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Psychiatric Complications of Ma-Huang

Received January 28, 1999; revised March 12, 1999; accepted April 13, 1999. From the Departments of Mental Health Services and Clinical Investigation, Naval Medical Center San Diego, California. Address correspondence and reprint requests to Dr. Jacobs, Clinical Investigation Department, Medical Editing Division, Naval Medical Center San Diego, 34800 Bob Wilson Drive, Suite 5, San Diego, CA 92134–1005; e-mail: wmacal{at}snd10.med.navy.mil

Key Words: Herbal Medicines • Ma-huang • Side Effects • Case Reports

The use of dietary supplements containing Ma-huang, an extract of the plant species Ephedra, has caused a significant rise in adverse health consequences attributable to the sympathomimetic and central stimulant properties of ephedrine, its active ingredient.

Ma-huang, a noncontrolled substance, has been used in traditional Chinese medicine since ancient times as a stimulant and as a remedy for asthma.¹ Between 1993 and 1997, the Food and Drug Administration (FDA) received notices of 34 deaths and about 800 medical and psychiatric complications directly linked to Ma-huang.² This trend reflects the increased use of the herbal medicines and dietary supplements. The sales of these drugs were $3.3 billion in 1990 and $6.5 billion in 1996.² Parallel national surveys of American use of alternative medicines estimated that the use of herbal remedies increased by 380% from 1990 to 1997. In 1997, 15 million adults in the United States used herbal remedies and/or high-dose vitamins together with prescribed medications.³

Herbal or botanical preparations are widely available, relatively inexpensive, and often attractively packaged to appeal to adolescents and young adult consumers.⁴ These preparations can be bought at rock concerts, via the Internet, in convenience stores, sports clubs, and shopping malls. Ma-huang–containing products with names such as "Herbal Ecstasy," "Nature's Sunshine," "Metabolift," and "Ripped Fuel" promise a "natural" means to improve health, increase energy and sexual functioning, obtain a legal "high," and to lose weight and build muscle.

In a recent review of the literature, Crone and Wise⁵ summarized the traits of alternative-medicine consumers, noting that they tend to be Caucasian, well-educated, employed, female, young-to-middle–aged, and "aware of the importance of a healthly lifestyle." According to Kaptchuk and Eisenberg,⁶ alternative medicine appeals to devotees who share the belief that the "innocence" and "benevolence" of nature is preferable to biomedicine that is, in contrast, associated with sophistication and technology and is therefore artificial and synthetic. These consumers may erroneously equate "natural" with safe.

The psychiatric complications linked to Ma-huang include psychosis and affective disturbances, akin to reactions previously observed in patients who misused asthma medications containing ephedrine. Herridge and O'Brook⁷ first described ephedrine-induced psychosis in 1968. Later reports of ephedrine-induced psychosis as well as mania occurred under three main circumstances: 1) abuse of over-the-counter asthma medications in otherwise psychiatrically well individuals,⁸ 2) abuse of ephedrine for its central nervous system-stimulant properties alone,^9,10 and 3) Ma-huang combined with other stimulants.¹¹ A recent case report described Ma-huang in a food supplement for weight loss that induced psychosis in a patient without a prior psychiatric history.¹²

The psychiatric features included psychotic and affective changes. Herridge and O'Brook noted that ephedrine and amphetamine induced a similar psychosis: paranoia with a clear sensorium.⁷ One patient had "florid and turbulent acute paranoid psychosis of some 2 months' duration," with visual hallucinations of "flashing lights."⁷ Roxanas⁹ reported the cases of one patient with auditory hallucinations and "delusions of persecution and of grandeur" and another patient with "markedly accelerated speech, tangential thinking, and paranoid delusions." Affective change included "extreme anger and hostility" and "depression with paranoid features."⁷ One case report noted mania characterized by irritability, uncharacteristic aggressiveness, and pressured speech.¹² In a review of 20 cases of ephedrine-induced psychosis, Whitehouse and Duncan⁸ noted that all patients experienced delusions, 90% had auditory hallucinations, and 45% visual hallucinations. Affective disturbance was present in 30% of the patients, and agitation with insomnia was present in 55% of the patients. Eighty-five percent of the patients presented with a clear consciousness.

Ephedrine psychosis, however, is time-limited and ranges from days to weeks in duration with supportive treatment. In Herridge and O'Brook's original case description of a 65-year-old hostile and paranoid man, the psychosis "evaporated" within 4 days of inpatient hospitalization.⁷ There is no mention of pharmacotherapy. A 26-year-old man, reported by Roxanas,⁹ was admitted with paranoid delusions, auditory hallucinations, ideas of reference, and "passivity feelings." Trifluoroperazine (5 mg po tid) and phenytoin sodium (100 mg po tid) alleviated his symptoms within 5 days, and antipsychotics were stopped. In a more recent case, a 45-year-old man presented to an emergency room with manic symptoms. He was treated as an outpatient by discontinuing Ma-huang and starting trazodone (50 mg po qd) for sedation. He returned to his normal premorbid condition within 4 days.¹²

Despite the limited time course of ephedrine-induced psychiatric disturbances, psychosocial consequences for patients can be severe. The following cases occurred in two young adult, active-duty Marines and illustrate the potential for significant morbidity and occupational consequences from using supplements containing Ma-huang.

Case Reports

Case 1. A single, 27-year-old male Marine sergeant with suicidal ideation and irritable mood presented to the emergency department (ED) of a tertiary military medical center. He had made an error in judgment while working as an avionics technician, became uncharacteristically agitated, and threatened to go home and kill himself.

Although he had no history of suicidality, he had a history of depression 1 year prior to presentation and a 2-week trial of treatment with sertraline (50 mg po qd). The patient had discontinued the medication because he was averse to taking prescribed medications. He was later lost to follow-up. There was no history of illicit drug or alcohol use. An excellent worker, he had no previous legal problems, had never been disciplined, and had been recognized by his command as an excellent worker. There was, however, a maternal family history of depression. The patient had no significant medical or surgical history. The physical examination was normal.

At admission, the patient complained of a 3-month history of "depression" characterized by tearfulness, feeling "overwhelmed," poor concentration, "thinking about too many things at once," irritability, guilt, and suicidal thoughts. He denied any disturbance of appetite, sleep, or energy. He endorsed episodes of "euphoria" lasting no longer than 3 days, but he denied flight of ideas, reckless behavior, or increased libido. Mental status examination was significant for depressed and tearful affect. The patient was guarded, but without psychosis or mania. Cognition was intact. A toxicological screen was normal, and routine admission labs, including complete blood cell count, thyroid-stimluating hormone, VDRL (test for syphilis), serum electrolytes, and urinalysis, were also normal. The patient agreed to inpatient psychiatric treatment, but on the day after admission, he requested discharge. There were insufficient criteria for involuntary commitment, and he was discharged.

Over the ensuing 5 months, the patient was followed in the outpatient clinic. He received 2- to 3-week trials each of bupropion (sustained release: 150 mg po bid), paroxetine (20 mg po qd), and fluoxetine (20 mg po qd) for treatment of depressive disorder not otherwise specified, but he discontinued each medication because of increased irritability or sedation. His irritability and agitation persisted, and he threatened a superior and was removed from his work station. In the ED, he received clonazepam. He voiced his poor opinion of allopathic medicine and expressed his preference for "natural" and non-Western treatments. When questioned directly, the patient revealed a 2-year history of regular use of two Ma-huang–containing supplements to enhance his workout performance. He was, however, guarded about the quantity and frequency of his use. The risks of psychiatric symptoms were discussed with him, and discontinuing these products was suggested. The patient refused and did not follow-up in the psychiatric clinic. He continued follow-up with a general physician who was a flight surgeon. Facing potential dismissal due to maladaptive behavior, the patient agreed to stop his use of Ma-huang. Mood returned to baseline, and he returned to full duty without further psychiatric intervention.

Case 2. A 20-year-old, single, male, Marine private first-class, with no prior psychiatric history, was evacuated from his ship in the Persian Gulf for evaluation of "acute psychosis and agitation." The patient had developed ideas of reference while watching a televised movie. When others failed to rally around him to "rescue" the film characters, he became agitated and destroyed the television set. The patient had no significant past medical or surgical history. The maternal family history was positive for depression. The patient had visited a school counselor for fighting while in junior high school. After high school, he enlisted in the Marines and had been disciplined once for fighting and lost a rank. He had no history of illicit drug use. He occasionally drank alcohol, but had no history of adverse consequences from his drinking.

The ship's psychologist noted "acute psychosis and agitation," and the patient was evacuated to another ship, where the ship's surgeon diagnosed "psychotic disorder, paranoid type" and administered midazolam prior to evacuation of the patient to a shore-based hospital in Bahrain. There, a head CT (computed tomography) scan was normal, and haloperidol (5 mg tid) was started. Over the ensuing 2 weeks, the patient was transported to a U.S. military hospital in California, near his parent command. En route, haloperidol was stopped because of dystonia, and both olanzapine (10 mg po qhs) and benztropine mesylate (1.0 mg bid) were started.

Three weeks after initial presentation, the patient was admitted to our facility. He complained of an "imbalance in my head," which he attributed to "working out too hard" while simultaneously preparing for a required written examination. Starting several months before his initial presentation, he had been ingesting two Ma-huang–containing dietary supplements, together with ginseng, DHEA (dehydroepiandrosterone), creatine monohydrate, and copious amounts of coffee. He complained of markedly decreased concentration. He denied sleep disturbance, but had increased appetite, which he attributed to increased exercise. He denied depressed mood and suicidal or homicidal ideation. Physical examination was normal. On mental status examination, sensorium was clear, and mood was described as "unsure." Affect was restricted, irritable, and fearful. The patient displayed no spontaneous humor, and thought process was circumstantial, with looseness of associations. The patient denied auditory, visual, or tactile hallucinations.

The patient was treated on the closed inpatient psychiatric ward for 7 days, during which his behavior in the milieu improved, as noted by reduced agitation and improved social interaction. He was observed for 1 additional day on the open psychiatric unit, then discharged for outpatient follow-up. He continued to display looseness of association and poor insight. The treating psychiatrist recommended and initiated medical retirement from the Marines. Over the following 3 months, the patient's mental status returned to normal, antipsychotic medication was discontinued, and he returned to full duty.

DISCUSSION

The traditional source of Ma-huang is the small, widely distributed evergreen shrub Ephedra. The total ephedrine alkaloid content varies by Ephedra species. The Asian species E. equisetina (Bunge), E. sinica (Stapf.), E. intermedia (Schrenk, CA Meyer), and E. geradiana Wall (ex Stapf.) contain the highest concentration of alkaloids, whereas the North American species E. nevadenis, common name "Mormon Tea," contains no significant amounts of alkaloid.^1,13

Chen and Schmidt¹⁴ first demonstrated ephedrine's sympathomimetic properties after its isolation from Ephedra at the turn of the century. The Japanese were the first to market ephedrine-based asthma treatment.⁹ Ephedrine remained a popular asthma treatment in the West until the development of more specific beta-agonist agents.⁸

The chemical structure of ephedrine resembles amphetamine, which was initially synthesized as a synthetic ephedrine substitute.⁸ The systemic effects of ephedrine include increased peripheral resistance, increased heart rate, increased blood pressure, urinary retention (due to alpha-agonist activity at smooth muscle receptors in the bladder), and bronchodilation (due to agonism of adrenergic receptors in the lungs). This last effect is the basis for ephedrine's use to treat asthma.¹⁵ The physical signs following ephedrine administration include increased heart rate, blood pressure, respiratory rate, and body temperature. Ephedrine has not been observed to cause significant pupillary dilation.¹⁵

Pharmacodynamically, ephedrine has both direct agonism at alpha- and beta-adrenergic receptors, and indirect enhancement of the release of norepinephrine from axon terminals. After oral administration, ephedrine is excreted in the urine largely unchanged and has an elimination half-time of between 3 and 6 hours.¹⁵

Studies of dose-related, stereotypic behavior in rats as an indicator of central dopaminergic action suggest that ephedrine possesses central noradrenergic and dopaminergic actions.¹⁶ The euphoric and stimulant effects of ephedrine are generally less intense than those of amphetamines, but may be indistinguishable. Martin observed that a group of narcotic-dependent men could not distinguish between five centrally acting stimulants (amphetamine, methamphetamine, phenmetrazine, methylphenidate, and ephedrine) when administered in doses sufficient to produce similar objective and quantifiable responses.¹⁷ Ephedrine is generally regarded as harboring less potential for abuse and has never been a controlled substance. Chait measured the reinforcing and subjective effects of ephedrine in a group of adults with no history of drug dependence.¹⁸ Compared with amphetamine, Chait found that ephedrine was a less efficacious reinforcer and may be less likely to cause abuse.

In the early 1980s, responding to the widespread abuse of the so-called amphetamine "look-alike" drugs that are legally obtainable combinations of synthetic ephedrine, phenylpropanolamine, and caffeine,¹⁹ the FDA banned this "triple combination" entirely and later banned the sale of phenylpropanolamine/caffeine combinations without a new drug license.²⁰ Similarly, the FDA recognized the need for rules to improve the safety of food supplements containing Ma-huang, and in 1995 the FDA convened a working group of medical and scientific experts to address the issue.

The newly proposed rules for supplements containing Ma-huang would 1) prohibit supplements containing more that 8 mg of ephedrine per dose; 2) prohibit combinations of ephedrine with other stimulants (e.g., caffeine or yohimbine); 3) require product labels to specify that use not exceed 24 mg of ephedrine per 24 hours; and 4) require labels to warn against use for more than 7 days.² Such admonitions, however, are likely to engender very limited impact if not emphasized by clinicians.

Beyond these efforts at primary prevention, clinicians encountering patients with new psychiatric symptoms should regularly inquire about the use of food supplements. Patients should be encouraged to bring these products with them to the office to discuss the risks of continued use. Historical trends in patterns of use of similar agents suggest that increasing use of such agents may be expected—without patients' recognizing the potential adverse effects. In certain respects, therefore, such agents may in fact be more dangerous than illicit substances. Users of illicit substances can be cognizant of the more common adverse effects. This awareness is not true, however, of those using licit agents such as "nutritional supplements." Even after the supplements had produced clear psychiatric symptoms, the patients we described were unaware of their potential side effects until they had been "proven" experientially.

A history should include focused questions about the duration, quantity, frequency, and intent of using a nutritional supplement such as Ma-huang. Such questions can provide important clinical information that might not otherwise be identified by the patient and may reveal attempted self-medicating of diagnosable and treatable psychiatric conditions. For example, the patient who states that he began using the supplement because of poor energy, hypersomnia, and depressed mood may be self-treating symptoms of an undiagnosed primary medical or psychiatric disorder. Maintaining a supportive and nonaccusatory stance with the patient fosters a therapeutic alliance to facilitate possible treatment and a discussion of potential risks of continued supplement use.

The management of ephedrine-induced psychoses and mood disorders is primarily supportive. Psychotic symptoms and agitation may require treatment with antipsychotics, benzodiazepines, or a combination of the two. These medications should be titrated to provide the most effective dosing while minimizing side effects. Psychiatric hospitalization may be indicated in frank mania, severe psychosis, and potential suicidality or homicidality. A careful physical examination is important to assess for medical complications of Ma-huang, such as cardiac arrhythmias. After cessation of ephedrine, symptoms may persist for days to weeks or even months.

These cases underscore the potential risks that patients face when consuming herbal preparations that have psychotropic properties. Continued efforts are necessary to inform both physicians and consumers about such risks. Well-informed psychiatrists can play an important and primary role in 1) the diagnosis and treatment of psychiatric complications that may arise from the use of complementary pharmacotherapies, and 2) the prevention of these complications in the first place.

FOOTNOTES

This report was sponsored by the Chief, Bureau of Medicine and Surgery, Navy Department, Washington, DC, Clinical Investigation Program (;ns84-16-1968-834), as required by NSHSBETHINST 6000.41A.

The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. Government.

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