Journal of Dietary Supplements, Early Online:1–7, 2014 C 2014 by Informa Healthcare USA, Inc. Available online at www.informahealthcare.com/jds DOI: 10.3109/19390211.2014.902001
ARTICLE
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Manic Psychosis Associated With Ginseng: A Report of Two Cases and Discussion of the Literature Lisa J. Norelli, MD, MPH1,2,3 & Chunying Xu2 1
Capital District Psychiatric Center, Albany, New York, USA, 2 Department of Psychiatry, Albany Medical College, Albany, New York, USA, 3 Department of Epidemiology and Biostatistics, SUNY Albany, School of Public Health, Rensselaer, New York, USA ABSTRACT. Background: Herbal medicine use, highly prevalent in the general population, is often a neglected component of the medical history. Herbs are presumed safe because they are “natural” self-care products. We call attention to the following issues: Panax ginseng, one of the most frequently used herbal medicines, has complex pharmacological activity, and can be associated with severe psychiatric symptoms. Physicians may be unfamiliar with herbal therapy risks, and the need for further education and systematic research is highlighted. Objective: To describe two cases of new onset manic psychoses associated with high dose, chronic ginseng use, and review the relevant literature. Case reports: A 23-year-old man developed acute mania after one month of daily ginseng use and intermittent cannabis use. A 79-year-old man developed hypomania while using ginseng and yohimbine for erectile dysfunction, and had a recurrence of mania after stopping yohimbine but increasing his daily intake of ginseng. Conclusions/Summary: Symptoms of mania fully remitted within days upon discontinuation of ginseng and supportive treatment. Available data prevent a clear determination of causation; however, ginseng-induced mania in the these and previous case reports is suggested by the following: patients had no prior psychiatric history, daily use of ginseng was temporally associated with mania onset, patients ingested much higher doses for a longer duration than recommended in Traditional Chinese Medicine (TCM), and withdrawal of ginseng led to rapid remission. Generally well tolerated, many physicians are unaware that ginseng may be associated with acute and significant psychiatric disturbances for certain at-risk individuals. KEYWORDS. complementary therapies, ginseng, herbal medicine, mania, panax ginseng, psychiatric disorders
INTRODUCTION Complementary and alternative treatments are increasingly prevalent among the general population worldwide (Winslow & Kroll, 1998; Harris & Rees, 2000; Barnes et al., 2008; Eisenberg et al., 1993; Eisenberg, Davis, & Ettner, 1998; Wong, Address correspondence to: Dr Lisa J Norelli, MD, MPH, Capital District Psychiatric Center, 75 New Scotland Avenue, Albany, NY 12208, USA (E-mail: [email protected]) (Received 5 July 2013; accepted 3 December 2013)
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Smith, & Boon, 1998). Humans have exploited the therapeutic effects of herbal preparations for thousands of years, and about a third of modern drugs are derived from plants (Winslow & Kroll, 1998; Kleiner, 1995). Despite widespread use and complex bioactivity, most herbal therapy users do not inform their physicians of this fact, nor do many physicians routinely elicit this history (Winslow & Kroll, 1998; Eisenberg et al., 1993; Eisenberg et al., 1998). People presume that herbal preparations are safe because they are “natural” self-care products, and physicians may be unaware of the potential health risks. Anecdotal reports of significant adverse effects and drug–herb interactions exist in the medical literature; however systematic research and guidance is limited regarding the optimal use of herbal medicines alone and in combination with Western medical approaches (Izzo & Ernst, 2009; Chen, Sneed, & Pan, 2012). Considered safe for the majority of people because most adverse effects appear to be minor, significant clinical problems occur in some individuals (Izzo & Ernst, 2009; Chen et al., 2012; Lian-Wen et al., 2011; Goodwin & Jamison, 2007; Krauthammer & Klerman, 1978; Arora & Daughton, 2007; Vazquez & Aguera-Ortiz, 2002). Panax ginseng, (whose Latin genus name reflects the notion that ginseng is a panacea or cure all) is used in Traditional Chinese Medicine (TCM) for enhancing wellness, vitality, and treating a multitude of ailments. Ginseng is now one of the most commonly used herbal supplements in the West. However, it has complex pharmacological activity and has been associated with significant psychiatric symptoms including insomnia, agitation, pressured speech, euphoria, psychosis, depression, depersonalization, and confusion. (Harris & Rees, 2000; Barnes et al., 2008; Eisenberg et al., 1993; Eisenberg et al., 1998; Izzo & Ernst, 2009; Chen et al., 2012; Lian-Wen et al., 2011; Goodwin & Jamison, 2007; Krauthammer & Klerman, 1978; Arora & Daughton, 2007; Vazquez & Aguera-Ortiz, 2002; Gonzlez-Seijo, Ramos, & Lastra, 1995; Ernst, 2010). Acute mania appears to be an uncommon, though possibly underrecognized, adverse reaction to ginseng. Manic episodes observed as a feature of the psychiatric illness bipolar disorder are characterized by family history of affective disorder, onset in young adulthood, with episodes of hypomania, mania, and depression in the absence of known underlying causes. The underlying pathophysiology of mania is not fully known, but dsyregulation of monoamine neurotransmitter, neuroendocrine (including the hypothalamic–pituitary–adrenal axis) and neuropeptide systems have been implicated. (Goodwin & Jamison, 2007) A manic episode due to an organic cause is referred to as secondary mania (Krauthammer & Klerman, 1978; Arora & Daughton, 2007). Secondary mania may be induced or precipitated by drug intoxication, drug withdrawal, endocrine dysfunction, nutritional deficiency, neurodegenerative disorders, traumatic brain injury, infection, metabolic disturbances, neoplasm, and seizure disorders. (Krauthammer & Klerman, 1978; Arora & Daughton, 2007) See Table 1 for common causes of secondary mania. We highlight these issues by describing two patients who presented with acute manic psychosis associated with ginseng use. METHODS The biomedical literature was searched using PubMed and the following keywords: ginseng, Panax ginseng, adverse effects, herbal medicine, psychiatric disorders,
Manic Psychosis Associated With Ginseng
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TABLE 1. Common Etiologies of Secondary Mania General Medical Conditions Infection Trauma Tumor Cardiovascular disease Metabolic disturbance
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Nutritional deficiency Neurological disorders
HIV, encephalitis, sepsis, urinary tract infection, influenza, pneumonia, syphilis Subdural hematoma, cerebral contusions, traumatic brain injury Central Nervous System (parasagittal meningioma, diencephalic tumors) Congestive heart failure, infarction, embolism, vasculitis Renal failure, hepatic failure, post-ictal states, electrolyte disturbances, hemodialysis, post-surgical states Vitamin B12 , folate deficiency Demyelinating diseases, Parkinson’s Disease, Huntington’s Disease, Wilson’s Disease, multiple sclerosis, stroke, seizure (right temporal focus) Medications and Drugs
Drug intoxication or withdrawal Medications or drugs
Nicotine, caffeine, alcohol, sedative-hypnotics, cocaine, amphetamines, phencyclidine, opioids, hallucinogens Corticosteroids, metoclopramide, H2 -receptor antagonists, antihypertensives, levodopa, isoniazid, disulfiram, cyclosporine, cimetidine, captopril, baclofen, bromocriptine, antipsychotics, antidepressants, sedative-hypnotics, yohimbine, stimulants (e.g., methyphenidate, amphetamines)
Ref: Krauthammer & Klerman, 1978; Arora & Daughton, 2007.
mania, psychosis, drug–herb interactions. Two case report articles were found describing ginseng-induced mania (Vazquez & Aguera-Ortiz, 2002; Gonzlez-Seijo et al., 1995). Six systematic reviews examined the general safety and efficacy of ginseng, including one article that included Korean randomized controlled trials that are not indexed in PubMed (Ernst, 2010; Lee & Son, 2011; Coon & Ernst, 2002; Choi, Kim, Choi, & Lee, 2013; Vogler, Pittler, & Ernst, 1999; Shergis, Zhang, Zhou, & Xue, 2013; Lee & Son, 2011). Two articles systematically reviewed cardiovascular benefits, one reviewed efficacy for erectile dysfunction, one for type 2 diabetes mellitus, and one on cognitive deficits in Alzheimer’s disease (Hur, Lee, Yang, Kim, & Bae, 2010; Buettner, Yeh, Phillips, Mittleman, & Kaptchuk, 2006; Jang, Lee, Shin, Lee, & Ernst, 2008; Lee, Yang, Kim, & Ernst, 2009; Kim, Shin, Lee, Lee, & Ernst, 2011). Four articles reviewed current knowledge regarding herb–drug interactions (Izzo & Ernst, 2009; Chen et al., 2012; Lian-Wen et al., 2011; Coon & Ernst, 2002). Two articles reported on the phenomenon of ginseng abuse syndrome (Chen, 1981; Jones & Runikis, 1987). Case Descriptions Case 1: A 23-year-old single, Caucasian man presented for emergency evaluation. His family reported he had severe insomnia, bizarre behavior (e.g., drinking water out of potholes in the street), and was uncharacteristically irritable and restless for two days. There was no prior history of mental illness in the patient or first-degree relatives. Mental status examination was significant for increased psychomotor activity, pacing, pressured speech, racing thoughts, anxious and irritable mood, labile affect, disorganized thought process, and almost constant distraction by
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auditory hallucinations. He was alert and fully oriented. Physical examination and laboratory tests were significant for mild dehydration, and mild elevation of heart rate, blood pressure, and temperature. Urine toxicology and blood alcohol levels were negative. Supportive care and treatment with risperidone 1 mg daily for three days led to remission of all symptoms. At subsequent interview, the patient admitted to intermittent cannabis use for years and the use of large quantities of Asian red ginseng every day for the month prior to this episode to boost his energy levels. He prepared red ginseng herbal soup from a TCM recipe, and we estimate that he was ingesting about 15 grams of ginseng daily, or about seven times the recommended TCM dose (typically 1–3 g daily in divided doses for 5–7 days). Case 2: A 79-year-old African-American man presented for emergency evaluation of increasingly peculiar thoughts and behaviors over the past week. His family reported that he was constantly distressed, nervous, and exhibiting inappropriate behavior such as calling the police to report “too much pollen in the air.” Mental status examination revealed motor restlessness, pressured speech, anxious mood, labile affect, racing thoughts, disorganized thought process, and paranoid ideas. He was alert and fully oriented. There was no history of alcohol or substance use. Physical examination was otherwise normal except for mild hypertension. Urine toxicology and blood alcohol levels were negative. Symptoms fully remitted within one week with supportive treatment and a short course of antipsychotic medication. Two months prior, the patient had been diagnosed with a substanceinduced hypomanic episode attributed to yohimbine, self-administered for erectile dysfunction. The hypomanic symptoms resolved upon yohimbine discontinuation. However, on subsequent interview, the patient admitted to daily use of Korean red ginseng for years. He reported upon stopping the yohimbine, to compensate he increased the ginseng dose repeatedly during the two months prior to this episode to treat erectile dysfunction. He consumed a condensed drink of ginseng boiled in water 3–4 times per day. We estimate that he ingested approximately 20 g of ginseng daily, or about ten times the usual TMC dose (typical range 1–3 g daily in divided doses for 5–7 days). DISCUSSION These two cases and the other case reports in the literature suggest an association of secondary mania due to ginseng toxicity, ginseng abuse syndrome, or a drug–herb interaction (Vazquez & Aguera-Ortiz, 2002; Gonzlez-Seijo et al., 1995; Siegal, 1979; Chen, 1981). The first patient’s episode was associated with daily high dose ginseng ingestion in combination with episodic cannabis use. The rapid remission of symptoms upon discontinuation of both substances, and the lack of similar symptoms with past cannabis use alone suggests that ginseng was contributory. The second patient had an earlier episode of hypomania attributed to yohimbine, which reportedly resolved upon discontinuation. However, he presented with more florid manic symptoms after a compensatory increase in his daily ginseng dose. Manic symptoms have been associated with yohimbine alone; however ginseng use was a common factor in both episodes (Arora & Daughton, 2007; Price, Charney, & Heninger, 1984). Furthermore, the second, more severe episode was associated
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Manic Psychosis Associated With Ginseng
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with increased and high dose ginseng ingestion daily, suggestive of a dose-response effect. Both patients used an estimated 7–10 times the daily dose, and 4–8 times the duration recommended in TCM recipes. These doses are consistent with previous reports of ginseng abuse syndrome (Siegal, 1979; Chen, 1981). Notably, in both cases the initial clinical assessment did not include an herbal therapy history and the treating physicians were unfamiliar with the adverse effects of ginseng. Ginseng was not initially recognized as a potentially contributory or causative factor to either patient’s acute mental status changes. Herbal remedies termed “ginseng” are derived from the roots of one or more different species of plants. These mainly include Panax ginseng (also known as Asian ginseng, or red ginseng, white ginseng, fresh ginseng depending on root age and preparation), Panax quinquefolius (American ginseng), and Eleutherococcus senticosus (Siberian ginseng). TCM uses Panax ginseng as an “adaptogen” as a stimulant to enhance physical and mental performance, longevity, vitality, resistance to stress, and as an aphrodisiac. A family of steroidal saponins, termed ginsenosides, mediates ginseng’s complex pharmacological activity Ginseng is also used to treat a wide variety of medical conditions including cardiovascular disease, cancer, diabetes, cognitive dysfunction, and erectile dysfunction (Ernst, 2010; Lee & Son, 2011; Choi et al., 2013; Vogler et al., 1999; Shergis et al., 2013; Lee & Son, 2011; Hur et al., 2010; Buettner et al., 2006; Jang et al., 2008; Lee et al., 2009; Kim et al., 2011). Ginseng is believed to have modulating effects on carbohydrate metabolism, lipids, immunity, cognition, coagulation pathways, as well as potential neuroprotective, and antineoplastic activity (Choi et al., 2013; Vogler et al., 1999; Shergis et al., 2013; Lee & Son, 2011; Hur et al., 2010; Buettner et al., 2006; Jang et al., 2008; Lee et al., 2009; Kim et al., 2011). Serious side effects are rarely reported in the literature, with the most commonly reported side effects being nervousness and hypertension (Choi et al., 2013; Lee & Son, 2011; Siegal, 1979; Chen, 1981). Ginseng can exert hypoglycemic effects, prolong coagulation time, stimulate hypothalamic–pituitary–adrenocorticoid (HPA) function, decrease platelet aggregation activity, and alter the activity of other medications and substances (Izzo & Ernst, 2009; Chen et al., 2012; Coon & Ernst, 2002; Jones & Runikis, 1987; Ang-Lee et al., 2001; Janetzky & Morreale, 1997; Hiai, Yokoyama, Oura, & Yano, 1979). Depression, mania, and psychosis have been reported, and mania has been associated with concomitant use of ginseng and phenelzine (Siegal, 1979; Chen, 1981; Jones & Runikis, 1987). Ginseng abuse syndrome, attributed to excessive long term doses of up to 15 g per day, has been described (Siegal, 1979; Chen, 1981) Physical symptoms include palpitations, hypertension, dizziness, insomnia, agitation, nausea, vomiting, abdominal pain, diarrhea, gastrointestinal bleeding, edema, and skin rash. The most common psychological symptoms were euphoria, depersonalization, and confusion with “effects similar to organic brain syndromes from corticosteroids” (Arora & Daughton, 2007; Chen, 1981). There is increasing reliance of the general population on complementary and alternative treatments for general wellness and medical conditions. While offering significant health benefits, the risks of herbal medicines in certain populations are not fully known. Standardized dosing and bioactivity is lacking in over the counter herbal preparations. Herbal therapy use should be routinely elicited for all patients, and considered in the evaluation of individuals who present with acute mental
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status changes. Risk factors may include: triggering of an underlying diathesis for affective disorder, pre-existing health conditions, drug–herb interactions, excess intake, or concomitant illicit substance use. An herbal medicine history should be considered during the assessment of patients with acute mental status changes. A low index of suspicion towards herbal remedies and omission of an herbal medicine history would contribute to serious side effects from ginseng being misattributed to other causes, and therefore, not reported to monitoring agencies or in the literature. Further research to better understand the pharmacological activity and develop clinical guidance for optimizing the use of herbal medicines is needed. Declaration of interest: The authors report no conflict of interest. The authors alone are responsible for the content and writing of this paper. We confirm this statement as true. ABOUT THE AUTHORS Lisa J Norelli, MD, MPH, Capital District Psychiatric Center, 75 New Scotland Avenue, Albany, 12208 United States, Albany Medical College, Department of Psychiatry, Albany, New York, USA, SUNY Albany School of Public Health, Rensselaer, New York, USA. Chunying Xu, Albany Medical College, Department of Psychiatry, 47 New Scotland Avenue, Albany, 12208 United States. REFERENCES Ang-Lee MK, Moss J, Yuan CS. Herbal medicines and perioperative care. JAMA. 2001;286:208–216. Arora M, Daughton J. Mania in the medically ill. Curr Psychiatry Rep. 2007;9:232–235. Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine use among adults and children: United States, 2007. National Health Statistics Reports; No. 12. Hyattsville, MD: National Center for Health Statistics. 2008. Buettner C, Yeh GY, Phillips RS, Mittleman MA, Kaptchuk TJ. Systematic review of the effects of ginseng on cardiovascular risk factors. Ann Pharmacother. 2006;40:83–95. Chen, KJ. The effect and abuse syndrome of Ginseng. J Tradit Chin Med. 1981;1:69–72. Chen XW, Sneed KB, Pan SY, Cao C, Kanwar JR, Chew H, Zhou SF. Herb-drug interactions and mechanistic and clinical considerations. Curr Drug Metab. 2012;13:640–651. Choi J, Kim TH, Choi TY, Lee MS. Ginseng for health care: A systematic review of randomized controlled trials in Korean literature. PLoS One. 2013;(8)4:e59978:1–14. Coon JT, Ernst E. Panax ginseng: a systematic review of adverse effects and drug interactions. Drug Saf. 2002;25:323–344. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990–1997: Results of a follow-up national survey. JAMA. 1998;280:1569–1575. Eisenberg DM, Kessler RC, Foster C, Norlock FE, Calkins DR, Delbanco TL. Unconventional medicine in the United States. Prevalence, costs, and patterns of use. N Engl J Med. 1993;328:246–252. Ernst E. Panax ginseng: an overview of the clinical evidence. J Ginseng Res. 2010;34:259–263. ´ Gonzalez-Seijo JC, Ramos YM, Lastra I. Manic episode and ginseng: report of a possible case. J Clin Psychopharmacol. 1995;15:447–448. Goodwin FK, Jamison KR. (2007) Chapter 14 Neurobiology, In: Manic depressive illness: bipolar disorders and recurrent depression (2nd ed.). New York: Oxford University Press. Harris P, Rees R. The prevalence of complementary and alternative medicine use among the general population: a systematic review of the literature. Complement Ther Med. 2000;8:88–96.
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Hiai S, Yokoyama H, Oura H, Yano S. Stimulation of pituitary adrenocortical system by ginseng saponin. Endocrinol Jpn. 1979;26(6):661–665. Hur MH, Lee MS, Yang HJ, Kim C, Bae IL, et al. Ginseng for reducing the blood pressure in patients with hypertension: a systematic review and meta-analysis. J Ginseng Res. 2010;34:342–347. Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs: an updated systematic review. Drugs. 2009;69:1777–1798. Janetzky K, Morreale AP. Probable interactions between warfarin and ginseng. Am J Health Syst Pharm. 1997;54:692–693. Jang DJ, Lee MS, Shin BC, Lee YC, Ernst E. Red ginseng for treating erectile dysfunction: a systematic review. Br J Clin Pharmacol. 2008;66:444–450. Jones BD, Runikis AM. Interaction of ginseng with phenelzine. J Clin Psychopharmacol. 1987;7:201–202. Kim S, Shin BC, Lee MS, Lee H, Ernst E. Red ginseng for type 2 diabetes mellitus: a systematic review of randomized controlled trials. Chin J Integr Med. 2011;17: 937–944. Kleiner SM. The true nature of herbs. Phys Sports Med. 1995;23:13–14. Krauthammer C, Klerman GL. Secondary mania: Manic symptoms associated with antecedent physical illness or drugs. Arch Gen Psychiatry. 1978;35:1333–1339. Lee NH, Son CG. Systematic review of randomized controlled trials evaluating the efficacy and safety of ginseng. J Acupunct Meridian Stud. 2011;4:85–97. Lee MS, Yang EJ, Kim JI, Ernst E. Ginseng for cognitive function in Alzheimer’s disease: a systematic review. J Alzheimers Dis. 2009;18:339–344 Lian-Wen Qi, Chong-Zhi Wang, Guang-Jian Du, Zhi-Yu Zhang, Tyler Calway, Chun-Su Yuan. Metabolism of ginseng and its interactions with drugs. Curr Drug Metab. 2011;12: 818–822. Price LH, Charney DS, Heninger GR. Three cases of manic symptoms following yohimbine administration. Am J Psychiatry. 1984;141:1267–1268. Shergis JL, Zhang AL, Zhou W, Xue CC. Panax ginseng in randomized controlled trials: a systematic review. Phytother Res. 2013;27(7):949–965. Siegal RK. Ginseng abuse syndrome. Problems with the panacea. JAMA. 1979;241:1614–1615. Vazquez I, Aguera-Ortiz LF. Herbal products and serious effects: a case of ginseng-induced manic episode. Acta Psychiatr Scand. 2002;105:76–77. Vogler BK, Pittler MH, Ernst E. The efficacy of ginseng: a systematic review of randomised clinical trials. Eur J Clin Pharmacol. 1999;55:567–575. Vuksan V, Sievenpiper JL, Koo VY, et al. American ginseng (Panax quinquefolius L) reduces postprandial glycemia in nondiabetic subjects and subjects with type 2 diabetes mellitus. Arch Intern Med. 2000;160:1009–1013. Winslow LC, Kroll DJ. Herbs as medicines. Arch Intern Med. 1998;158:2192–2199. Wong AH, Smith M, Boon HS. Herbal remedies in psychiatric practice. Arch Gen Psychiatry. 1998;55:1033–1044.
ARTICLE
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Manic Psychosis Associated With Ginseng: A Report of Two Cases and Discussion of the Literature Lisa J. Norelli, MD, MPH1,2,3 & Chunying Xu2 1
Capital District Psychiatric Center, Albany, New York, USA, 2 Department of Psychiatry, Albany Medical College, Albany, New York, USA, 3 Department of Epidemiology and Biostatistics, SUNY Albany, School of Public Health, Rensselaer, New York, USA ABSTRACT. Background: Herbal medicine use, highly prevalent in the general population, is often a neglected component of the medical history. Herbs are presumed safe because they are “natural” self-care products. We call attention to the following issues: Panax ginseng, one of the most frequently used herbal medicines, has complex pharmacological activity, and can be associated with severe psychiatric symptoms. Physicians may be unfamiliar with herbal therapy risks, and the need for further education and systematic research is highlighted. Objective: To describe two cases of new onset manic psychoses associated with high dose, chronic ginseng use, and review the relevant literature. Case reports: A 23-year-old man developed acute mania after one month of daily ginseng use and intermittent cannabis use. A 79-year-old man developed hypomania while using ginseng and yohimbine for erectile dysfunction, and had a recurrence of mania after stopping yohimbine but increasing his daily intake of ginseng. Conclusions/Summary: Symptoms of mania fully remitted within days upon discontinuation of ginseng and supportive treatment. Available data prevent a clear determination of causation; however, ginseng-induced mania in the these and previous case reports is suggested by the following: patients had no prior psychiatric history, daily use of ginseng was temporally associated with mania onset, patients ingested much higher doses for a longer duration than recommended in Traditional Chinese Medicine (TCM), and withdrawal of ginseng led to rapid remission. Generally well tolerated, many physicians are unaware that ginseng may be associated with acute and significant psychiatric disturbances for certain at-risk individuals. KEYWORDS. complementary therapies, ginseng, herbal medicine, mania, panax ginseng, psychiatric disorders
INTRODUCTION Complementary and alternative treatments are increasingly prevalent among the general population worldwide (Winslow & Kroll, 1998; Harris & Rees, 2000; Barnes et al., 2008; Eisenberg et al., 1993; Eisenberg, Davis, & Ettner, 1998; Wong, Address correspondence to: Dr Lisa J Norelli, MD, MPH, Capital District Psychiatric Center, 75 New Scotland Avenue, Albany, NY 12208, USA (E-mail: [email protected]) (Received 5 July 2013; accepted 3 December 2013)
1
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Smith, & Boon, 1998). Humans have exploited the therapeutic effects of herbal preparations for thousands of years, and about a third of modern drugs are derived from plants (Winslow & Kroll, 1998; Kleiner, 1995). Despite widespread use and complex bioactivity, most herbal therapy users do not inform their physicians of this fact, nor do many physicians routinely elicit this history (Winslow & Kroll, 1998; Eisenberg et al., 1993; Eisenberg et al., 1998). People presume that herbal preparations are safe because they are “natural” self-care products, and physicians may be unaware of the potential health risks. Anecdotal reports of significant adverse effects and drug–herb interactions exist in the medical literature; however systematic research and guidance is limited regarding the optimal use of herbal medicines alone and in combination with Western medical approaches (Izzo & Ernst, 2009; Chen, Sneed, & Pan, 2012). Considered safe for the majority of people because most adverse effects appear to be minor, significant clinical problems occur in some individuals (Izzo & Ernst, 2009; Chen et al., 2012; Lian-Wen et al., 2011; Goodwin & Jamison, 2007; Krauthammer & Klerman, 1978; Arora & Daughton, 2007; Vazquez & Aguera-Ortiz, 2002). Panax ginseng, (whose Latin genus name reflects the notion that ginseng is a panacea or cure all) is used in Traditional Chinese Medicine (TCM) for enhancing wellness, vitality, and treating a multitude of ailments. Ginseng is now one of the most commonly used herbal supplements in the West. However, it has complex pharmacological activity and has been associated with significant psychiatric symptoms including insomnia, agitation, pressured speech, euphoria, psychosis, depression, depersonalization, and confusion. (Harris & Rees, 2000; Barnes et al., 2008; Eisenberg et al., 1993; Eisenberg et al., 1998; Izzo & Ernst, 2009; Chen et al., 2012; Lian-Wen et al., 2011; Goodwin & Jamison, 2007; Krauthammer & Klerman, 1978; Arora & Daughton, 2007; Vazquez & Aguera-Ortiz, 2002; Gonzlez-Seijo, Ramos, & Lastra, 1995; Ernst, 2010). Acute mania appears to be an uncommon, though possibly underrecognized, adverse reaction to ginseng. Manic episodes observed as a feature of the psychiatric illness bipolar disorder are characterized by family history of affective disorder, onset in young adulthood, with episodes of hypomania, mania, and depression in the absence of known underlying causes. The underlying pathophysiology of mania is not fully known, but dsyregulation of monoamine neurotransmitter, neuroendocrine (including the hypothalamic–pituitary–adrenal axis) and neuropeptide systems have been implicated. (Goodwin & Jamison, 2007) A manic episode due to an organic cause is referred to as secondary mania (Krauthammer & Klerman, 1978; Arora & Daughton, 2007). Secondary mania may be induced or precipitated by drug intoxication, drug withdrawal, endocrine dysfunction, nutritional deficiency, neurodegenerative disorders, traumatic brain injury, infection, metabolic disturbances, neoplasm, and seizure disorders. (Krauthammer & Klerman, 1978; Arora & Daughton, 2007) See Table 1 for common causes of secondary mania. We highlight these issues by describing two patients who presented with acute manic psychosis associated with ginseng use. METHODS The biomedical literature was searched using PubMed and the following keywords: ginseng, Panax ginseng, adverse effects, herbal medicine, psychiatric disorders,
Manic Psychosis Associated With Ginseng
3
TABLE 1. Common Etiologies of Secondary Mania General Medical Conditions Infection Trauma Tumor Cardiovascular disease Metabolic disturbance
J Dietary Suppl Downloaded from informahealthcare.com by Laurentian University on 11/23/14 For personal use only.
Nutritional deficiency Neurological disorders
HIV, encephalitis, sepsis, urinary tract infection, influenza, pneumonia, syphilis Subdural hematoma, cerebral contusions, traumatic brain injury Central Nervous System (parasagittal meningioma, diencephalic tumors) Congestive heart failure, infarction, embolism, vasculitis Renal failure, hepatic failure, post-ictal states, electrolyte disturbances, hemodialysis, post-surgical states Vitamin B12 , folate deficiency Demyelinating diseases, Parkinson’s Disease, Huntington’s Disease, Wilson’s Disease, multiple sclerosis, stroke, seizure (right temporal focus) Medications and Drugs
Drug intoxication or withdrawal Medications or drugs
Nicotine, caffeine, alcohol, sedative-hypnotics, cocaine, amphetamines, phencyclidine, opioids, hallucinogens Corticosteroids, metoclopramide, H2 -receptor antagonists, antihypertensives, levodopa, isoniazid, disulfiram, cyclosporine, cimetidine, captopril, baclofen, bromocriptine, antipsychotics, antidepressants, sedative-hypnotics, yohimbine, stimulants (e.g., methyphenidate, amphetamines)
Ref: Krauthammer & Klerman, 1978; Arora & Daughton, 2007.
mania, psychosis, drug–herb interactions. Two case report articles were found describing ginseng-induced mania (Vazquez & Aguera-Ortiz, 2002; Gonzlez-Seijo et al., 1995). Six systematic reviews examined the general safety and efficacy of ginseng, including one article that included Korean randomized controlled trials that are not indexed in PubMed (Ernst, 2010; Lee & Son, 2011; Coon & Ernst, 2002; Choi, Kim, Choi, & Lee, 2013; Vogler, Pittler, & Ernst, 1999; Shergis, Zhang, Zhou, & Xue, 2013; Lee & Son, 2011). Two articles systematically reviewed cardiovascular benefits, one reviewed efficacy for erectile dysfunction, one for type 2 diabetes mellitus, and one on cognitive deficits in Alzheimer’s disease (Hur, Lee, Yang, Kim, & Bae, 2010; Buettner, Yeh, Phillips, Mittleman, & Kaptchuk, 2006; Jang, Lee, Shin, Lee, & Ernst, 2008; Lee, Yang, Kim, & Ernst, 2009; Kim, Shin, Lee, Lee, & Ernst, 2011). Four articles reviewed current knowledge regarding herb–drug interactions (Izzo & Ernst, 2009; Chen et al., 2012; Lian-Wen et al., 2011; Coon & Ernst, 2002). Two articles reported on the phenomenon of ginseng abuse syndrome (Chen, 1981; Jones & Runikis, 1987). Case Descriptions Case 1: A 23-year-old single, Caucasian man presented for emergency evaluation. His family reported he had severe insomnia, bizarre behavior (e.g., drinking water out of potholes in the street), and was uncharacteristically irritable and restless for two days. There was no prior history of mental illness in the patient or first-degree relatives. Mental status examination was significant for increased psychomotor activity, pacing, pressured speech, racing thoughts, anxious and irritable mood, labile affect, disorganized thought process, and almost constant distraction by
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auditory hallucinations. He was alert and fully oriented. Physical examination and laboratory tests were significant for mild dehydration, and mild elevation of heart rate, blood pressure, and temperature. Urine toxicology and blood alcohol levels were negative. Supportive care and treatment with risperidone 1 mg daily for three days led to remission of all symptoms. At subsequent interview, the patient admitted to intermittent cannabis use for years and the use of large quantities of Asian red ginseng every day for the month prior to this episode to boost his energy levels. He prepared red ginseng herbal soup from a TCM recipe, and we estimate that he was ingesting about 15 grams of ginseng daily, or about seven times the recommended TCM dose (typically 1–3 g daily in divided doses for 5–7 days). Case 2: A 79-year-old African-American man presented for emergency evaluation of increasingly peculiar thoughts and behaviors over the past week. His family reported that he was constantly distressed, nervous, and exhibiting inappropriate behavior such as calling the police to report “too much pollen in the air.” Mental status examination revealed motor restlessness, pressured speech, anxious mood, labile affect, racing thoughts, disorganized thought process, and paranoid ideas. He was alert and fully oriented. There was no history of alcohol or substance use. Physical examination was otherwise normal except for mild hypertension. Urine toxicology and blood alcohol levels were negative. Symptoms fully remitted within one week with supportive treatment and a short course of antipsychotic medication. Two months prior, the patient had been diagnosed with a substanceinduced hypomanic episode attributed to yohimbine, self-administered for erectile dysfunction. The hypomanic symptoms resolved upon yohimbine discontinuation. However, on subsequent interview, the patient admitted to daily use of Korean red ginseng for years. He reported upon stopping the yohimbine, to compensate he increased the ginseng dose repeatedly during the two months prior to this episode to treat erectile dysfunction. He consumed a condensed drink of ginseng boiled in water 3–4 times per day. We estimate that he ingested approximately 20 g of ginseng daily, or about ten times the usual TMC dose (typical range 1–3 g daily in divided doses for 5–7 days). DISCUSSION These two cases and the other case reports in the literature suggest an association of secondary mania due to ginseng toxicity, ginseng abuse syndrome, or a drug–herb interaction (Vazquez & Aguera-Ortiz, 2002; Gonzlez-Seijo et al., 1995; Siegal, 1979; Chen, 1981). The first patient’s episode was associated with daily high dose ginseng ingestion in combination with episodic cannabis use. The rapid remission of symptoms upon discontinuation of both substances, and the lack of similar symptoms with past cannabis use alone suggests that ginseng was contributory. The second patient had an earlier episode of hypomania attributed to yohimbine, which reportedly resolved upon discontinuation. However, he presented with more florid manic symptoms after a compensatory increase in his daily ginseng dose. Manic symptoms have been associated with yohimbine alone; however ginseng use was a common factor in both episodes (Arora & Daughton, 2007; Price, Charney, & Heninger, 1984). Furthermore, the second, more severe episode was associated
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with increased and high dose ginseng ingestion daily, suggestive of a dose-response effect. Both patients used an estimated 7–10 times the daily dose, and 4–8 times the duration recommended in TCM recipes. These doses are consistent with previous reports of ginseng abuse syndrome (Siegal, 1979; Chen, 1981). Notably, in both cases the initial clinical assessment did not include an herbal therapy history and the treating physicians were unfamiliar with the adverse effects of ginseng. Ginseng was not initially recognized as a potentially contributory or causative factor to either patient’s acute mental status changes. Herbal remedies termed “ginseng” are derived from the roots of one or more different species of plants. These mainly include Panax ginseng (also known as Asian ginseng, or red ginseng, white ginseng, fresh ginseng depending on root age and preparation), Panax quinquefolius (American ginseng), and Eleutherococcus senticosus (Siberian ginseng). TCM uses Panax ginseng as an “adaptogen” as a stimulant to enhance physical and mental performance, longevity, vitality, resistance to stress, and as an aphrodisiac. A family of steroidal saponins, termed ginsenosides, mediates ginseng’s complex pharmacological activity Ginseng is also used to treat a wide variety of medical conditions including cardiovascular disease, cancer, diabetes, cognitive dysfunction, and erectile dysfunction (Ernst, 2010; Lee & Son, 2011; Choi et al., 2013; Vogler et al., 1999; Shergis et al., 2013; Lee & Son, 2011; Hur et al., 2010; Buettner et al., 2006; Jang et al., 2008; Lee et al., 2009; Kim et al., 2011). Ginseng is believed to have modulating effects on carbohydrate metabolism, lipids, immunity, cognition, coagulation pathways, as well as potential neuroprotective, and antineoplastic activity (Choi et al., 2013; Vogler et al., 1999; Shergis et al., 2013; Lee & Son, 2011; Hur et al., 2010; Buettner et al., 2006; Jang et al., 2008; Lee et al., 2009; Kim et al., 2011). Serious side effects are rarely reported in the literature, with the most commonly reported side effects being nervousness and hypertension (Choi et al., 2013; Lee & Son, 2011; Siegal, 1979; Chen, 1981). Ginseng can exert hypoglycemic effects, prolong coagulation time, stimulate hypothalamic–pituitary–adrenocorticoid (HPA) function, decrease platelet aggregation activity, and alter the activity of other medications and substances (Izzo & Ernst, 2009; Chen et al., 2012; Coon & Ernst, 2002; Jones & Runikis, 1987; Ang-Lee et al., 2001; Janetzky & Morreale, 1997; Hiai, Yokoyama, Oura, & Yano, 1979). Depression, mania, and psychosis have been reported, and mania has been associated with concomitant use of ginseng and phenelzine (Siegal, 1979; Chen, 1981; Jones & Runikis, 1987). Ginseng abuse syndrome, attributed to excessive long term doses of up to 15 g per day, has been described (Siegal, 1979; Chen, 1981) Physical symptoms include palpitations, hypertension, dizziness, insomnia, agitation, nausea, vomiting, abdominal pain, diarrhea, gastrointestinal bleeding, edema, and skin rash. The most common psychological symptoms were euphoria, depersonalization, and confusion with “effects similar to organic brain syndromes from corticosteroids” (Arora & Daughton, 2007; Chen, 1981). There is increasing reliance of the general population on complementary and alternative treatments for general wellness and medical conditions. While offering significant health benefits, the risks of herbal medicines in certain populations are not fully known. Standardized dosing and bioactivity is lacking in over the counter herbal preparations. Herbal therapy use should be routinely elicited for all patients, and considered in the evaluation of individuals who present with acute mental
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status changes. Risk factors may include: triggering of an underlying diathesis for affective disorder, pre-existing health conditions, drug–herb interactions, excess intake, or concomitant illicit substance use. An herbal medicine history should be considered during the assessment of patients with acute mental status changes. A low index of suspicion towards herbal remedies and omission of an herbal medicine history would contribute to serious side effects from ginseng being misattributed to other causes, and therefore, not reported to monitoring agencies or in the literature. Further research to better understand the pharmacological activity and develop clinical guidance for optimizing the use of herbal medicines is needed. Declaration of interest: The authors report no conflict of interest. The authors alone are responsible for the content and writing of this paper. We confirm this statement as true. ABOUT THE AUTHORS Lisa J Norelli, MD, MPH, Capital District Psychiatric Center, 75 New Scotland Avenue, Albany, 12208 United States, Albany Medical College, Department of Psychiatry, Albany, New York, USA, SUNY Albany School of Public Health, Rensselaer, New York, USA. Chunying Xu, Albany Medical College, Department of Psychiatry, 47 New Scotland Avenue, Albany, 12208 United States. REFERENCES Ang-Lee MK, Moss J, Yuan CS. Herbal medicines and perioperative care. JAMA. 2001;286:208–216. Arora M, Daughton J. Mania in the medically ill. Curr Psychiatry Rep. 2007;9:232–235. Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine use among adults and children: United States, 2007. National Health Statistics Reports; No. 12. Hyattsville, MD: National Center for Health Statistics. 2008. Buettner C, Yeh GY, Phillips RS, Mittleman MA, Kaptchuk TJ. Systematic review of the effects of ginseng on cardiovascular risk factors. Ann Pharmacother. 2006;40:83–95. Chen, KJ. The effect and abuse syndrome of Ginseng. J Tradit Chin Med. 1981;1:69–72. Chen XW, Sneed KB, Pan SY, Cao C, Kanwar JR, Chew H, Zhou SF. Herb-drug interactions and mechanistic and clinical considerations. Curr Drug Metab. 2012;13:640–651. Choi J, Kim TH, Choi TY, Lee MS. Ginseng for health care: A systematic review of randomized controlled trials in Korean literature. PLoS One. 2013;(8)4:e59978:1–14. Coon JT, Ernst E. Panax ginseng: a systematic review of adverse effects and drug interactions. Drug Saf. 2002;25:323–344. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990–1997: Results of a follow-up national survey. JAMA. 1998;280:1569–1575. Eisenberg DM, Kessler RC, Foster C, Norlock FE, Calkins DR, Delbanco TL. Unconventional medicine in the United States. Prevalence, costs, and patterns of use. N Engl J Med. 1993;328:246–252. Ernst E. Panax ginseng: an overview of the clinical evidence. J Ginseng Res. 2010;34:259–263. ´ Gonzalez-Seijo JC, Ramos YM, Lastra I. Manic episode and ginseng: report of a possible case. J Clin Psychopharmacol. 1995;15:447–448. Goodwin FK, Jamison KR. (2007) Chapter 14 Neurobiology, In: Manic depressive illness: bipolar disorders and recurrent depression (2nd ed.). New York: Oxford University Press. Harris P, Rees R. The prevalence of complementary and alternative medicine use among the general population: a systematic review of the literature. Complement Ther Med. 2000;8:88–96.
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