Part 2 of a series on potentially hazardous supplements
By Francis Brinker, ND
Editor’s Note—From time to time, Alternative Medicine Alert breaks from its typical format to present unique information requiring significant space. Such is the case this month, as one of the world’s foremost experts on herbal dietary supplements addresses issues of safety in the now infamous Consumer Reports "Dirty Dozen." While many, if not most, Alternative Medicine Alert readers do not routinely use the agents mentioned by Consumer Reports, it is nonetheless important to understand the distinctions between preparations and patterns of use. This is what most determines safe use vs. risk. In this regard, what is necessary in most cases is education and information involving appropriate label warning requirements (as opposed to universal bans). It is especially important to recognize the degree of scientific support, or lack thereof, behind such classifications of safe and unsafe.
— Russell H. Greenfield, MD, Medical Director, Carolinas Integrative Health Carolinas HealthCare System Charlotte, NC
The May 2004 issue of Consumer Reports (CR) designated 12 dietary supplements as hazardous.1 (See table.) One (aristolochic acid) was categorized by CR as definitely hazardous, while five (germander, comfrey, chaparral, kava, and androstenedione) were described as very likely hazardous. The first part of this review [see the August 2004 issue of Alternative Medicine Alert] confirmed the CR assessment of botanical products containing aristolochic acid and included germander preparations as definitely hazardous. The other four were described as potentially hazardous with long-term internal use. This categorization was based, with respect to the botanicals, on there being isolated cases of liver toxicity associated with long-term use of certain preparations of comfrey, chaparral, and kava. (There were also appropriate uses and benefits without evidence of significant adverse effects noted with short-term use of certain preparations of these three.) Finally, as a steroid precursor, androstenedione is intended for long-term consumption that influences circulating sex hormone levels. Substances like androstenedione are subject to abuse by athletes and may affect gender expression, especially in children and fetuses. For these reasons the federal government appears poised to ban such steroid precursors from the dietary supplement marketplace.
This second part reviews the six dietary supplements CR identified as likely hazardous. Based on the evidence and known pharmacology of these agents, four will be discussed as hazardous with acute excessive dosage. One of these contains an essential oil with known toxicity to the liver, while the other three contain alkaloids that affect both central and peripheral neural functions. Another two are deemed unlikely hazardous. As in Part 1, classifications compiled by competent herbalists and naturopathic doctors as published in the 1997 Botanical Safety Handbook (BSH) will be relied upon as a practical expert perspective on safety concerns for the five botanical products.2 Judgments expressed here as to the relative danger imposed by these botanical substances are based on the author’s 25 years of experience and study involving potentially toxic botanicals, including the publication in 1983 of the first edition of a clinical toxicology handbook on such preparations.3
Category 3: Hazardous with Acute Excessive Dosage
1. Pennyroyal oil (from Hedeoma pulegioides leaves and tops)
The CR article identifies pennyroyal oil as a product of the North American species Hedeoma pulegioides, but an equivalent oil with similar phytochemistry can be obtained from the European pennyroyal species, Mentha pulegium. Pennyroyal oil is a volatile distillate, often referred to as an aromatic or essential oil as distinct from vegetable oils used as food. Like other essential oils it is a potent concentrate, since it accounts for only 1-2% of the weight of the fresh plant.
In general, volatile components are mucosal irritants unless dispersed in a suitable vehicle like honey, vegetable oils, glycerine, or alcohol. These components are rapidly absorbed, metabolized, conjugated in the liver, and excreted by the kidneys. Some free volatiles are expelled in the lungs. The volume of a single drop of essential oil is about 0.05 mL, and the oral dosage range is usually 0.5-1.0 mL/d (10-20 drops daily) for adults and 0.15-0.3 mL/d (3-6 drops daily) for a 50 lb child. Essential oils should not be used systemically during pregnancy without professional supervision, but may be used as topical applications in concentrations of 2% or less. Essential oils should not be applied in or near the eyes, around the noses of children younger than 5 years of age, orally in those weighing less than 45 lbs, or topically in those younger than 2 years of age. Children are more prone to adverse effects from essential oils, and their skin tends to be more thin, sensitive, and permeable. Camphor, menthol, and eucalyptol (cineole), found in many plant essential oils and topical products, can produce serious mucosal irritation and central nervous system (CNS) dysfunction following inhalation by young children.3,4
The oil from American pennyroyal is 60-80% pulegone, compared to 55-95% pulegone in European pennyroyal. The acute oral lethal dose of pulegone in 50% of rats (LD50) is 0.5 g/kg, and the LD50 for the essential oil is 0.4 g/kg. In Europe, the proportion of pulegone allowed in food as flavoring is 0.025 g/kg. The purified essential oils of both pennyroyal species are considered severely toxic and should not be used therapeutically, either internally or externally.4 Pulegone is converted to toxic menthofuran by several cytochrome P450 isozymes in the liver.5 Amounts of the essential oil considered toxic are 4-10 mL, while lethal doses lie in the range of 15-30 mL.3
In 1975, the Food and Drug Administration (FDA) designated both species of pennyroyal as "generally recognized as safe."6 Adults may safely consume up to 10 g/d of the dried herb powder, but more commonly consumption involves 1-2 cups/d of a tea (made from one teaspoon herb per cup) or up to 10 mL/d of the tincture. These can be used on occasion either warm as a carminative to relax circular smooth muscle spasms for dyspepsia, or hot as a diaphoretic to induce sweating with colds. All pennyroyal preparations should be avoided during pregnancy,3,7 as well as in those with liver and kidney disease.3 The BSH acknowledges pregnancy as a contraindication for both species.2
Two cases of pennyroyal and/or pulegone-associated toxicity occurred with Hispanic infants in California given home-grown pulegone-containing mint teas for respiratory symptoms or colic. One infant aged 8 weeks suffered multiple organ failure and died after consumption of 4 oz of the tea; menthofuran was found in two serum samples. A 6-month old infant who had received 3 oz of the tea threes time weekly for three months suffered from lethargy, seizures, and liver failure but survived after two months of hospitalization. Pulegone and menthofuran were detected in the serum. No pulegone-containing herb preparations should be used with infants.8 Brook mint (Mentha arvensis), also known as field mint or poleo, grows along the Pacific coast and also contains pulegone, though in lesser amounts than the pennyroyal species.9
Around 1980, pennyroyal essential oils were taken in toxic doses in several unsuccessful attempts by women about 20 years old to induce abortions. Oral doses of 7.5 mL essential oil proved to be mildly toxic but an ineffective abortifacient in two women. They experienced nausea, vomiting, dizziness, and/or digital paresthesia, but no liver damage or sequelae were detected.10 Another woman ingested 10 mL pennyroyal oil as an abortifacient, having used pennyroyal leaves many times for inducing tardy menstruation with no ill effects. She became dizzy and was hospitalized for two days with normal physical and laboratory findings.11 Another woman used a teaspoon of pennyroyal leaves per cup of tea three times daily off and on for two weeks, in addition to three pennyroyal leaf capsules. After failing to menstruate she consumed 15 mL of pennyroyal oil and began vomiting within two hours. Following hospitalization and treatment with gastric lavage, magnesium citrate, activated charcoal, acetylcysteine, and intravenous steroids, her condition stabilized after 12 hours. Released after four days, a two-week follow-up found no physical or laboratory abnormalities.12 In a suspected abortion or suicide attempt, a single 1 oz (30 mL) dose proved fatal after seven days due to massive hepatic necrosis. This woman had frequently used pennyroyal tea in the past to induce menses.10,11
Another series of four cases in the mid-1990s included two cases of young women drinking 1 cup or 3 cups of pennyroyal tea (one teaspoon per cup) to induce menses that resulted in dizziness and weakness for one hour or abdominal cramps for four days, respectively, with no residual symptoms. Another young woman ingested repeated doses of a pennyroyal tincture and black cohosh root extract for two weeks in an attempt to induce abortion, followed by a final additional dosing of unknown quantity. She developed chills, vomiting, cramping, and syncope, then cardiopulmonary arrest and coma, and died 46 hours after the final ingestion. Lastly, a 22-month-old girl accidentally consumed an unknown quantity of pennyroyal oil. Examined 15 minutes later, she received gastric lavage and activated charcoal and sorbitol along with oral N-acetylcysteine. Serum samples obtained after 10 hours contained menthofuran. Her liver enzymes and clinical course were otherwise unremarkable. This case series included a review of the 22 published cases (four fatal, nine severe or moderate, and nine mild, not including the two fatal California infant cases) of pennyroyal poisoning over 127 years. It revealed that 18 were due to pennyroyal oil or essence (one part oil to seven parts alcohol). All cases followed a large acute dosing. Documented contemporary fatal cases had evidence of liver and kidney damage within 24 hours, whereas 15 survivors had no documented liver damage.13
While toxicity can be experienced with any form of pennyroyal product based on dosage, the preparations with the most concentrated pulegone content (especially essential oil, but also pennyroyal essence and even alcoholic extract) carry the highest risks. Use by infants and pregnant women should be avoided entirely.
2. Yohimbe (Pausinystalia yohimbe, syn. Corynanthe yohimbe) bark
Yohimbe has a traditional African and modern American use as an aphrodisiac. From five to 10 teaspoons of the shaved bark are used to make a decoction with one pint of water. Extracts are also sold. The potential benefits and risks of yohimbe have been tied to the effects of its major alkaloidal component, yohimbine. It is the most abundant of its many alkaloids whose content depends on the portion of the bark utilized. Total alkaloid content is 2.7-5.9% in stem bark. In samples with 5.3-5.7% total alkaloids, yohimbine yield accounted for about 1.1-2.2%.14 Yohimbine has been marketed for more than 80 years to treat sexual difficulties. It has no apparent effect on sex drive in humans, but has demonstrated benefit for erectile disorder due to its antagonism of alpha2-adrenoceptors at therapeutic doses of 5-10 mg three times daily. Yohimbine is usually well tolerated, though it can increase systolic blood pressure, heart rate, and anxiety levels in certain individuals, especially at the higher dose of 30 mg per day but also in amounts as low as a single 5 mg dose.14,15
The BSH notes that yohimbe is contraindicated in liver and kidney disease and chronic inflammation of sexual organs or the prostate gland. It warns that yohimbe is not appropriate for excessive or long-term use and that it may potentiate monoamine oxidase (MAO) inhibitors.2 Other noteworthy contraindications include pregnancy, children, coronary artery disease, hypertension, and depression. It should be avoided by those suffering from agoraphobia or panic attacks. Adverse effects include nausea, vomiting, abdominal distress, weakness, loss of coordination, dizziness, and excitation. Its toxicity can also be increased by other drugs including CNS stimulants, phenothiazines, and other adrenergic antagonists.3 Most concerns about the possible risks of unmonitored use of yohimbe are based on yohimbine’s potential for drug interactions and influence on specific medical conditions. While 15-20 mg of oral yohimbine can induce anxiety or increase blood pressure in otherwise healthy individuals, only 12 mg daily is needed to cause hypertension in patients using tricyclic antidepressants, and 10 mg can elicit mania in bipolar patients. Yohimbine also can antagonize therapeutic effects of antihypertensive drugs like clonidine.16
A case of lupus-like syndrome with generalized skin eruption and progressive renal failure occurred in a man following use of 16 mg of yohimbine for impotence.17 The risk of yohimbine abuse exists not only for those desperate to regain sexual function, but also among youth for whom the drug is inappropriately touted as an aphrodisiac, stimulant, and/or hallucinogen. In one case a 16-year-old girl ingested about 250 mg of a white powder purported to be yohimbine. A urine toxico- logical assay identified salicylates, caffeine, and two unidentified alkaloids that may (or may not) have been yohimbine metabolites. Though she experienced chest pain, anxiety, nausea, sweating, fine tremors, tachypnea, and tachycardia, by the next morning she was asymptomatic.18
Analytical evidence shows, however, that an American "yohimbe" product contained no yohimbine but may have been adulterated with caffeine instead.16 One analysis compared authentic yohimbe bark with 7,089 parts per million (ppm) yohimbine to 18 commercial products in America supposedly containing yohimbe bark or its extract. Seven were combination products with < 0.1-12.3 ppm yohimbine. Of the yohimbe monopreparations, nine contained < 0.1-2.3 ppm yohimbine, while two others contained 296 and 489 ppm.19 A recent European analysis of 20 commercial products found that, based on the maximal dose per day as indicated on the label, the amount of yohimbine delivered ranged from 1.32 mg to 23.16 mg.20 One risk of yohimbe preparations with low or no alkaloid content lies in becoming accustomed to consuming what is marketed as a high dose and then switching to a more potent product.
The risks of using the isolated drug yohimbine are clear, but it has not been established that these effects are equivalent to those of the complex alkaloid combinations that exist in authentic yohimbe bark. For example, yohimbe bark is used in traditional medicine to treat angina and hypertension, conditions contraindicated for isolated yohimbine.14 The other yohimbe alkaloids are less potent, but may compete with yohimbine, alter its pharmacokinetics, antagonize certain of its pharmacodynamic effects, act synergistically for other effects, or all of the above. Besides research on the bark and its extracts, what is needed at a minimum are requirements for good manufacturing practices that provide consistent levels of yohimbine in a given product. In addition, clear label instructions noting yohimbine content per dose should be accompanied by warnings for those with conditions or on medications that put them at higher risk.
3. Lobelia (Lobelia inflata) aerial plant
Also known as Indian tobacco and emetic weed, lobelia has long been a favorite in American herbalism for treating respiratory conditions as an expectorant. Due to its antispasmodic properties, it was an early standard for use in bronchial asthma and whooping cough. Yet, due to its effect on the nervous system and emetic effect in large doses, it has long been recognized as potentially toxic and best used as professionally manufactured preparations taken under medical supervision.7 The dried herb powder has usually been taken in doses of 65-195 mg (average 100 mg) and the tincture in doses of 0.3-1.8 mL (5-30 drops), but some people are sensitive to even therapeutic doses. The toxic dose range is normally about 0.6-1.0 g of the dried leaf powder, while 4 g is considered potentially lethal. Tobacco smokers are typically less sensitive, since the effect of the alkaloid lobeline is similar to nicotine but about 1/10 as potent. Signs and symptoms of overdose include esophageal burning, nausea, vomiting, anxiety, dizziness, headache, weakness, stupor, rapid breathing, and cardiac arrhythmias.3 The BSH warns that lobelia should not be used during pregnancy or taken in large doses, since dose-dependent cardioactivity has been noted. Due to the rapid induction of vomiting in large doses, the absorption of fatal amounts of lobeline is unlikely under normal circumstances. In cases of toxic exposure, activated charcoal is not advocated since this may block the emetic effect; gastric lavage is preferable.2
Dried mature lobelia contains a group of structurally related alkaloids,21 and lobeline accounts for 20-40% of the total alkaloids.22 Lobeline decreases with age from 1.95% in juvenile to 1.46% in adolescent to 0.76% in mature plants.21,23 Its content varies from 0.38% in the leaves and 0.58% in the stems to 3.03% in the flowers.23 In a comparative study, lobeline was found inferior to gastric lavage and syrup of ipecac for gastric evacuation of a barium sulfate test meal.24 An aerosol with lobeline and a local anesthetic was patented 50 years ago as a quick, effective, long-lasting bronchodilating treatment for asthma and respiratory infections.25 Lobeline acts as a primary stimulant and secondary depressant of parasympathetic and sympathetic ganglia, the adrenal medulla, carotid and aortic bodies, and neuromuscular junctions. Clinically, lobeline was used as a short-acting respiratory stimulant in cases of respiratory insufficiency due to poisoning by alcohol, soporifics, morphine, or spinal anesthesia and asphyxia in newborns. It has been replaced for these purposes by more effective agents. Yet, a recently discovered potential application is the use of lobeline as a treatment for amphetamine and methamphetamine abuse. Lacking its own addiction liability, it has been shown to inhibit amphetamine-induced hyperactivity and release of dopamine.26
Lobeline is potent in competing for the binding site that mediates the nicotine discriminative stimulus in the brains of rats27 and is a strong nicotine antagonist, blocking prostration, seizures, and the mortality caused by nicotine in rats.28 A major clinical application of lobeline has been as a smoking deterrent. In an early 1960s placebo-controlled, double-blind study completed by 63 subjects, 0.5 mg of lobeline was taken about 10 times per day the first week, reduced to about five, then four, then three times per day over the following three weeks. By the fourth week, 66.6% of the lobeline group decreased their cigarette consumption 51-100%, with 13.8% stopping completely, compared to the 14.8% in the placebo group that had reduced their consumption with no one stopping entirely. The only side effects were mild nausea and a burning sensation in the throat or mouth during the first two weeks.29 Another randomized, placebo-controlled, double-blind clinical trial of 313 subjects in eight clinics used 5 mg lobeline tablets morning and evening with 0.5 mg lobeline lozenges during the day (up to 10 lozenges/d) in the treated group. After seven days 66% of the treated subjects had stopped smoking, compared with 50% in the placebo group.30 Lobeline was available until December 1993, when the FDA banned nonprescription aids for smoking cessation. Still, of about 30 published reports between 1936 and 1973, two-thirds claimed efficacy. A new trial to reduce nicotine withdrawal symptoms using a variety of sublingual lobeline tablet doses (2.5, 5.0, or 7.5 mg) and frequencies (three, six, nine, or 12 times daily) found significant symptom reduction with increasing dosage. Maximum efficacy was noted with 7.5 mg 9-12 times per day with no clinically significant adverse effects.31 However, a subsequent multicenter trial of 7.5 mg sublingual lobeline nine times daily with 750 subjects for six weeks found no significant differences in cessation efficacy between lobeline and placebo. There was a positive trend for lobeline among highly dependent smokers.32
Lobeline and other alkaloids are not the only active components in lobelia. A study in mice using a crude methanolic extract of lobelia leaves demonstrated antidepressant activity. Upon fractionation, beta-amyrin palmitate was determined to be the active component.33 It was found to increase norepinephrine in brain synaptosomes in mice.34 Thus, like yohimbe, lobelia effects represent more than the activity of one major alkaloid. This is reflected in the lobeline content of an average herb dose (0.76% of 100 mg = 0.76 mg) amounting to only one tenth of the therapeutic lobeline dose for smoking cessation (7.5 mg). Due to its potentially toxic effect on sensitive or compromised individuals, lobelia should not be used in full or large doses by individuals suffering from heart disease, hypertension, dyspnea, or pneumonia. Its use is best avoided by young children, pregnant women, or those having low vitality including the elderly or victims of chronic anxiety with fatigue.35
Most herbalists and naturopathic doctors who use lobelia combine its liquid extracts in low-to-moderate amounts with other herbal extracts, either to use topically as a muscle relaxant or internally to treat respiratory symptoms associated with infections and asthma. Like nicotine, dermal absorption of lobeline is significant and can result in nausea and vomiting when lobelia is applied externally. Certainly, clear instructions as to proper restricted dosage and warnings about symptoms of excess should accompany any product or prescription (for internal or external use) that contains lobeline in significant amounts.
4. Bitter orange (Citrus aurantium) peel or unripe fruit
The dried rind of bitter orange (also known as Seville or sour orange and in China as chih-shi or zhishi) traditionally has been used for its bitterness and flavor as an aromatic digestive tonic in cases of dyspepsia.7 Due to its bitter tonic action, the dried peel should not be used in cases of gastrointestinal ulcers.3,35 Ingestion of large amounts of orange peel reportedly have caused colic, convulsions, and even death in children. Still, the BSH classifies bitter orange peel as safe when used appropriately.2 The peel has been used in Brazilian folk medicine for insomnia, anxiety, and epilepsy, and the oil from the peel has been found to be sedative, anxiolytic, and anticonvulsant in rats at 0.5-1.0 g/kg.36 The oil derived from the fresh peel also is used internally for flatulence and as a flavoring agent.7 This aromatic oil has photosensitizing furanocoumarin components, as do other citrus oils, that should not be applied externally less than 12 hours before ultraviolet exposure.3
However, it is not based on traditional uses of the peel or its oil that bitter orange has come under increased scrutiny. Bitter orange unripe fruit extracts have recently become popular components of antiobesity treatments based on their content of adrenergic amines including synephrine, octopamine, and tyramine. Octopamine and synephrine increase lipolysis and fat oxidation in insect and mammalian fat cells.37,38 Commercial extracts are typically standardized to their synephrine content. In the fresh fruit, synephrine content is only 0.02%, but in dried fruit it rises to 0.35%. Two dried extracts each contained about 3.0% synephrine, while three other herbal products had yields of 0.25%, 0.66%, and 0.99% synephrine. The dried extracts had low levels of octopa-mine (0.02-0.03%) and tyramine (0.06%), while the other three herbal products had half these amounts except for one with 0.15% octopamine. The fresh and dried fruit were below the limits of quantification for these two amines.39 Documented efficacy and safety of such bitter orange antiobesity products remains to be published.
Concern about bitter orange arises due to the adrenergic cardiovascular effects of these bioamines, especially synephrine. A study in rats using a "special extract" of bitter orange standardized to 6% synephrine found that a daily oral dose of 2.5-20 mg/kg for 28 days led to weight loss and reduced food intake. However, there was a dose-dependent mortality of 10-50% due to ventricular dysrhythmias but no blood pressure abnormalities.40 Synephrine (at 0.1, 0.2, and 0.4 mg/kg/min) and the traditional Chinese digestant preparation, an aqueous extract of bitter orange unripe fruit with 1.25% synephrine (at 1.25, 2.5, and 5.0 mg/kg/min), were each administered intravenously to rats. Both increased mean arterial pressure in a dose-dependent manner.41 In China, a synthetic mixture of bitter orange bioamines (synephrine and N-methyltyrosamine) has been shown to increase cardiac output and constrict dilated microvessels in dogs with endotoxic shock. It was used by injection to treat 50 children with septic shock with 96% efficacy.42 Synephrine (also called oxedrine) delivered intravenously to 12 healthy men at 4 mg/min increased systolic and mean arterial blood pressure along with left ventricular contractility while reducing peripheral vascular resistance, but did not affect heart rate.43
The juice from bitter orange contains 57 mcg/mL synephrine but no measurable octopamine. In a cross-over trial with normal subjects 8 oz of the juice (13.7 mg synephrine) did not change heart rate, systolic and diastolic blood pressure, or mean arterial pressure. Yet based on the potential effects of its synephrine content, it is considered contraindicated for individuals with tachyarrhythmias, severe hypertension, narrow-angle glaucoma, and MAO inhibitor recipients.44 Based on results of consumption by two individuals of 8 oz of the juice containing 6,7-dihydroxybergamottin, drug substrates of cytochrome P450 (CYP) 3A4 may be better absorbed and and have increased activity due to the reduction of enterocyte content of CYP3A4 by 40%.45 However, a bitter orange product lacking the compound 6,7-dihydroxybergamottin failed to alter bioavailability of 3A4 substrate midazolam in 12 humans after four weeks.46
A recent case report of a serious cardiovascular event made note of the use of a bitter orange antiobesity extract. A 55-year-old white woman developed chest pain and an aching shoulder. An arteriogram displayed a lesion in her left main coronary artery, and she was diagnosed as having an acute lateral wall myocardial infarction (MI). For a year she had been ingesting a multicomponent dietary supplement (Edita’s Skinny Pill) for weight loss that contained 300 mg of bitter orange extract. She smoked but did not have a history of hypertension, coronary disease, or hyperlipidemia. Though this case did not establish bitter orange or synephrine as the cause of her MI, this was suspected due to similar cases associated with ephedra.47 According to a major meta-analysis of ephedra and ephedrine safety, these agents are associated with increased risk of cardiac, psychiatric, gastrointestinal, and autonomic symptoms, though the majority of adverse event case reports are not documented sufficiently to allow for a meaningful assessment.48 The actual risk with bitter orange extracts appears small compared to ephedra preparations. However, the safety of using ephedra or bitter orange extract is complicated by the combination of these products with sources of caffeine and other ingredients such as diuretics.48,49
Concentrated synephrine extracts of bitter orange do not only concentrate this one alkaloid. N-methyltyramine, similar in structure and activity to synephrine, is possibly available in higher amounts than found in the peel. In addition, the flavonoid compounds methyhesperidin and its derivatives are present in small amounts in the fruit, but in higher amounts can produce cardiac effects similar to the extract.
The tendency to abuse natural substances promoted to enhance weight loss by taking larger amounts than recommended is an issue for some individuals. The risk is further increased when pharmacologically potent substances in plants are specifically concentrated in extracts, even though bitter orange and other botanicals may be safe when normal doses are used in their whole form or as a traditional extract such as a tea.
In China, decoctions of 3-10 g of the peel are used for digestive complaints. This would provide about 7.5-22.5 mg synephrine or 0.11-0.33 mg/kg for someone with 70 kg body weight. Bitter orange should be avoided in pregnancy.50 The dose approved by the German Commission E for loss of appetite or dyspepsia is 4-6 g of the dried peel made into a tea or 2-3 mL of tincture with no specified contraindications.51
1. Skullcap (Scutellaria lateriflora) plant
Skullcap, also called blue skullcap, is a native Am-erican plant that has a long history of use as a mild sedative and antispasmodic for insomnia, restlessness, and skeletal muscle spasms. The infusion is prepared by steeping one teaspoon in a cup of water for 30 minutes and can be taken three to four times daily. The tincture can be effective in doses as low as 3-12 drops and is best taken in hot water.7 A recent placebo-controlled, double-blind study in healthy volunteers showed that encapsulated freeze-dried skullcap herb and its freeze-dried extract are both effective anxiolytic agents compared to placebo.52 Skullcap is designated in the BSH as an herb "that can be safely consumed when used appropriately." However, this book acknowledges a controversy about reports of hepatotoxicity associated with skullcap. In all likelihood, these reports appear to associated with products that had been adulterated with a species of Teucrium.2 [On the issue of the hepatotoxicity of germander (Teucrium chamaedrys), see Part 1 of this article in the August 2004 issue of Alternative Medicine Alert.]
Four cases of hepatotoxicity in Great Britain were reported in the late 1980s in association with herbal products that purportedly contained skullcap. The symptoms of jaundice, dark urine, and/or pale stools in each case followed use of tablets labeled as containing skullcap and/or valerian. Consumption occurred over three days, three weeks in two cases, or two months. It took from two to 13 months for liver function tests to return to normal.53 Reports of other cases of products containing skullcap with or without other herbs such as valerian or mistletoe were noted. No experimental data support the hepatotoxicity of valerian, mistletoe, or skullcap.53,54 On examining commercial sedative preparations in Great Britain, it was found that the skullcap was not a Scutellaria species but rather from the genus Teucrium.55 Several other cases of liver damage were reported in Norway with patients using skullcap alone or with several other herbal remedies. No positive identification of the hepatotoxic agents was reported.6
A case report in America also followed the use of skullcap (six capsules daily for six months) and a separate product labeled as pau d’arco at an unspecified dosage. This resulted in fatal hepatic failure, but the liver demonstrated evidence of hepatic veno-occlusive disease typical of pyrrolizidine alkaloid toxicity rather than typical toxic hepatitis.56 [On the issue of hepatotoxicity of pyrrolizidine alkaloids, see the section on comfrey in Part 1.] Substitution of Teucrum species for Scutellaria also has reportedly occurred in America.57 Although some skullcap is grown commercially, most is wild-harvested. The wholesale supply of blue skullcap labeled as S. lateriflora may include other indigenous Scutellaria species as well. However, "pink skullcap," also known as wild germander (Teucrium canadense) is available at a lower wholesale price. It has been known as an adulterant to commercial supplies of skullcap.58 Although the morphological features of the two generally are distinct, once powdered, the microscopic characteristics are similar. A simple thin layer chromatogram produces an identifiable fingerprint of the flavonoids that allows for easy detection of substitution. A standard high performance liquid chromatogram also can readily distinguish between Scutellaria and Teucrium species because of the 6-hydroxy flavones without a B ring that are detected as constituents of Scutellaria only. Each genus has characteristic patterns that differ distinctly from the other.59
There is suspicion but no solid evidence to indicate that skullcap is a likely hazardous herbal supplement. Reports of hepatotoxicity in Europe associated with its use in most cases involve consumption of other herbal products as well, at a time when other herbs now known as hepatotoxins had not been removed from the commercial market. The few cases in which a skullcap product was reportedly used alone failed to document that the product actually contained skullcap. Subsequent analysis of commercial skullcap products indicates that germander species were substituted. Since the source for wholesale skullcap is largely wild-harvested plants from North America where wild germander is sold as pink skullcap, the cause for confusion, though unacceptable, is understandable. The situation is analogous to the Belgium use of a toxic Aristolochia species because of similarities between common Chinese names. [On the issue of this mistaken herbal identity, see the section on aristolochic acid in Part 1.] What is required is the establishment of good manufacturing regulations that assure product identity and accurate commercial labeling, beginning with correct labeling of wholesale herbs according to their scientific nomenclature, not just their common names.
2. Organ/glandular extracts
The CR inclusion of these animal products encompasses an extremely long list of possible products that the CR article summarizes as "brain/adrenal/pituitary/ placenta/other gland" substance or concentrate. The basis for the inclusion of such products on their list as likely hazardous is due to a "theoretical risk of mad cow disease, particularly from brain extracts." However, CR also notes that in January 2004, the FDA banned from use in foods and supplements all high-risk bovine materials from older cows. Organ tissues from cows younger than 30 months of age are still permitted.1 The ban recently was extended to cosmetic products such as lipstick and hairspray. The excluded high-risk material from cattle 30 months or older includes the skull, brain, eyes, and spinal cord. The tonsils and small intestine are prohibited from cattle of all ages, as well as tallow rendered with a concentration of impurities greater than 0.15%. This follows the first case of mad cow disease, or bovine spongiform encephalopathy, reported in the United States in December 2003, to prevent its spread to humans, which may result in the fatal variant Creutzfeldt-Jakob disease. The reason for the distinction in cattle age is that animals older than age 30 months can harbor prions, the misshapen proteins associated with the wasting away of brain tissue.60
Animal products typically carry a risk of contamination with infectious material that supercedes that of dried plants or their extracts. Since government regulations banning tissues that can harbor mad cow disease apply to foods, supplements, and cosmetics, the "likely hazardous" designation would seem to apply equally to these different types of products that contain FDA-approved bovine parts. Nonetheless, those dietary supplements that specifically utilize bovine material should clearly indicate compliance with these standards on the label. For the sake of consumer confidence, all dietary supplements that contain animal products of any sort should specifically indicate on the label the animal source, part, and country and date of origin. Such label information acknowledges the personal importance of dietary and cultural/religious preferences and taboos by allowing customers to make informed choices. It also provides a means of assessing product safety in the wake of future unforeseen issues of contamination.
Safety Through Moderation, Good Manufacturing, and Proper Labeling
Obvious dangers exist when dietary supplements, including herbs but especially herbal concentrated extracts, are indiscriminately consumed. In the case of pennyroyal oil, the content delivered in the whole herb or its traditional water extracts make an acute, unintentional over-exposure unlikely. However, the purified aromatic distillate, or large doses of an alcoholic extract, dramatically increase the potential risk of acute toxicity. In the case of yohimbe products, authentic extracts with significant levels of yohimbine can result in anxiety, high blood pressure, and other complications, especially for those using psychogenic or cardiovascular medications. Thus, its contraindication for iatrogenic impotence secondary to antidepressant or antihypertensive use should be clearly stated. Lobelia is a reliable bronchodilator whose usefulness is limited by its obvious emetic effect when used in large doses. However, this activity helps prevent absorption of amounts that could have seriously detrimental outcomes. Bitter orange extracts that are manufactured to concentrate synephrine content for the purposes of weight loss have a potential for abuse similar to ephedra products. The less potent activity of synephrine in comparison to ephedrine likely lessens both its effectiveness and risk when taken for obesity. The traditional use of its decoction as a digestive tonic is regarded as safe. With moderate consumption of traditional forms of these herbs the documented adverse effects associated with acute overdosage can be avoided.
The issue of misidentification has left its mark on the reputation of skullcap. Strict labeling requirements that assure proper identification of product contents is necessary to avoid toxicity from spurious herbs with similar common names or appearances. Requirements for appropriate sources and clear labeling of animal-derived dietary supplement material is warranted, especially in the case of bovine organ material. The implementation of good manufacturing practices, including record keeping to document sourcing and processing, is vital to public and professional assurance of safety for all dietary supplements. While absolute safety in health products may be an impossible goal, appropriate efforts need to be made to establish procedures that provide reliable products. It is inherently imperative that dietary supplements and their instructional labeling serve to enhance and improve, rather than threaten, the public’s health and well-being.
Dr. Brinker is an Instructor at the Program in Integrative Medicine at the University of Arizona, Tucson.
1. Anonymous. Dangerous supplements: Still at large. Consumer Reports May 4, 2004.
2. McGuffin M, et al, eds. Botanical Safety Handbook. Boca Raton, FL: CRC Press; 1997.
3. Brinker F. The Toxicology of Botanical Medicines. 3rd ed. Sandy, OR: Eclectic Medical Pub.; 2000.
4. Tisserand R, Balacs T. Essential Oil Safety. New York, NY: Churchill Livingstone; 1995.
5. Khojasteh-Bakht SC, et al. Metabolism of (R)-(+)-pulegone and (R)-(+)-menthofuran by human liver cytochrome P-450s: Evidence for formation of a furan epoxide. Drug Metab Dispos 1999;27:574-580.
6. DeSmet PAGM, et al, eds. Adverse Effects of Herbal Drugs. Vol. 2. New York, NY: Springer-Verlag; 1993.
7. Lust J. The Herb Book. New York, NY: Bantam Books; 1974.
8. Bakerink JA, et al. Multiple organ failure after ingestion of pennyroyal oil from herbal tea in two infants. Pediatrics 1996;98:944-947.
9. Moore M. Medicinal Plants of the Pacific West. Santa Fe, NM: Red Crane Books; 1993.
10. Anonymous. Fatality and illness associated consumption of pennyroyal oil—Colorado. Morbid Mortal Weekly Rep 1978;27:511-513.
11. Sullivan JB, et al. Pennyroyal oil poisoning and hepatotoxicity. JAMA 1979;242:2873-2874.
12. Buechel DW, et al. Pennyroyal oil ingestion: Report of a case. J Am Osteopath Assoc 1983;82:793-794.
13. Anderson IB, et al. Pennyroyal toxicity: Measurement of toxic metabolite levels in two cases and review of the literature. Ann Intern Med 1996;124:726-734.
14. DeSmet PAGM, et al, eds. Adverse Effects of Herbal Drugs. Vol. 3. New York, NY: Springer-Verlag, 1997.
15. Riley AJ. Yohimbine in the treatment of erectile disorder. Br J Clin Pract 1994;48:133-136.
16. DeSmet PAGM, Smeets OSNM. Potential risks of health food products containing yohimbe extracts. Br Med J 1994;309:958.
17. Sandler B, Aronson P. Yohimbine-induced cutaneous drug eruption, progressive renal failure, and lupus-like syndrome. Urology 1993;41:343-345.
18. Linden CH, et al. Yohimbine: A new street drug. Ann Emerg Med 1985;14:1002-1004.
19. Betz J, et al. Gas chromatographic determination of yohimbine in commercial yohimbe products. J AOAC Int 1995;78:1189-1194.
20. Zanolari B, et al. Qualitative and quantitative determination of yohimbine in authentic yohimbe bark and in commercial aphrodisiacs by HPLC-UV-API/MS methods. Phytochem Anal 2003;14:193-201.
21. Krochmal A, et al. Lobeline content of four Appalachian lobelias. Lloydia 1972;35:303-304.
22. Simon IS, Shostenko YC. Lobeline determination in plant material. Farmastsevt Zh (Kiev) 1959;14:51-53.
23. Krochmal A, et al. Lobeline content of Lobelia inflata. Structural, environmental, and developmental effects. U.S. Dept Agr Forest Serv Res Paper NE-178, 1970.
24. Abdallah AH, Tye A. A comparison of the efficacy of emetic drugs and stomach lavage. Am J Dis Child 1967;113:571-575.
25. Dautrebande L. Lobeline aerosol dilating medicament. Chem Abs 1952;46:6797c.
26. Dwoskin LP, Crooks PA. A novel mechanism of action and potential use for lobeline as a treatment for psychostimulant abuse. Biochem Pharmacol 2002;63: 89-98.
27. Reavill C, et al. High affinity binding of [3H] (-)- nicotine to rat brain membranes and its inhibition by analogues of nicotine. Neuropharmacology 1988;27: 235-241.
28. Abood LG, et al. Structure-activity studies of carbamate and other esters: Agonists and antagonists to nicotine. Pharmacol Biochem Behav 1988;30:403-408.
29. London SJ. Clinical evaluation of a new lobeline smoking deterrent. Curr Ther Res 1963;5:167-175.
30. Plakun AL, et al. Clinical factors in smoking withdrawal: Preliminary report. Am J Public Health Nations Health 1966;56:434-441.
31. Schneider FH, et al. Reduction of tobacco withdrawal symptoms by sublingual lobeline sulfate. Am J Health Behav 1996;20:346-363.
32. Glover ED, et al. A smoking cessation trial with lobeline sulfate: A pilot study. Am J Health Behav 1998:22:62-74.
33. Subarnas A, et al An antidepressant principle of Lobelia inflata L. (Campanulaceae). J Pharm Sci 1992;81:620-621.
34. Subarnas A, et al. A possible mechanism of antidepressant activity of beta-amyrin palmitate isolated from Lobelia inflata leaves in the forced swimming test. Life Sci 19932;52:289-296.
35. Brinker F. Herb Contraindications and Drug Interactions. 3rd ed. Sandy, OR: Eclectic Medical Pub., 2001.
36. Carvalho-Freitas MI, Costa M. Anxiolytic and sedative effects of extracts and essential oil from Citrus aurantium L. Biol Pharm Bull 2002;25:1629-1633.
37. Park JH, Keeley LL. The effect of biogenic amines and their analogs on carbohydrate metabolism in the fat body of the cockroach Blaberus discoidalis. Gen Comp Endocrinol 1998;110:88-95.
38. Carpene C, et al. Selective activation of beta3-adrenoceptors by octopamine: Comparative studies in mammalian fat cells. Naunyn Schmiedebergs Arch Pharmacol 1999; 359:310-321.
39. Pellati F, et al. Determination of adrenergic agonists from extracts and herbal products of Citrus aurantium L. var. amara by LC. J Pharm Biom Anal 2002;29: 113-119.
40. Firenzuoli F, et al. Physicians discuss orange extract. HerbalGram 1999;46:76-77.
41. Huang YT, et al. Fructus aurantii reduced portal pressure in portal hypertensive rats. Life Sci 1995;57: 2011-2020.
42. Zhao XW, et al. Anti-shock effects of synthetic effective compositions of Fructus aurantii immaturus. Experimental study and clinical observation. Chin Med J 1989;102:91-93.
43. Hofstetter R, et al. The effect of oxedrine on the left ventricle and peripheral vascular resistance. [in German] Arzneimittelforschung 1985;35:1844-1846.
44. Penzak SR, et al. Seville (sour) orange juice: synephrine content and cardiovascular effects in normotensive adults. J Clin Pharmacol 2001;41: 1059-1063.
45. Edwards DJ, et al. 6’,7’-Dihydroxybergamottin in grapefruit juice and Seville orange juice: Effects on cyclosporine disposition, enterocyte CYP3A4, and P-glycoprotein. Clin Pharmacol Ther 1999;65:237-244.
46. Gurley BJ, et al. Assessment of botanical supplementation on human cytochrome P450 phenotype: Citrus aurantium, echinacea, milk thistle, saw palmetto. Clin Pharmacol Ther 2004;75:P35.
47. Nykamp DL, et al. Possible association of acute lateral-wall myocardial infarction and bitter orange supplement. Ann Pharmacother 2004;38:812-816.
48. Shekelle PG, et al. Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: A meta-analysis. JAMA 2003;289:1537-1545.
49. Roan S. Trouble with ephedra: Controversy over the weight loss supplement is creating a demand for alternatives. Los Angeles Times 2002;Dec. 9:F1.
50. Dharmananda S. Synephrine: Is chih-shi (zhishi) toxic? November 2003. Available at: www.itmonline.org.
51. Blumenthal M, et al, eds. The Complete German Commission E Monographs. Boston, MA: Integrative Medicine Communications; 1998.
52. Wolfson PE, Hoffman DL. An investigation into the efficacy of Scutellaria lateriflora in healthy individuals. Altern Ther 2003;9:74-78.
53. MacGregor FB, et al. Hepatotoxicity of herbal remedies. BMJ 1989;299:1556-1157.
54. Larrey D, Pageaux GP. Hepatotoxicity of herbal remedies and mushrooms. Semin Liver Dis 1995;15:183-188.
55. Phillipson JD, Anderson LA. Herbal remedies used in sedative and antirheumatic preparations: Part 1. Pharmaceut J 1984;233:80-82.
56. Hullar TE, et al. Herbal toxicity and fatal hepatic failure. Am J Med 1999;106:267-268.
57. Huxtable RJ. The myth of beneficent nature: The risks of herbal preparations. Ann Intern Med 1992; 117:165-166.
58. Foster S. Scullcap: An herbal enigma. Bus Herbs 1996; May/June:14-16.
59. Peck JM, et al. Chromatographic methods for the rapid identification of skullcap. Pharmacol Res 1993;27:15-16.
60. Associated Press. FDA prohibits use of brains, other cow parts in cosmetics. Arizona Daily Star 2004; July 10:A2.