*3.9.2. Stimulant laxatives*

Stimulant laxatives act by irritating the lining of the gastrointestinal tract, resulting in increased propulsive muscle contractions that aid elimination of intestinal contents. Because of the quick and efficacious activity, stimulant laxatives are most frequently abused to promote weight loss by increasing gastrointestinal transit time [273, 274]. The most common stimulant laxative herbs are senna (*Cassia senna*), aloe latex (*Aloe vera*), and Cascara sagrada (*Frangula purshiana*). The leaves and pods from *Cassia senna* contain anthroquinone stimulant laxative compounds effective in the treatment of constipation and for bowel evacuation prior to medical procedures [27, 275-295]. The herb has been approved by the U.S. FDA as a non-prescription medication. Similarly, aloe latex, derived from the peripheral bundle sheath cells of the aloe leaf, contains anthracene compounds that are cleaved in the colon by bacterial enzymes into active anthrone compounds with stimulant laxative properties [296-299]. However, concerns over possible carcinogenic properties of certain anthraquinones in aloe latex, along with lack of safety evidence, prompted the U.S. FDA to ban aloe latex in 2002, although the herb is still used in other countries [178, 300, 301]. The bark of the deciduous buckthorn shrub Cascara sagrada is effective for the treatment of constipation due to the stimulant laxative properties of its anthraglycoside constituents [27, 302]. Like aloe latex, Cascara had previously been approved by the U.S. FDA as a non-prescription medication, but the designation was withdrawn into 2002 based on lack of safety and efficacy evidence, although the herb is still available as a supplement [300].

weight subjects for two months reports a significant decrease in body fat mass but not body

Interactions with Drugs and Dietary Supplements Used For Weight Loss

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Acquisition of mineralocorticoid excess syndrome following high dose consumption of licorice results in the potential for licorice-drug interactions with multiple drug classes, including aldosterone receptor antagonists, antiarrhythmics, antihypertensives, cardiac glycosides, corticosteroids, diuretics, and potassium lowering agents [321-324, 326]. In one study, 10 healthy subjects were given 32 grams of licorice daily for two weeks along with 25 mg of hydrochlorothiazide (HCTZ); a significant reduction in potassium levels was observed, while two patients experience hypokalemia, compared to HCTZ alone [346]. Glycyrrhizin and βglycyrrhetinic acid may also affect complement activity and decrease neutrophil generated oxides and peroxides, resulting in anti-inflammatory activity [347-350]. Therefore, licorice should be used with caution in patients taking other anti-inflammatory medications. Licorice constituents may also have an effect on hormonal agents via anti-estrogenic activity, inhibition of 17β-hydroxysteroid dehydrogenase, or associated decreases in prolactin levels [351-358]. In *in vitro* and animal studies it has been shown that constituents in licorice can promote the intestinal absorption of some drugs and therefore it is recommended that oral drugs be taken at least an hour before or two hours after licorice consumption [359]. Theoretically licorice may interact with antidepressant agents, since increases in norepinephrine and dopamine have been observed in mice while *in vitro* cell culture studies suggest potential serotonin reuptake

St. John's Wort (SJW) is a perennial herb native to Europe that is commonly used to treat depression, anxiety, post-menopausal symptoms, attention deficit hyperactivity disorder (ADHD), and other mood disorders [362-367]. The active constituents of SJW are hypericin and hyperforin, which are thought to act by inhibiting the synaptic uptake of serotonin (5-HT), GABA, noradrenaline, dopamine, and L-glutamate via a novel mechanism compared to synthetic antidepressants [362, 368-373]. Although there are no official studies regarding the use of SJW for weight loss, anecdotal reports suggest a positive effect on satiety, which may be attributable to the serotonergic uptake inhibition (see *Sibutramine* above). Following the removal of fenfluramine, an anorectic agent commonly used in the combination product "Phen-Fen" (phentermine – fenfluramine), from the market in 1997, SJW was combined with *Ephedra* or *Citrus aurantium* (see above) and marketed for weight loss as "Herbal Phen-Fen". Because of the expanding popularity of SJW in the 1990s – 2000s, a great deal of research on

Drug interactions with SJW are primarily related to binding of active constituents to the pregnane X receptor leading to induction of cytochrome P450 metabolizing or induction of pglycoprotein efflux mechanisms via the MDR-1 drug transporter [374-388]. As a result, pharmacokinetics of many cytochrome P450 drug substrates is altered, often leading to decreased plasma concentrations and reduced efficacy [27]. There have been numerous studies that have demonstrated potential metabolism-related drug interactions with CYP 3A4, 1A2, 2C9 and 2C19 [389]. Kinetics of antiplatelet and anticoagulant agents may be altered in the

the mechanism of action and herb-drug interactions has been reported.

mass index [344, 345].

inhibition [360, 361].

**3.11. St. John's Wort (***Hypericum perforatum***)**

Stimulant laxatives share multiple common adverse effects and potential drug interactions. Because of decreased gastrointestinal transit time, absorption of some drugs, especially those with poor permeability, may be decreased [303, 304]. Experimental evidence in rats suggests absorption of carbohydrates may result in decreased blood glucose levels and therefore monitoring of patients receiving hypoglycemic agents or insulin is warranted [305-307]. Concomitant use of stimulant laxatives with diuretics, cardiac glycosides and licorice is contraindicated due to hypokalemic effects, especially with long term use of these laxatives [27, 178, 304, 308, 309]. Senna can potentially interfere with antiplatelet and anticoagulant activity by causing excessive bleeding [310]. There is one case report of a possible interaction of aloe and sevoflurane, in which a 35 year old female patient undergoing surgery for heman‐ gioma experienced perioperative bleeding [311]. Although the size and vascularization of the hemangioma were noted as partial root causes of the bleeding episodes, the authors felt that the combination of anesthetic and aloe administration (4 tablets daily for 2 weeks prior to surgery) may have contributed to the adverse event.

#### **3.10. Licorice (***Glycyrrhiza glabra***)**

Licorice has historically been used both medicinally and as a food product and its relative safety at low doses has placed it on the U.S. FDA GRAS (generally recognized as safe) list, although at high doses licorice can cause severe adverse effects [27]. The main active components of licorice are glycyrrhizin and glycyrrhizic acid, although several other active constituents have been identified [312, 313]. One of the main adverse effects of high licorice consumption includes mineralocorticoid excess syndrome and resulting hypokalemia with associated increases in blood pressure, as well as secondary pseudohyperaldosteronism [314-338]. Licorice consumption may also alter blood glucose levels, potentially via binding to PPAR-γ [339, 340]. Although licorice is used in dietary supplements for weight loss, contradictory evidence reports weight gain with licorice consumption [341-343]. However, one study in which 3.5 grams daily licorice consumption was administered to 15 normal weight subjects for two months reports a significant decrease in body fat mass but not body mass index [344, 345].

Acquisition of mineralocorticoid excess syndrome following high dose consumption of licorice results in the potential for licorice-drug interactions with multiple drug classes, including aldosterone receptor antagonists, antiarrhythmics, antihypertensives, cardiac glycosides, corticosteroids, diuretics, and potassium lowering agents [321-324, 326]. In one study, 10 healthy subjects were given 32 grams of licorice daily for two weeks along with 25 mg of hydrochlorothiazide (HCTZ); a significant reduction in potassium levels was observed, while two patients experience hypokalemia, compared to HCTZ alone [346]. Glycyrrhizin and βglycyrrhetinic acid may also affect complement activity and decrease neutrophil generated oxides and peroxides, resulting in anti-inflammatory activity [347-350]. Therefore, licorice should be used with caution in patients taking other anti-inflammatory medications. Licorice constituents may also have an effect on hormonal agents via anti-estrogenic activity, inhibition of 17β-hydroxysteroid dehydrogenase, or associated decreases in prolactin levels [351-358]. In *in vitro* and animal studies it has been shown that constituents in licorice can promote the intestinal absorption of some drugs and therefore it is recommended that oral drugs be taken at least an hour before or two hours after licorice consumption [359]. Theoretically licorice may interact with antidepressant agents, since increases in norepinephrine and dopamine have been observed in mice while *in vitro* cell culture studies suggest potential serotonin reuptake inhibition [360, 361].
