The Journal of Urology, 159, 122-124.

[90]   Natural Standard: The Authority on Integrative Medicine (US) (2014) Yohimbe Bark Extract.,-herbs-supplements/y/

[91]   Morales, A. (2000) Yohimbine in Erectile Dysfunction: The Facts. International Journal of Impotence Research, 12, S70-S74.

[92]   Betz, J.M., White, K.D. and der Marderosian A.H. (1995) Gas Chromatographic Determination of Yohimbine in Commercial Yohimbe Products. Journal of AOAC International, 78, 1189-1194.

[93]   Tanaka, M., Yoshida, M., Emoto, H. and Ishii, H. (2000) Noradrenaline Systems in the Hypothalamus, Amygdala and Locus Coeruleus Are Involved in the Provocation of Anxiety: Basic Studies. European Journal of Pharmacology, 405, 397-406.

[94]   Kearney, T., Tu, N. and Haller, C. (2010) Adverse Drug Events Associated with Yohimbine-Contaming Products: A Retrospective Review of the California Poison Control System Reported Cases. The Annals of Pharmacotherapy, 44, 1022-1029.

[95]   Susset, J.G., Tessier, C.D., Wincze, J., Bansal, S., Malhotra, C. and Schwacha M.G. (1989) Effect of Yohimbine Hydrochloride on Erectile Impotence: A Double Blind Study. The Journal of Urology, 141, 1360-1363.

[96]   Henauer, S.A., Gillespie, H.K. and Hollister, L.E. (1984) Yohimbine and the Model Anxiety State. The Journal of Clinical Psychiatry, 45, 512-515.

[97]   Charney, D.S., Heninger, G.R. and Redmond, D.E. (1983) Yohimbine Induced Anxiety And Increased Noadrenergic Function in Humans: Effects of Diazepam and Clonidine. Life Sciences, 33, 19-29.

[98]   Vasa, R.A., Pine, D.S., Masten, C.L., Vythilingam, M., Collin, C., Charney, D.S., et al. (2009) Effects of Yohimbine and Hydrocortisone on Panic Symptoms, Autonomic Responses and Attention to Threat in Healthy Adults. Psychopharmacology(Berlin), 204, 445-455.

[99]   Kaplan, J.S., Arnkoff, D.B., Glass, C.R., Tinsley, R., Geraci, M., Hernandez, E., et al. (2012) Avoidant Coping in Panic Disorder: A Yohimbine Biological Challenge Study. Anxiety, Stress & Coping: An International Journal, 25, 425-442.

[100]   Charney, D.S., Woods, S.W., Krystal, J.H., Nagy, L.M. and Heninger, G.R. (1992) Noradrenergic Neuronal Dysregulation in Panic Disorder: The Effects of Intravenous Yohimbine and Clonidine in Panic Disorder Patients. Acta Psychiatrica Scandinavica, 86, 273-282.

[101]   Price, L.H., Charney, D.S. and Heninger, G.R. (1984) Three Cases of Manic Symptoms Following Yohimbine Administration. The American Journal of Psychiatry, 141, 1267-1268.

[102]   Albus, M., Zahn, T.P. and Breier, A. (1992) Anxiogenic Properties of Yohimbine. I. Behavioral, Physiological and Biochemical Measures. European Archives of Psychiatry and Clinical Neuroscience, 241, 337-344.

[103]   Soni, M.G., Carabin, I.G., Griffiths, J.C. and Burdick, G.A. (2004) Safety of Ephedra: Lessons Learned. Toxicology Letters, 150, 97-110.

[104]   Natural Medicine Comprehensives Database (US) (2012) Ephedra.

[105]   National Center for Complementary and Alternative Medicine (US) (2013) Ephedra.

[106]   Blanck, H., Khan, L. and Serdula, M. (2001) Use of Nonprescription Weight Loss Products: Results from a Multistate Survey. The Journal of the American Medical Association, 286, 930-935.

[107]   Marraffa, J.M. (2011) Goldfrank’s Toxicologic Emergencies. McGraw-Hill Companies, Inc., China.

[108]   Haller, C.A. and Benowitz, N.L. (2000) Adverse Cardiovascular and Central Nervous System Events Associated with Dietary Supplements Containing Ephedra Alkaloids. The New England Journal of Medicine, 343, 1833-1838.

[109]   Food and Drug Administration (2004) Final Rule Declaring Dietary Supplements Containing Ephedrine Alkaloids Adulterated Because They Present an Unreasonable Risk. Federal Register, 69, 6787-6854.

[110]   Andraws, R., Chawla, P. and Brown, D.L. (2005) Cardiovascular Effects of Ephedra Alkaloids: A Comprehensive Review. Progress in Cardiovascular Diseases, 47, 217-225.

[111]   Woolf, A.D., Watson, W.A., Smolinski, S. and Litovitz, T. (2005) The Severity of Toxicity Reactions to Ephedra: Comparison to Other Botanical Products and National Trends from 1993-2002. Clinical Toxicology, 43, 347-355.

[112]   Bent, S., Tiedit, T.N., Odden, M.C. and Shlipak, M.G. (2003) The Relative Safety of Ephedra Compared with Other Herbal Products. Annals of Internal Medicine, 138, 468-471.

[113]   McBride, B.F., Karapanos, A.K., Krudysz, A., Kluger, J., Coleman, C.I. and White, C.M. (2004) Electrocardiographic and Hemodynamic Effects of a Mutlicomponent Dietary Supplement Containing Ephedra and Caffeine. The Journal of the American Medical Association, 291, 216-221.

[114]   Shekelle, P.G., Hardy, M.L., Morton, S.C., Maglione, M., Mojica, W.A., Suttorp, M.J., et al. (2003) Efficacy and Safety of Ephedra and Ephedrine for Weight Loss and Athletic Performance: A Meta-Analysis. The Journal of the American Medical Association, 289, 1537-1545.

[115]   Bents, R.T. and Marsh, E. (2006) Patterns of Ephedra and Other Stimulant Use in Collegiate Hockey Athletes. International Journal of Sport Nutrition and Exercise Metabolism, 16, 636-643.

[116]   Palamar, J. (2011) How Ephedrine Escaped Regulation in the United States: A Historical Review of Misuse and Associated Policy. Health Policy, 99, 1-9.

[117]   Natural Medicine Comprehensives Database (US) (2012) Country Mallow Full Monograph.

[118]   Natural Standard: The Authority on Integrative Medicine (US) (2014) Bala.,-herbs-supplements/b/bala/professional.aspx

[119]   Franzotti, E.M., Santos, C.V.F., Rodrigues, H.M.S.L., Mourao, M.R., Andrade, M.R. and Antoniolli, A.R. (2000) Anti-Inflammatory, Analgesic Activity and Acute Toxicity of Sida cordifolia L. (Malva-Branca). Journal of Ethnopharmacology, 72, 273-278.

[120]   Kanth, V.R. and Diwan, P.V. (1999) Analgesic, Antiinflammatory and Hypoglycaemic Acitivities of Sida cordifolia. Phytotherapy Ressearch, 13, 75-77.

[121]   Momin, M.A., Bellah, S.F., Rahman, S.M., Rahman, A.A., Murshid, G.M. and Emran, T.B. (2014) Phytopharmacological Evaluation of Ethanol Extract of Sida cordifolia L. Roots. Asian Pacific Journal of Tropical Biomedicine, 4, 18-24.

[122]   Konaté, K., Bassolé, I.H., Hilou, A., Aworet-Samseny, R., Souza, A., Barro, N., et al. (2012) Toxicity Assessment and Analgesic Activity Investigation of Aqueous Acetone Extracts of Sida acuta Burn F. and Sida cordifolio L. (Malvaceae), Medicinal Plants of Burkina Faso. BMC Complementary & Alternative Medicine, 12, 120-131.

[123]   Thompson, C.A. (2004) Ephedrine Alkaloids Banned from Dietary Supplements. American Journal of Health-System Pharmacy, 61, 750-753.