Caffeine is a naturally occurring xanthine derivative used as a CNS and respiratory stimulant, or as a mild diuretic. Other xanthine derivatives include the bronchodilator theophylline and theobromine, a compound found in cocoa and chocolate. Caffeine is found in many beverages and soft drinks. Caffeine is often combined with analgesics or with ergot alkaloids for the treatment of migraine and other types of headache. Caffeine is also sold without a prescription in products marketed to treat drowsiness, or in products for mild water-weight gain. Caffeine was first approved by the FDA for use in a drug product in 1938. Clinically, it is used both orally and parenterally as a respiratory stimulant in neonates with apnea of prematurity. Caffeine reduces the frequency of apneic episodes by 30—50% within 24 hours of administration.1 Caffeine is preferred over theophylline in neonates due to the ease of once per day administration, reliable oral absorption, and a wide therapeutic window. A commercial preparation of parenteral caffeine, Cafcit®, was FDA approved for the treatment of apnea of prematurity in October 1999, after years of availability only under orphan drug status (e.g., Neocaf). The FDA has continued the orphan drug status of the approved prescription formulation.

L-theanine is a water-soluble amino acid that can be found in mushrooms and green tea. Purified L-theanine is marketed as an oral dietary supplement with purported antioxidant and sedative properties. Numerous investigations conducted on animals and in vitro reveal that the compounds have lipid-lowering,  neuroprotective, antiobesity, and anticancer effects. Other laboratory research suggests L-theanine may influence neurotransmitter levels, reduce cognitive impairment brought on by beta-amyloid, and lengthen life expectancy in C. elegans.
There have been a few studies done on humans as well. Although there were good effects on sleep, there were no significant effects on anxiety in a double-blind trial of supplementary L-theanine for generalized anxiety disorder. Although bigger, well-designed trials are required, several small studies in patients with other illnesses point to benefits in sleep quality as well as a potential reduction in depression, anxiety, and cognitive deficits. Although effects seen with caffeine alone in one study were lost with concurrent L-theanine, some studies testing L-theanine with caffeine suggest increases in cognitive performance. L-theanine helped schizophrenia patients sleep better and with less anxiety when used in conjunction with antipsychotic medication.
Epidemiological evidence suggests drinking green tea may help prevent strokes, but it's not obvious if L-theanine by itself can have this effect.
According to preclinical research, doxorubicin and idarubicin's chemotherapeutic effectiveness are enhanced by L-theanine, and their side effects are reduced. However, since these effects are not supported by clinical research and epigallocatechin-3-gallate (EGCG), a compound found in green tea, decreases the efficacy of the chemotherapy medicine bortezomib, patients receiving chemotherapy should talk with their doctors before using L-theanine. 2

Dehydroepiandrosterone (DHEA) is a C19 steroid also known as 5-androsten-3 beta-ol-17-one. DHEA and DHEAS (an active, sulfated form of DHEA), are endogenous hormones secreted by the adrenal cortex in primates and a few non-primate species in response to ACTH. DHEA is a steroid precursor of both androgens and estrogens, and thus is often called 'the mother hormone'. Endogenous DHEA is thought to be important in several endocrine processes, but current medical use of DHEA is limited to controlled clinical trials. In 1997, Pharmadigm, Inc. received an orphan drug designation to enroll patients with thermal burns who require skin-grafting into trials using injectable DHEAS, known as PB-005. Researchers continue to investigate the role of both endogenous and exogenous DHEA in CNS, psychiatric, endocrine, gynecologic and obstetric, immune, and cardiovascular functions.3 GeneLabs Technologies, Inc., submitted an NDA in September 2000 for its proprietary DHEA product, called prasterone (Prestara™, formerly known Aslera™ or GL-701). Prasterone appears to attentuate some symptoms of mild-to-moderate systemic lupus erythematosus (SLE) and may increase bone density based on evidence from two phase III studies in women; studies in men with SLE are ongoing. The FDA placed Prestara™ under a 6-month priority review status in October 2000; on April 19, 2001 the FDA stated that although the drug showed advantages over placebo in one study, the advantages were not statistically significant. Additional data were submitted to the FDA following a 'not approvable' letter on June 26, 2001. On September 2, 2002, the FDA issued an 'approvable' letter for the Prestara™ product, but the agency has asked for additional clinical trial data regarding the drug's effects on bone mineral density before granting final approval for SLE. The manufacturer began a confirmatory phase III trial in early 2003; the primary endpoint will be measurement of bone mineral density of the lumbar spine; the trial is targeted for completion at the end of 2003. In October 2004, the manufacturer released information that Prestara™ therapy did not meet the primary end point in the confirmatory trial. In August 2003, Paladin Labs Inc., received orphan drug designation from the FDA for prasterone, dehydroepiandrosterone, DHEA, under the brand name Fidelin™, for adrenal insufficiency.

Exogenously administered DHEA is sold as a nutritional supplement in health and drug stores and many older individuals are using it to 'maintain the vitality of their youth'. There is currently no objective, well-controlled, large-scale, scientific evidence to back claims that taking DHEA combats the signs or symptoms of aging, diabetes, neurologic disease, sexual dysfunction, or heart disease.4 Some athletes abuse DHEA believing that it can enhance the body's synthesis of testosterone; the potential action of DHEA as an anabolic steroid has lead to the prohibition of supplementation in competitive sport, even though evidence of anabolic effects in athletes is lacking.5 DHEA is also abused by athletes in an attempt to normalize the testosterone:epitestosterone ratio. However, the sensitivity and specificity of currently available testing for athletic 'doping' can readily identify the presence of banned substances, including testosterone. Because of DHEA's complex physiologic actions, more than 500 scientific articles investigating it have been published since 1993. Many of the short-term trials of DHEA to date have lacked the rigor and statistical applications needed to support therapeutic claims. Most claims will need to be confirmed by large-scale, properly conducted, and controlled studies. In 1984, the FDA banned the non-prescription (OTC) sale of exogenous DHEA due to concern over hepatotoxicity (hepatitis and hepatic tumors) as noted in animal studies. The FDA formally relegated DHEA to a Category II OTC ingredient at that time (i.e., not generally recognized as safe and effective). However in 1994, the passage of the US Dietary Supplement Health and Education Act (DSHEA) allowed DHEA to be marketed as a nutritional or dietary supplement.

Inositol is a family of cyclic sugar alcohols consisting of nine stereoisomers of hexahydroxycyclohexane. The stereoisomers of the inositol family are myo-, scyllo-, muco-, neo-, allo-, epi-, cis-, and the enantiomers L- and D-chiro-inositol. Of these, myo-inositol and D-chiro-inositol are among the most abundant biologically active forms. The enzyme epimerase converts myo-inositol to the D-chiro-inositol isomer, maintaining organ-specific ratios of the two isomers. Physiologically, the concentration of myo-inositol is several times higher than D-chiro-inositol in most tissues.6

The myo-inositol derivative phosphatidylinositol is an important component of the lipid bilayer of cell membranes. Phosphatidylinositol and its phosphorylated forms act as second messengers that are involved in a host of cellular functions including membrane trafficking, autophagy, cell migration, and survival. Disruption of phosphoinositide lipid signaling is implicated in cancer, diabetes, and cardiovascular disorders.7

Inositol has shown clinical benefits in treating disorders associated with metabolic syndrome. Inositol supplementation has been effectively used to accelerate weight loss, reduce fat mass,8 improve serum lipid profiles and upregulate the expression of genes involved in lipid metabolism and insulin sensitivity9 in women with polycystic ovarian syndrome. Myo-inositol alone or in combination with D-chiro-inositol significantly reduced weight, BMI, and waist-hip circumference ratios in overweight/obese women with PCOS. Weight loss, reduction in fat mass and increase in lean mass were accelerated when inositol supplementation was accompanied by a low-calorie diet.10 In addition, inositol supplementation was associated with lower rate of gestational diabetes and preterm delivery in pregnant women.8 Currently, research is being performed to assess whether inositol may be used in treating various cancers.

Methionine is a sulfur-containing branched-chain amino acid. A precursor for cellular methylation reactions, methionine plays an important role in lipid metabolism, polyamine synthesis, immune function, heavy metal chelation, and maintenance of redox balance.11 Conversely, dietary methionine restriction in rodents increased energy expenditure, improved insulin resistance, and enhanced lipolysis and fatty acid oxidation in adipose tissue.12

The lipotropic effects of methionine may be attributed to its metabolite S-adenosyl methionine (SAM). SAM is synthesized from methionine via an energy-consuming reaction. SAM administered orally or by injection has been investigated as a treatment for liver diseases, osteoarthritis, and depression.13 The benefits bestowed by SAM may be due to its role as a methyl donor in biochemical processes governing lipid homeostasis, DNA stability, gene expression, and neurotransmitter release.141516

Methylcobalamin, or vitamin B12, is a B-vitamin. It is found in a variety of foods such as fish, shellfish, meats, and dairy products. Although methylcobalamin and vitamin B12 are terms used interchangeably, vitamin B12 is also available as hydroxocobalamin, a less commonly prescribed drug product (see Hydroxocobalamin monograph), and methylcobalamin. Methylcobalamin is used to treat pernicious anemia and vitamin B12 deficiency, as well as to determine vitamin B12 absorption in the Schilling test. Vitamin B12 is an essential vitamin found in the foods such as meat, eggs, and dairy products. Deficiency in healthy individuals is rare; the elderly, strict vegetarians (i.e., vegan), and patients with malabsorption problems are more likely to become deficient. If vitamin B12 deficiency is not treated with a vitamin B12 supplement, then anemia, intestinal problems, and irreversible nerve damage may occur.

The most chemically complex of all the vitamins, methylcobalamin is a water-soluble, organometallic compound with a trivalent cobalt ion bound inside a corrin ring which, although similar to the porphyrin ring found in heme, chlorophyll, and cytochrome, has two of the pyrrole rings directly bonded. The central metal ion is Co (cobalt). Methylcobalamin cannot be made by plants or by animals; the only type of organisms that have the enzymes required for the synthesis of methylcobalamin are bacteria and archaea. Higher plants do not concentrate methylcobalamin from the soil, making them a poor source of the substance as compared with animal tissues.

Naltrexone is an oral opiate receptor antagonist. It is derived from thebaine and is very similar in structure to oxymorphone. Like parenteral naloxone, naltrexone is a pure antagonist (i.e., agonist actions are not apparent), but naltrexone has better oral bioavailability and a much longer duration of action than naloxone. Clinically, naltrexone is used to help maintain an opiate-free state in patients who are known opiate abusers. Naltrexone is of greatest benefit in patients who take the drug as part of a comprehensive occupational rehabilitative program or other compliance-enhancing program. Unlike methadone or LAAM, naltrexone does not reinforce medication compliance and will not prevent withdrawal. Naltrexone has been used as part of rapid and ultrarapid detoxification techniques. These techniques are designed to precipitate withdrawal by administering opiate antagonists. These approaches are thought to minimize the risk of relapse and allow quick initiation of naltrexone maintenance and psychosocial supports. Ultrarapid detoxification is performed under general anesthesia or heavy sedation. While numerous studies have been performed examining the role of these detoxification techniques, a standardized procedure including appropriate medications and dose, safety, and effectiveness have not been determined in relation to standard detoxification techniques.17 Naltrexone supports abstinence, prevents relapse, and decreases alcohol consumption in patients treated for alcoholism. Naltrexone is not beneficial in all alcoholic patients and may only provide a small improvement in outcome when added to conventional therapy. The FDA approved naltrexone in 1984 for the adjuvant treatment of patients dependent on opiate agonists. FDA approval of naltrexone for the treatment of alcoholism was granted January 1995. The FDA approved Vivitrol, a once-monthly intramuscular naltrexone formulation used to help control cravings for alcohol in April 2006, and then in October 2010, the FDA approved Vivitrol for the prevention of relapse to opioid dependence after opioid detoxification.

Phentermine is an oral sympathomimetic amine used as an adjunct for short-term (e.g., 8—12 weeks) treatment of exogenous obesity. The pharmacologic effects of phentermine are similar to amphetamines. Phentermine resin complex was approved by the FDA in 1959, but is no longer marketed in the US. Phentermine hydrochloride was FDA approved in 1973. In the mid-90s, there was renewed interest in phentermine in combination with another anorectic, fenfluramine, for the treatment of obesity and substance abuse, however, little scientific data support this practice. On July 8, 1997, the FDA issued a 'Dear Health Care Professional' letter warning physicians about the development of valvular heart disease and pulmonary hypertension in women receiving the combination of fenfluramine and phentermine; fenfluramine was subsequently withdrawn from the US market in fall of 1997. Use of phentermine with other anorectic agents for obesity has not been evaluated and is not recommended. In May 2011, the FDA approved a phentermine hydrochloride orally disintegrating tablet (Suprenza) for the treatment of exogenous obesity.18

Yohimbine is an oral alpha-2 blocker that is chemically related to reserpine. It is an alkaloid found in the bark of Rubiaceae and related trees, but can also be found in Rauwolfia serpentina. Yohimbine has been proposed as a treatment for erectile dysfunction (ED), however only limited evidence exist. According to ED treatment guidelines, only one small study in the published literature used acceptable efficacy outcome measures; therefore, conclusions about the clinical efficacy of yohimbine have not been established and its use in the treatment of ED is not recommended. Further, associated adverse events such as elevations of blood pressure and heart rate, increased motor activity, irritability, and tremor may limit its use.1920 Yohimbine has been available since before 1938.

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