**3.3. Caffeine-containing herbs**

the drug with other CYP 3A4 substrates, including coadministration with grapefruit juice, is contraindicated [111]. One case report describes a possible interaction between sibutramine and citalopram in a 43 year old female patient who experienced hypomanic symptoms shortly after adding 10 mg sibutramine to her current citalopram and fluoxetine regimen [119]. Symptoms ceased within one day of discontinuing sibutramine. Although the exact mecha‐ nism of the interaction is unknown, the author hypothesized a possible amphetamine-like hypomania or serotonin syndrome due to increased brain serotonin levels via the combination of a serotonin reuptake inhibitor and serotonin-norepinephrine reuptake inhibitor. Another case report notes a possible interaction between sibutramine and cyclosporine in a 26 year old transplant patient resulting in significant increases in cyclosporine trough plasma levels, likely due to inhibition of CYP 3A4 metabolism [120]. Coadministration of α<sup>2</sup> adrenergic blockers, such as the herb yohimbine, with sibutramine has been recognized as potentially life threat‐ ening due to potential sympathetic side effects resulting in hypertension and tachycardia [121]. Due to the potential risk of bleeding caused by sibutramine, the drug should be used with

The açaí berry is harvested from the palm species *Euterpe oleracea* and is used mainly for dietary consumption as whole fruit, juice, or as a flavoring and coloring agent [27]. The fruit, widely used in Brazil, has gained in popularity as a food product and dietary supplement in the past several years, mainly due to its antioxidant and anti-inflammatory effects related to high polyphenol content[122-126].Althoughthere is little scientific evidence to supportthe berry for any of its purported health benefits, it can be found in several dietary supplements promoted for weight loss. In a pilot study investigating the effect of açaí supplementation on metabolic parameters in healthy overweight patients, the authors found a significant decrease in fasting glucose, insulin and cholesterol levels and a mild decrease in LDL-cholesterol and ratio of total cholesterol to HDL-cholesterol [127]. However, the authors did not assess weight loss in this study and therefore the activity of açaí as an anorectic agent cannot be determined. There have been no reported adverse drug interactions or interactions with others herbs and açaí [27].

Bitter orange is the fruit of *Citrus aurantium* or *Citrus naringin*, used as both a food product and the medicinal properties of the juice and peel [27]. There are multiple active constituents in bitter orange including several flavonoids (e.g. naringin) and the adrenergic agonists syn‐ ephrine and octopamine [128-134]. Synephrine is structurally similar to ephedrine, therefore prompting the replacement of ephedra with bitter orange in weight loss supplements, although the fruit has been used dichotomously as both an appetite stimulant and for weight loss [27]. However, there is insufficient evidence to confirm the efficacy of bitter orange as an

caution in patients taking warfarin and other anticoagulants [106].

**3. Herbs and dietary supplements used in weight loss**

**3.2. Bitter orange (***Citrus aurantium, Citrus naringin, synephrine***)**

anti-obesity agent, especially given its inclusion in combination products [27].

**3.1. Açaí (***Euterpe oleracea***)**

114 Drug Discovery

Caffeine is a methylxanthine that is commonly found in food, beverages, and dietary supple‐ ments. It is used as an additive in beverages and dietary supplements for its energy enhancing properties. Many dietary supplements marketed for weight loss contain high levels of caffeine, often from multiple sources, for increased thermogenesis and lipid metabolism [143, 144]. Most studies investigating the anti-obesity effects of caffeine have been done using combination products that include ephedra, or have looked at enhancement of athletic endurance [145-151]. Therefore, it is difficult to assess the effect of caffeine alone on weight loss. One study dem‐ onstrated an increase in thermogenic metabolic rate in subjects drinking coffee along with food, compared to ingestion of decaffeinated coffee [144].

Adverse effects associated with caffeine consumption include restlessness, jitteriness, anxiety, insomnia, and cardiovascular effects [152-156]. Most drug and herb interactions with caffeine are mild to moderate and are related to increased adverse effects resulting from decreased caffeine elimination or additive effects with other methylxanthine containing products [157]. For example, estrogen drugs (e.g. oral contraceptives and estrogen replacement therapy) have been shown to decrease clearance of caffeine up to 50 – 65% [158, 159]. The most significant caffeine interaction occurs with coadministration of *Ephedra* or ephedrine containing products (see *Ephedra* below). The ban on ephedra in the United States has resulted in marketing of "ephedra-free" dietary supplements using ephedra alternatives, including caffeine containing herbs and bitter orange (see *Bitter Orange* above). In one randomized controlled trial study, subjects were administered products containing *Citrus aurantium* standardized to either a high dose of synephrine (46.9 mg) or a product containing caffeine and a low synephrine dose (5.5 mg) [136]. A significant increase on blood pressure was observed in patients taking the product containing both caffeine and synephrine, but not high dose synephrine alone, suggesting an interaction between the two herbs.

#### *3.3.1. Green tea (Camellia sinensis; EGCG)*

Green tea has gained in popularity for the treatment of a wide variety of diseases and for promotion of general wellbeing. The addition of green tea to weight loss supplements is due in part to the caffeine content of *Camellia sinensis*. However, in addition to alkaloid content (caffeine, theobromine, theophylline) green tea also contains polyphenols, most notably the catechin epigallocatechin-3-gallate (EGCG) [160-164]. EGCG, in concert with caffeine, is proposed to elicit anti-obesity effects via inhibition of catechol O-methyl transferase and phosphodiesterase [164]. A meta-analysis of clinical trials involving green tea in weight loss concluded that weight loss is decreased, relative to placebo, in treatment involving both green tea ECGC and caffeine but not with decaffeinated green tea products [165].

Thepatientdeniedchanges incalorie consumption, exercise,orinsulindosing.Diabeticpatients

Interactions with Drugs and Dietary Supplements Used For Weight Loss

http://dx.doi.org/10.5772/51145

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Ephedra, derived from the evergreen shrub *Ephedra sinica*, contains multiple plant alkaloids including ephedrine and pseudoephedrine that are chemically related to amphetamines. These compounds act by increasing availability and activity of endogenous neurotransmitters such as epinephrine and norepinephrine, resulting in brain and cardiovascular catecholamine receptor stimulation [184]. The herb has traditionally been used for bronchodilation in the treatment of respiratory ailments such as asthma, as an athletic performance enhancer, and for its thermogenic properties in weight loss [148, 185-189]. Ephedra as a weight loss dietary supplement is commonly found in combination products also containing caffeine or caffeinecontaining herbs. In one study a product containing 90 mg and 192 mg of ephedra alkaloids and caffeine, respectively, administered daily over six months in a randomized, double-blind placebo controlled trial resulted in significant decreases in body weight, body fat and LDLcholesterol with an increase in HDL-cholesterol [148]. The addition of aspirin to ephedrine containing products can potentiate the thermogenic properties of ephedra, improving weight loss compared to products containing ephedra alone [190-201]. Due to high risk of cardiovas‐ cular toxicities and cardiomyopathies, ephedra has been banned in the United States [202-211].

Because of the controversial nature of ephedra related to cardiac toxicity and its eventual ban via the U.S. FDA, there are a significant number of clinical studies and case reports related to toxicities and interactions with ephedra and ephedrine. Ephedra can potentially interact with anesthetics since it is known that administration of ephedrine can reverse anesthesia induced hypotension and regression of analgesia following epidural blockade [213, 214]. Ephedrine has both chrontropic and inotropic effects, and therefore interactions with cardiovascular agents may be possible [184, 211, 215, 216]. However, no effects on heart rate or blood pressure were seen in clinical trials investigating the efficacy of ephedra in weight loss [192, 217, 218]. Theoretically interactions with antiadrenergic agents and MAOIs can occur due to sympatho‐ mimetic effects of ephedrine, potentially increasing risk of hypertensive crisis. There is a case report of a patient taking a product containing caffeine, ephedrine, and theophylline who experienced multiple adverse effects including encephalopathy, hypotension, tachycardia, and hypothermia 24 hours following discontinuation of phenelzine [219]. Interactions with ephedrine and tricyclic antidepressants are also possible [220]. Some evidence from clinical trials suggests that ephedra in combination with caffeine can cause hyperglycemia, and therefore interactions with antidiabetic agents is possible [147, 148, 221]. A lowering of seizure threshold has been observed in patients taking ephedrine, and therefore use of ephedra in this patient population is cautioned [222]. A major interaction between ephedra and methylxan‐ thines (e.g. caffeine, theophylline) is possible due to increased risk of cardiovascular, neuro‐ logic and psychiatric adverse effects due to additive sympathomimetic and CNS stimulant activity [184, 223, 224]. One case study reports a 21 year old male patient admitted to the hospital emergency room with a blood pressure of 220/110 mmHg and ventricular arrhythmia following ingestion of a caffeine/ephedra containing product ("Herbal Ecstasy") [225].

taking hypoglycemic agents while consuming dandelion should be monitored.

**3.5. Ephedra (***Ephedra sinica***, ma huang)**

However, the herb is still available in other countries [212].

As expected, the majority of drug interactions associated with green tea are related to caffeine content. However, a few interactions described in the literature are due to other constituents of green tea. Green tea may be contraindicated, especially at high doses, in patients taking anticoagulants such as warfarin due to the high Vitamin K content of the herb. There is one case report of a patient taking warfarin who experienced a significant reduction in INR following initiation of daily consumption of one-half to one gallon of green tea [166]. Once green tea consumption was stopped INR normalized. Green tea is also thought to cause decreased estrogen levels and combination products containing the herb have been used to improve fertility and relieve menopausal symptoms [167-170]. Therefore, use of high doses of green tea in patients taking oral contraceptives or estrogen replacement therapy may be cautioned.

### *3.3.2. Guarana (Paullinia cupana)*

Guarana (*Paullinia cupana*) is a plant native to South America that is used traditionally and in anti-obesity supplements for its high caffeine content, although other minor constituents including theophylline, theobromine, catechin and epicatechin are found in these extracts [171-176]. There are no studies investigating the effects of Guarana alone on weight loss so it is difficult to determine the anti-obesity properties of the herb. In one double-blind, parallel, placebo controlled trial 47 subjects were administered three capsules containing yerba mate (*Ilex paraguayensis*, 112 mg), guarana (95 mg) and damiana (*Turnera diffusa*, 36 mg) daily for 45 days, resulting in significant weight loss (-5.1 ± 0.5 kg) compared to placebo (-0.3 ± 0.08 kg) [145]. One of the few interactions reported with guarana not related to caffeine content suggests possible interference with anticoagulants since platelet aggregation was observed *in vitro* and in animal studies [177].
