Книги фарма 2 / Bertram G. Katzung-Basic & Clinical Pharmacology(9th Edition)

Pharmacologic Effects

Central Nervous System Effects

The mechanism of action of kava on the central nervous system is not known. Since kava shares similar central nervous system effects with the benzodiazepines, GABA receptors were thought to be involved. In vitro, kavalactones have been shown to bind readily to GABAA receptors located in the hypothalamus and amygdala, areas thought to be largely responsible for emotion and memory rather than cognition and movement. However, kavalactones do not compete with flunitrazepam or diazepam for benzodiazepine binding sites. Kava may also increase the number of GABA-binding sites.

Other suggested mechanisms include reduced excitatory neurotransmission by decreasing the release of glutamate, inhibition of norepinephrine uptake, reversible MAO-B inhibition, or dopamine antagonism.

Kava has also been shown to have mild anticonvulsant properties in animals, possibly involving voltage-dependent sodium channels.

Research is needed to assess reported analgesic effects in humans. Animal data suggest that opioid receptors are not involved in the actions of kava.

Antiplatelet Effects

One of the kavalactones, kavain, has in vitro cyclooxygenase-inhibiting activity. The potential for antiplatelet and anti-inflammatory effects needs further study.

Clinical Trials

Anxiety

Kava is most often used as a sedative-hypnotic to treat anxiety. The substance has been evaluated in Europe and in the USA for the treatment of anxiety in several placebo-controlled studies. Most of these trials have shown significant improvements in anxiety symptoms in patients with moderate to severe anxiety within 8 weeks after starting treatment. In one study, kava was compared with oxazepam, a benzodiazepine. Similar reductions in anxiolytic effects and fewer adverse effects were reported for the kava group. Kava appears to have a slow onset of action for the treatment of anxiety symptoms, most patients responding only after 4–8 weeks. Kava should not be used to treat acute symptoms of anxiety or panic attacks.

Adverse Effects

In most patients, kava's adverse effects are mild at recommended doses. These effects include tingling in the mouth and gastrointestinal upset. Kava does not seem to impair memory or cognitive function to the same degree as benzodiazepines.

Kava can cause central nervous system effects such as sedation, euphoria, and visual and auditory changes. Ataxia, muscle weakness, paresthesias, and even ascending paralysis have also been reported with excessive kava doses. Clinical evidence suggests that kava does not induce physiologic dependence, though it may lead to psychologic dependence. Reactions resembling dopaminergic antagonism have been reported. All patients were using kava at recommended doses

and experienced dystonic extrapyramidal reactions.

Kava has been shown to alter uterine tone in vitro and should be avoided during pregnancy. Kavalactones are soluble and excreted into breast milk. Women who are nursing should avoid kava.

An ichthyosiform skin rash has been seen when kava is taken at very high doses chronically. It is associated with facial swelling and photosensitivity. Exfoliation on the palms of the hands and soles of the feet, forearms, back, and shins has also been described. Sebaceous gland skin eruptions have been reported, with lymphocytic infiltrates on biopsy. Kava dermopathy is reversible on cessation of consumption.

Since 1999, eleven cases of kava-induced hepatitis have been reported in the USA, Germany, and Switzerland. Various kava products were used at varying doses (60–240 mg/d). Liver biopsies revealed hepatic necrosis requiring liver transplants. As a result, kava products have been removed from the market in Canada, Germany, Switzerland, and Australia.

Drug Interactions

Kava predictably potentiates the effects of other central nervous system depressants such as alcohol and possibly barbiturates. Combining kava with alcohol may result in additive or greater impairment of cognitive performance. Impaired motor function can also occur when kava is combined with central nervous system depressants. One case has been reported of a patient who combined alprazolam with kava and presented in a semicomatose state. Kavalactones inhibit cytochrome P450 isozymes, particularly 3A4, 2C9, 2C19, 2D6, and 1A2. Alprazolam is primarily metabolized by CYP3A4. A decrease in levodopa effectiveness was reported in one patient with Parkinson's disease. The use of kava with dopamine agonists or antagonists should be avoided.

Dosage

Fifty to 70 milligrams of purified kavalactones three times daily appears to be the optimal antianxiety dosage. This is equivalent to 100–250 mg of dried kava root extract three times daily. As a hypnotic, 180–210 mg of kavalactones may be taken 30 minutes to 1 hour before bedtime. Until more is known about the risk of kava-induced hepatotoxicity and drug interactions, kava is not recommended for use. If patients insist on using kava, use should be limited to 3 months or less to minimize the potential for dependence and hepatotoxicity.

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Milk Thistle (Silybum Marianum)

Chemistry

The fruit and seeds of the milk thistle plant contain a lipophilic mixture of flavonolignans known as silymarin. Silymarin comprises 2–3% of the dried herb and is composed of three primary isomers, silybin (also known as silybinin or silibinin), silychristin (silichristin), and silydianin (silidianin).

Silybin is the most prevalent and potent of the three isomers and accounts for about 50% of the silymarin complex. Products should be standardized to contain 70–80% silymarin.

Pharmacologic Effects

Liver Disease

In animal models, milk thistle limits hepatic injury associated with a variety of toxins, including Amanita mushrooms, galactosamine, carbon tetrachloride, acetaminophen, radiation, cold ischemia, and ethanol. In vitro studies and some in vivo studies demonstrate that silymarin reduces lipid peroxidation, scavenges free radicals, and enhances glutathione and superoxide dismutase levels. This may contribute to membrane stabilization and reduce toxin entry.

Milk thistle may have anti-inflammatory properties. In vitro, silybin strongly and noncompetitively inhibits lipoxygenase and leukotriene formation. On the other hand, concentrations required to inhibit thromboxane and prostaglandin formation in vivo probably exceed dosing capabilities. Inhibition of leukocyte migration has also been observed in vivo and may be a factor when acute inflammation is present.

One of the most unusual mechanisms claimed for milk thistle involves an increase in RNA polymerase I activity in nonmalignant hepatocytes but not in hepatoma or other malignant cell lines. By increasing this enzyme's activity, enhanced protein synthesis and cellular regeneration may occur in diseased but not malignant cells. Milk thistle may have a role in hepatic fibrosis. In an animal model of cirrhosis, it reduced collagen accumulation, and in an in vitro model it reduced expression of the profibrogenic cytokine TGF-.

It has been suggested that milk thistle may be beneficial in the management of hypercholesterolemia and gallstones. A small trial in humans showed a reduction in bile saturation index and biliary cholesterol concentration. The latter may reflect a reduction in liver cholesterol synthesis. To date, however, there is insufficient evidence to warrant the use of milk thistle for either of these disorders.

Chemotherapeutic Effects

Preliminary in vitro and mouse studies have been carried out with skin, breast, and prostate cancer cell lines. In murine models of skin cancer, milk thistle reduced tumor initiation and promotion. It also inhibited cell growth and proliferation by inducing a G1 cell cycle arrest in cultured human breast and prostate cancer cell lines. However, the use of milk thistle in the treatment of cancer has not yet been adequately studied and should not be recommended to patients.

Clinical Trials

Milk thistle has been used to treat acute and chronic viral hepatitis, alcoholic liver disease, and toxin-induced liver injury in human patients. Milk thistle has most often been studied in the treatment of alcoholic hepatitis and cirrhosis. In both of these disorders, outcomes have been mixed and reports include significant reductions in markers of liver dysfunction and in mortality, as well as no effect. In acute viral hepatitis, studies have generally involved small sample sizes and have shown mixed outcomes of improved liver function (eg, aminotransferase values, bilirubin, prothrombin time) or no effect. Studies in chronic viral hepatitis and toxin-induced injury have also been of small size but have reported mostly favorable results. Parenteral silybin is marketed and used in Europe as an antidote in Amanita phalloides mushroom poisoning, based on favorable outcomes reported in case-control studies.

Overall, milk thistle may be effective in improving survival and liver function in a variety of conditions, but additional well-designed clinical trials are needed to confirm these findings.

Adverse Effects

Milk thistle has rarely been reported to cause adverse effects. Loose stools associated with increased bile secretion may occur at high doses.

Drug Interactions, Precautions, & Dosing

There are no reported drug-drug interactions or precautions for milk thistle. Recommended dosage is 200–400 mg/d, calculated as silybin, in three divided doses.

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St. John's Wort (Hypericum Perforatum)

Chemistry

St. John's wort, also known as hypericum, contains a variety of constituents that may contribute to its pharmacologic activity. Hypericin, a marker of standardization for currently marketed products, was thought to be the primary antidepressant constituent. Recent attention has focused on hyperforin, but a combination of several compounds is probably involved. Commercial formulations are usually prepared by soaking the dried chopped flowers in methanol to create a hydroalcoholic extract that is then dried.

Pharmacologic Effects

Anti-Depressant Action

The hypericin fraction was initially reported to have MAO-A and -B inhibitor properties. Later studies found that the concentration required for this inhibition was higher than that which could be achieved with recommended dosages. In vitro studies using the commercially formulated hydroalcoholic extract have shown inhibition of serotonin, norepinephrine, and dopamine reuptake. While the hypericin constituent did not show reuptake inhibition for any of these systems, a concentrated hyperforin extract did. Chronic administration of the commercial extract has also been shown to significantly down-regulate the expression of cortical -adrenoceptors and up-regulate the expression of serotonin receptors in a rodent model.

Other effects observed in vitro include opioid sigma receptor binding using the hypericin fraction and GABA receptor binding using the commercial extract. Interleukin-6 production is also reduced in the presence of the extract.

A number of clinical trials have shown St. John's wort to be more efficacious than placebo and just as efficacious as some prescription antidepressants for mild to moderate depression. It does not appear to be effective, however, for more severe depression. Most trials used doses of St. John's wort ranging from 300 mg/d to 1000 mg/d and lasted 4–8 weeks.

Antiviral and Anticarcinogenic Effects

The hypericin constituent of St. John's wort is photolabile and can be activated by exposure to certain wavelengths of visible or UVA light. Parenteral formulations of hypericin (photoactivated just before administration) have been used investigationally to treat HIV infection (given

intravenously) and basal and squamous cell carcinoma (given by intralesional injection). In vitro, photoactivated hypericin inhibits a variety of enveloped and nonenveloped viruses as well as the growth of cells in some neoplastic tissues. Inhibition of protein kinase C and of singlet oxygen radical generation have been proposed as possible mechanisms. The latter could inhibit cell growth or cause cell apoptosis. These studies were carried out using the isolated hypericin constituent of St. John's wort; the usual hydroalcoholic extract of St. John's wort has not been studied for these indications and should not be recommended for patients with viral illness or cancer.

Adverse Effects

Photosensitization has been reported, and patients should be instructed to wear sunscreen while using this product. Hypomania, mania, and autonomic arousal have also been reported in patients using St. John's wort.

Drug Interactions & Precautions

Inhibition of reuptake of various amine transmitters has been highlighted as a potential mechanism of action for St. John's wort. Drugs with similar mechanisms (ie, antidepressants, stimulants) should be used cautiously or avoided in patients using St. John's wort due to the risk of serotonin syndrome or MAO crisis (see Chapters 30 and 59). This herb may induce hepatic CYP enzymes and the P- glycoprotein drug transporter. This has led to case reports of subtherapeutic levels of digoxin, birth control drugs (and subsequent pregnancy), cyclosporine, HIV protease and nonnucleoside reverse transcriptase inhibitors, warfarin, irinotecan, theophylline, and anticonvulsants.

Dosage

The most common commercial formulation of St. John's wort is the dried hydroalcoholic extract. Products are currently standardized to contain 0.3% hypericin. This may change to reflect the new results implicating hyperforin, which should be 2–5%. The recommended dosing for mild to moderate depression is 900 mg of the dried extract per day in three divided doses. Onset of effect may take 2–4 weeks. Long-term benefits beyond 8 weeks have not been sufficiently studied.

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Saw Palmetto (Serenoa Repens or Sabal Serrulata)

Chemistry

The active constituents in saw palmetto berries are not well defined. Phytosterols (eg, -sitosterol), aliphatic alcohols, polyprenic compounds, and flavonoids are all present. Marketed preparations are lipophilic extracts that contain 85–95% fatty acids and sterols.

Pharmacologic Effects

Saw palmetto is most often used in the treatment of benign prostatic hyperplasia. Enzymatic conversion of testosterone to dihydrotestosterone (DHT) by 5-reductase is inhibited by saw palmetto in vitro. This effect is similar to that of finasteride, which is also used to treat the disorder (Chapter 40: The Gonadal Hormones & Inhibitors). In vitro, saw palmetto also inhibits the binding of DHT to androgen receptors. Additional effects that have been observed in vitro include inhibition of prostatic growth factors, blockade of 1-adrenoceptors, and inhibition of inflammatory mediators

produced by the 5-lipoxygenase pathway.

The clinical pharmacology of saw palmetto is not well defined. One week of treatment in healthy volunteers failed to influence 5-reductase activity, DHT concentration, or testosterone concentration. Six months of treatment in patients with benign prostatic hyperplasia also failed to affect prostate-specific antigen (PSA) levels, a marker that is typically reduced by enzymatic inhibition of 5-reductase. In contrast, other researchers have reported a reduction in epidermal growth factor, DHT levels, and estrogen expression after three months of treatment in patients with benign prostatic hyperplasia. The largest clinical trial to date compared saw palmetto, 320 mg/d, with finasteride, 5 mg/d, in 1098 patients. At 6 months, overall symptom score, quality of life, and peak urinary flow were significantly improved for both groups. Finasteride was significantly better at reducing prostate volume (18% versus 6%, respectively). Adverse effects were comparable in both groups except for a significantly greater degree of sexual dysfunction in patients receiving finasteride versus saw palmetto. Shortcomings in the latter trial included lack of placebo control and failure to extend the study duration beyond 6 months.

In a systematic review of seven double-blind placebo-controlled trials, saw palmetto was found to be significantly more effective than placebo in reducing nocturnal urinary frequency (33–74% versus 13–39%, respectively), in reducing daytime urinary frequency (11–43% versus 1–29%, respectively), and in increasing peak urinary flow (26–50% versus 2–35%, respectively). A recent meta-analysis of randomized controlled trials also indicated a therapeutic advantage of saw palmetto over placebo in improving urologic symptoms and flow measures.

Small comparative trials of saw palmetto versus -blockers showed greater symptomatic improvement with -blockers.

Adverse Effects

In the largest clinical trial conducted to date, adverse events reported with an incidence of 1–3% included hypertension, decreased libido, abdominal pain, impotence, back pain, urinary retention, and headache. In another large-scale trial, gastrointestinal upset was the most common side effect.

Drug Interactions, Precautions, & Dosing

No drug-drug interactions have been reported for saw palmetto. Patients should be instructed that it may take 4–6 weeks for onset of clinical effects. Recommended dosing of a standardized dried extract (containing 85–95% fatty acids and sterols) is 160 mg orally twice daily. The efficacy of saw palmetto in benign prostatic hyperplasia beyond 6 months has not been established.

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Dehydroepiandrosterone

Dehydroepiandrosterone (DHEA) is a precursor hormone secreted by the adrenal cortex and to a lesser extent by the central nervous system (Chapter 40: The Gonadal Hormones & Inhibitors). It is readily converted to androstenedione, testosterone, and androsterone. In peripheral tissues, aromatase converts DHEA to estradiol. In the plasma, DHEA is converted to DHEA sulfate (DHEAS).

Although no specific physiologic function has been attributed to DHEA or DHEAS, the

relationships between their endogenous levels and various diseases have been widely studied. Exogenous DHEA supplementation has been advocated for a variety of indications, including relief of age-related disorders, promotion of weight loss, reduction of heart disease risk, prevention of a variety of cancers, and strengthening of the immune system.

Clinical Uses

Weight Loss

Only a few poorly designed studies have assessed the effects of DHEA supplements in facilitating weight loss. Each of these studies employed a very small sample size and varying measures of weight loss. The effects of DHEA on weight loss are therefore uncertain. Until more is known, DHEA should not be recommended as a weight loss agent.

Cardiovascular Disease

DHEA may affect the synthesis of cholesterol and other lipids involved in atherogenesis. Many studies have assessed the relationship between endogenous DHEA levels and the risk for developing cardiovascular disease. Both high and low DHEA levels have been associated with increased risk of cardiovascular morbidity in men. In postmenopausal women, cardiovascular morbidity was greater in women with high DHEAS levels.

Hypercholesterolemia

The effects on cholesterol values in the few studies reported to date have been modest and variable. Thus, the role of DHEA in hypercholesterolemia in men and women has not been determined. According to existing information, endogenous levels of DHEA do not correlate with cholesterol regulation or synthesis. DHEA supplementation might have a role in decreasing HDL cholesterol in postmenopausal women since DHEA is converted to estradiol and to a lesser extent testosterone. These proposed effects need to be assessed using adequate study design.

Aging

Because DHEA and DHEAS levels decline with age, DHEA has been advocated as replacement therapy to prevent age-associated changes (especially in sexual function in men) and diseases. DHEA has demonstrated some antioxidant effects. The extent to which DHEA may decrease free radical formation, however, requires further study.

A low DHEA dose is adequate to increase DHEAS levels to those of a 20or 30-year-old individual, and some evidence suggests that DHEA replacement dosing increases mean free testosterone levels in elderly men (by 5–10% after DHEA initiation, remaining slightly elevated for 2–3 months). The clinical significance of this effect is not known.

There is insufficient evidence at present to recommend DHEA in preventing any age-associated diseases.

Alzheimer's Disease

The role of DHEA supplementation in Alzheimer's disease remains controversial. Some research suggests that low endogenous DHEA and DHEAS levels correlate with dementia, while other reports are negative. Research is continuing to assess the effects of DHEA supplementation on

dementia and Alzheimer's disease.

Treatment of HIV Infection and AIDS

Early studies in mice demonstrated that DHEA supplementation afforded protection against certain virus infections. Furthermore, DHEA affected T lymphocytes by increasing IL-2 production and decreasing IL-4, IL-5, and IL-6 release. The effect of DHEA supplementation on HIV disease progression has therefore been assessed in both men and women. Women reported improvements in energy, cognitive and physical functioning, emotional well-being, and health perception. Modest increases in body weight and CD4 cell counts were seen in women receiving DHEA. No patients displayed a statistically significant decline in viral load. Although male subjects reported improvements in well being, changes in CD4 cell counts were not observed.

Systemic Lupus Erythematosus (SLE)

SLE is associated with low levels of endogenous DHEA and DHEAS in women. In one study, patients receiving DHEA for 6 months had fewer lupus flares and improved global assessment scores of disease activity as measured by retrospective medical record review. Adverse effects included acne, hirsutism, menstrual alterations, emotional changes, and weight gain. In another study, statistically significant improvements were observed in the SLE disease activity index during the first 3 months of therapy. However, nearly 60% of patients discontinued DHEA supplementation prior to the 1-year study completion. Reasons for discontinuation included lack of efficacy (30%) and androgenic side effects (14%).

Diabetes

Early evidence suggested that DHEA might be used to ameliorate insulin resistance in patients with diabetes. DHEA and DHEAS levels appear to decline in a variety of disease states characterized by insulin resistance or states associated with hyperinsulinism such as hypertension, obesity, and type 2 diabetes mellitus. These relationships have prompted the promotion of DHEA as a regulator of blood glucose levels. However, a role for DHEA in regulating blood glucose and the management of diabetes has not been adequately demonstrated. Until more information is available, patients with diabetes should not rely on DHEA to help control blood glucose.

Adverse Effects & Risks of DHEA & DHEAS Use

Benign Prostatic Hyperplasia and Prostate Cancer

The effects of DHEA on the prostate are still unknown. However, since DHEA supplementation can increase mean testosterone levels, it might contribute to increased prostate cell growth, and worsening of prostate cancer must be considered. Because the ultimate effects are unknown, patients with benign prostatic hyperplasia should avoid using DHEA. If a patient uses DHEA therapy, he should be closely monitored for signs and symptoms of prostate disease.

Other Cancers

DHEA supplementation can increase production of gonadal hormones. Therefore, DHEA should be avoided by patients with any type of hormone-dependent cancer.

Endocrine Effects

Endocrine adverse effects depend on gender and DHEA dose. DHEA is a precursor of gonadal hormones, and it appears to be preferentially converted to the hormone present in lowest quantities. In premenopausal women, DHEA is converted mainly to testosterone and minimally to estrogen. In men, conversion favors increased production of estrogen and to a lesser extent testosterone. Women therefore may complain of masculinizing effects such as hirsutism, acne, and deepening of the voice. Men may experience gynecomastia and breast tenderness.

Reports of euphoria or an increased sense of well-being are also common and may be related to increased release of corticosteroid congeners. DHEA has also been reported to cause mania and cardiac arrhythmias. Although these reports are rare, patients at risk for these effects should avoid taking DHEA.

Drug Interactions

Drug-drug interactions have not been systematically studied for DHEA. It is unknown whether DHEA interacts with over-the-counter medicine or prescription drugs.

Dosage

Replacement dosage sufficient to maintain DHEA levels at young adult values varies with gender and the individual. Approximately 25–50 mg daily is adequate for women, whereas 25–100 mg may be required for men. Adverse effects appear to be uncommon at these doses. Doses greater than 100 mg daily have been used to increase androgens and other hormones. Doses of 1600 mg daily have resulted in significant adverse effects, often requiring drug discontinuation.

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Melatonin

Melatonin, a serotonin derivative produced by the pineal gland and some other tissues (see also Chapter 16: Histamine, Serotonin, & the Ergot Alkaloids), is believed to be responsible for regulating sleep-wake cycles. Melatonin release coincides with darkness; it typically begins around 9 PM and lasts until about 4 AM. Melatonin release is suppressed by daylight. Melatonin has also been studied for a number of other functions, including contraception, protection against endogenous oxidants, prevention of aging, and treatment of depression, HIV infection, and a variety of cancers. Currently, melatonin is most often administered to induce sleep and to prevent jet lag.

Pharmacologic Effects & Clinical Uses

Jet Lag

Jet lag, a disturbance of the sleep-wake cycle, occurs when there is a disparity between the external time and the traveler's endogenous circadian clock (internal time). The internal time regulates not only daily sleep rhythms but also body temperature and many metabolic systems. The synchronization of the circadian clock relies on light as the most potent "zeitgeber" (time giver).

Jet lag is especially common among frequent travelers and airplane cabin crews. Typical symptoms of jet lag may include daytime drowsiness, insomnia, frequent awakenings, and gastrointestinal upset. Clinical studies with administration of melatonin have reported subjective reduction in daytime fatigue, improved mood, and a quicker recovery time (return to normal sleep patterns,

energy, and alertness). Unfortunately, many of these studies were characterized by inconsistencies in dosing, duration of therapy, and time of drug administration. In addition to melatonin, maximizing exposure to daylight on arrival at the new destination can aid in resetting the internal clock.

Insomnia

Melatonin has been studied in the treatment of various sleep disorders, including insomnia and delayed sleep-phase syndrome. Melatonin has been shown to improve sleep onset, duration, and quality when administered to healthy volunteers, suggesting a pharmacologic hypnotic effect.

Melatonin has also been shown to increase rapid-eye-movement (REM) sleep.

Clinical studies in patients with sleep disorders have shown that oral melatonin supplementation may alter sleep architecture. Subjective improvements in sleep quality and improvements in sleep onset and sleep duration have been reported. However, the significance of these findings is impaired by many study limitations.

Patients over 65 years of age tend to suffer from sleep maintenance insomnia; melatonin serum levels have been reported to be low in these patients. Elderly patients with sleep maintenance insomnia who received immediate-release and sustained-release melatonin had improved sleep onset time. They did not, however, experience an improvement in sleep maintenance or total sleep time.

Female Reproductive Function

Melatonin receptors have been identified in granulosa cell membranes, and significant amounts of melatonin have been detected in ovarian follicular fluid. Melatonin has been associated with midcycle suppression of luteinizing hormone surge and secretion. This may result in partial inhibition of ovulation. Nightly doses of melatonin (75–300 mg) given with a progestin through days 1–21 of the menstrual cycle resulted in lower mean LH levels. Therefore, melatonin should not be used by women who are pregnant or attempting to conceive. Furthermore, melatonin supplementation may decrease prolactin release in women and therefore should be used cautiously or not at all while nursing.

Male Reproductive Function

In healthy men, chronic melatonin administration ( 6 months) decreased sperm quality, possibly by aromatase inhibition in the testes. Until more is known, melatonin should not be used by couples who are actively trying to conceive.

Adverse Effects

Melatonin appears to be well tolerated and is often used in preference to over-the-counter "sleepaid" drugs. Although melatonin is associated with few adverse effects, some next-day drowsiness has been reported as well as tachycardia, depression, vivid dreams, and headache. Sporadic case reports of movement disorders and psychoses have also appeared.

Drug Interactions

Melatonin drug interactions have not been formally studied. Various studies, however, suggest that melatonin concentrations are altered by a variety of drugs, including NSAIDs, antidepressants, -