Drugs and Herbs for Weight Loss

Carolyn VanCouwenberghe RN PhD

September 29, 2001

Objectives: 

1. List drugs and herbs used for weight loss.
2. Identify mechanism of action and adverse reactions for each.
3. Describe strategies for evaluating claims that a given product would be useful in a weight loss program.

Abstract

In this session we will examine how drugs and the “alternative” or “complementary” therapies called “dietary supplements” (herbs, vitamins, minerals, enzymes, amino acids, organ tissues, glandulars and metabolites) work in a weight loss plan.  Many products are available which claim to decrease appetite, increase satiety, decrease fat absorption or speed metabolism.  Some have good research supporting their efficacy; for others the research is less convincing.  To date there is no “magic bullet” and no “morning after pill” for binge eaters.  Drugs or herbs may be useful as one component of a weight loss plan.  The process of bring an herb to market is very different than the process for bringing a drug to market.  From case reports and theoretical possibilities to double-blinded randomized multi-center trials, the data to support efficacy of the various products will be reviewed.  All products carry a risk of adverse reactions.  Users should be familiar with these risks in advance of product consumption.

1. What is the difference between a drug and a dietary supplement?
1. Both are substances that interact with the body to cause an effect.
2. Herbs come from “natural” plant sources.  Most drugs, at least originally, were obtained from these same natural sources.
3. Regulation is different.

                                                               i.      To bring a drug to market the pharmaceutical company must first conduct extensive research to show the drug is efficacious (it works) and safe.  The Food and Drug Administration reviews the data and may approve the drug to be sold and marketed.  Research on safety continues post-marketing.  Manufacturing standards are government regulated.

                                                             ii.      In 1994, the Dietary Supplement Health and Education Act (DSHEA) was signed into law creating regulatory requirements very different from those used for drugs.  To bring a dietary supplement to market, a company just needs a “reasonable” belief in it.  No research is required.  If significant adverse effects are found, the product is mislabeled, or advertising is very misleading, the FDA or the Federal Trade Commssion (FTC) can intervene.  Dietary supplements cannot be advertised as diagnosing, preventing, treating or curing a disease, but they can advertise that they affect the function or structure of the body. Inconsistency in herbal preparation has been noted.  (Cytotoxicity from various Ma-huang extracts could not be explained by the ephedrine contents alone suggesting the presence of other toxins. [1]   In Europe, at least 100 women taking Chinese herbs for weight loss developed kidney disease when one herb was substituted for another during preparation. [2] )

2. Research on drugs tends to be extensive and of good quality.  Research on dietary supplements is often sparse and of lesser quality.  Some things to look for in evaluating the research that supports the efficacy and safety of a weight loss product:
1. Mechanism: illogical ® reasonable idea proposed ® proven
2. Subjects: test tube ® non-human animals® healthy normal weight humans ® obese/overweight humans
3. Sample size: small ® large
4. Reproducible:  one group of investigators, one study or site ® multi-center, several studies by different investigators with consistent findings
5. Placebo effect:  not controlled for ® double blind
6. Extraneous variables:  not measured or controlled for ® randomized or measured/controlled
3. Taking drugs or herbs for weight loss
1. Who should: Appropriate patients are those with BMI>30 (or >27 for those with other obesity associated health problems such as diabetes or hypertension).  Patients should be motivated and compliant and should also be exercising and dieting.  Given the long-term consequences of obesity on health, should drugs be considered as an adjunct to diet, exercise and behavior modification in children and adolescents [3] ?  Currently there are no FDA approved drugs to treat obesity in children, [4] but trials are underway with subitramine and orlistat.
2. Who does:  A recent telephone survey provided estimates that more than 17 million Americans took over-the-counter (OTC) weight loss products (‘96-‘97), more than ¼ of young obese women and 8% of normal-weight women use nonprescription weight loss products, and more than 1/3 of women and 1/10 of men who use prescription weight loss products also use OTC products. [5] Direct-to-consumer advertising has dramatically increased the sales of products for weight loss.  By 1997, over 10 million prescriptions for “phen-fen” had been written. [6]   Americans consume 225,000 capsules of Metabolife every hour. (Annual retail revenues of $900 million. [7] )
4. Mechanisms for a drug or herb to reduce body weight or body fat.
1. Decrease appetite
2. Increase satiety
3. Decrease absorption
4. Increase metabolism
5. Specific agents
1. Phentermine (FASTIN, ADIPEX-P, IONOMIN, OBY-TRIM)

                                                               i.      Mechanism:  The “phen” of the recently withdrawn “phen-fen”, this drug increases amount of the neurotransmitter norepinephrine.  In brain, this reduces appetite.  Norepinephrine is the neurotransmitter for the sympathetic nervous system.  In the periphery, “fight or flight” sympathetic response stimulates fat cells to release energy for use by muscles and antagonizes use of glucose by cells.

                                                             ii.      Efficacy: In a 36 week study, subjects given phentermine continuously or every other month lost 26-28 pounds compared to 11 pounds lost in the placebo group. [8]

                                                            iii.      Safety:  Most people tolerate well with some complaints of insomnia or agitation. Tolerance to the appetite suppressant effect often develops after a few weeks of therapy.  Increasing norepinephrine level can cause rapid heart rate and high blood pressure.  People at risk for brain attacks (strokes), other complications of high blood pressure, hyperthyroidism, or abnormal heart rhythms should avoid or at least be closely monitored.  Diabetics use with caution as blood sugar may increase, and cells may have some resistance to insulin.

                                                                 iv.      Similar drugs: phedimetrazine (BONTRIL, PLEGINE, PRELU-2, X-TROZINE), mazindol (SANOREX, MAZANOR), and diethylproprion (TENUATE, TENUATE DOSPAN).  Phenylpropanolamine (DEXATRIM, ACCUTRIM, PPA) is no longer on the market due to adverse reactions associated with similar products such as ephedra.  Metamphetamine (AMPHETAMINE) is not used therapeutically due to problems with substance abuse.

2. Simutramine (MERIDIA)

                                                               i.      Mechanism:  Increases the neurotransmitters serotonin and norepinepherine.  Thus, it inhibits appetite, increases satiety and increases metabolism.  Effectiveness is probably related to the norepinephrine. [9]

                                                             ii.      Efficacy:  Research is of excellent quality to support its efficacy.  When coupled with diet and exercise, the average weight loss in one year is 10-14 pounds with benefits on lipid profiles (cholesterol, trigylcerides) and blood sugar in diabetics compared to 4 pounds lost for those people who took a placebo. [10] ^{, [11]}

                                                            iii.      Safety:  Generally very well tolerated.  Some people complain about dry mouth, insomnia and constipation.  A small increase in blood pressure and pulse can be expected.  One of only 2 products currently approved by FDA for long-term therapy (>1year).

3. Orlistat (XENICAL)

                                                               i.      Mechanism:  Works locally in the gut (not absorbed).  Inhibits the enzyme (lipase) that breaks fat down for absorption.  Thus about 30% of the ingested fat is not absorbed.  Must be taking at the same time as the fatty meal.

                                                             ii.      Efficacy:  Research is of excellent quality to support efficacy.  Over 1-2 years, people who took this drug in conjunction with diet and exercise lost about 10% of body weight compared to about 5% for people on placebo.  Treatment also reduced blood pressure, improved lipid profiles and reduced blood sugar in diabetics. [12]

                                                            iii.      Safety:  Well tolerated and without systemic side effects.  Early in therapy some complaints of gas and oily stools which are usually mild and transient.  Reduced absorption of fat-soluble vitamins and beta-carotene has been shown and these should be supplemented.  One of only 2 products approved by the FDA for long term >1 year use.

4. Fluoxetine (PROZAC)

                                                               i.      Mechanism:  Better known as an anti-depressant, it works by inhibiting reuptake of serotonin into nerves.  Because depression is often associated with weight gain, there has been interest in using antidepressants in helping with weight loss.

                                                             ii.      Efficacy:  Fluoxetine therapy for depression is often associated with weight loss during the first few weeks of therapy [13] , but this effect does not persist when longer-term studies are reviewed. [14] ^{, [15]}

                                                            iii.      Safety: Generally well tolerated.  Up to 10% of those taking will experience headache, insomnia, nausea and dry couth.

5. Bupropion (WELLBUTRIN, ZYBAN)

                                                               i.      Mechanism:  Approved as an antidepressant and smoking deterrent, this drug blocks serotonin, norepinephrine and dopamine reuptake.

                                                             ii.      Efficacy:  Many antidepressant drugs cause weight gain.  Bupropion does not seem to have this effect and may even be associated with weight loss [16] in 1 out of every 5-6 people who take it.

                                                            iii.      Safety; Most common adverse reactions are dry mouth and insomnia, but there is risk of agitation and seizures esp. at high doses.

6. Ephedra (Ma Huang, herbal phen-fen, METABOLIFE)

                                                               i.      Mechanism:  Ephedra contains the amphetamine-like substance ephedrine and is the natural form of phenylpropanolamine (PPA).  Thus its mechanism is similar to that of the drugs increasing norepinephrine.

                                                             ii.      Efficacy:  One of the best studied herbs if one considers ephedrine and PPA research.  Most studies have looked at combinations of ephedra with caffeine (guarana is herbal equivalent) and sometimes aspirin (willow bark is herbal equivalent).  Ephedrine (with caffeine and aspirin) results in a small but significant weight loss. [17] Evidence for efficacy of ephedra without caffeine or for the addition of aspirin to ephedra and caffeine is lacking. [18]  

                                                            iii.      Safety:

1.      12/93-9/95: The Texas Dept of Public Health received approx. 500 reports of adverse events associated with dietary supplements containing ephedrine-type ingredients.  Eight people died (usually from heart attack or stroke).  These adverse reactions were not always dose dependent.

2.      The FDA received more than 800 reports of adverse events associated with ephedra (1993-1997).   Restrictions were proposed to limit the suggested dose to no more than 8mg/serving and 24 mg/day with a maximum duration of 1 week.  Restrictions not passed.

3.      PPA was voluntarily withdrawn from the US market in November 2000.  The herbal equivalents are not regulated and remain available.

4.      Do not take if you have angina, high blood pressure, glaucoma, enlarged prostate or over-active thyroid.  Restricted herb in some countries.

7. Chromium (Cr)

                                                               i.      Mechanism:  Cr is an essential element for carbohydrate and lipid metabolism.  When deficient, lipid and glucose blood levels are elevated.  It is hypothesized that Cr may protect lean muscle mass and basal metabolic rate from diminishing during dieting.  If this is true, the higher metabolic rate might limit weight regain after dieting.

                                                             ii.      Efficacy: 

1.      Most research on Cr has been done on non-obese persons attempting to increase muscle mass in conjunction with weight training. 

2.      When taken for weight loss, studies have conflicting conclusions. For example, no benefit was found in a study on 95 navy personnel (Trent, 1995), while in another study, the group who took Cr lost significantly more weight than the placebo group (7.8 vs. 1.8kg) (Kaats, 1998)

3.      The FTC concluded that there was insufficient evidence to support advertising claims that Cr causes long-term weight loss, reduced body fat, or built muscle.  Product sales continue in excess of $100 million/year.

                                                            iii.      Safety:  In animal studies, even high doses of Cr were found to be safe.  However, in humans, there have been reports of severe muscle injury (rhabdomylosis) and kidney damage when the recommended dose is exceeded.

8. Garcinia cambogia (Hydroxycitric acid, HCA, brindle berry rind)

                                                               i.      Mechanism:  Thought to suppress appetite and inhibit citrate lyase, an enzyme involved in fat production.

                                                             ii.      Efficacy:  Compared with placebo, when administered alone, HCA resulted in significantly more weight loss in one study ^[19] but had no effect in another. [20]  Studies combining HCA with other agents such as Cr or Cr plus combinations of caffeine, L-carnitine, chitosan and/or fiber found greater reductions in body fat or weight using the herbs as compared to placebo in two studies [21] ^{, [22]} but no difference between the herbs and placebo in one study. [23]   HCA treatment was not found to increase fat burning during rest or moderately intense exercise. [24] ^{, [25]}

                                                            iii.      Safety: No significant safety concerns have been reported.

9. Benzocaine

                                                               i.      Mechanism:  Taken by mouth, this OTC anesthetic appears to impair the ability to detect sweetness.

                                                             ii.      Efficacy:  In a controlled study adding benzocaine to phenylpropanolamine increased adverse effects without increasing weight loss. [26]   No studies found to support efficacy.

                                                            iii.      Safety:  Infrequent rash and inflammation around blood vessels cited but may be based on experience with topical application.

10. Bladderwrack (focus vesiculosus)

                                                               i.      Mechanism:  Advertised as “organic iodine”, it claims to increase thyroid activity but likely has this effect only in poorly functioning thyroids.  Normal thyroid activity helps maintain metabolic rate.

                                                             ii.      Efficacy:  No evidence of efficacy in obesity. Thyroid hormone is ineffective for weight reduction.

                                                            iii.      Safety:  No safety data on herb.  Excessive thyroid hormone is associated with chest pain, rapid and abnormal heart beats, insomnia, nervousness, heat intolerance, seizures and a host of other unpleasant/dangerous effects.

11. Chitosan

                                                               i.      Mechanism: A polymer of glucosamine produced from the shells of crabs, shrimp and lobster. Purported to block absorption of fat from the gut.

                                                             ii.      Efficacy:  Limited research has been done.  Chitosan prevented weight gain in mice on a high-fat diet. [27] In a recent randomized double-blind study in humans, no difference in BMI was found between chitosan and placebo. [28]

                                                            iii.      Safety:  Minimal safety assessment has been done.  Long-term effect on fat-soluble vitamins is unknown.

12. Nomame Herba

                                                               i.      Mechanism:  Inhibit lipase activity.

                                                             ii.      Efficacy:  In mice, reduced weight gain and elevation in trigycerides when fed a high fat diet. [29]

                                                            iii.      Safety: Unknown.

13. Galega (Goat’s Rue, French Lilac)

                                                               i.      Mechanism: Herb with hypoglycemic effects and possible weight reduction effects by unknown mechanism thought to involve body fat.

                                                             ii.      Efficacy: In mice shown to reduce food intake and then prevent weight gain even with increased eating. [30]   No human studies found.

                                                            iii.      Safety:  Diabetics should not use unless medically supervised.

14. Conjugated Linoleic Acid (CLA)

                                                               i.      Mechanism: CLA describes a class of trans-fatty acids found primarily in meat and dairy products of ruminant animals.  It inhibits deposition of fat in peripheral tissues, increases metabolism and lean body mass.

                                                             ii.      Efficacy:  Animal studies in several species demonstrate weight loss and reduced body fat.  This effect may be limited to periods of refeeding after the caloric restriction diet is over.   Human studies are just beginning.

                                                            iii.      Safety: No evidence pertaining to safety in humans.

15. L-carnitine

                                                               i.      Mechanism: Transports fatty acids into mitochondria for burning.

                                                             ii.      Efficacy:  In cats, weight loss was accelerated. [31]   In obese humans, when compared to placebo, there was no benefit for weight loss, body fat or energy expenditure. [32]

                                                            iii.      Safety:  Studies using L-carnitine for other purposes revealed no significant adverse reactions.

16. Fiber (psyllium, plantago, guar fiber)

                                                               i.      Mechanism: Fiber remains in the gut and thus may increase subjective feelings of fullness and decrease food intake.

                                                             ii.      Efficacy:  Several studies support the use of fiber to promote weight loss. [33] ^{, [34] , [35] , [36] , [37]} Other research found that fiber was not associated with weight loss [38] or satiety ratings. [39]

                                                            iii.      Safety:  Large amounts of fiber can cause GI distress.  Guar gum has caused obstruction.  The FDA has taken legal action against some promoters of guar gum.  Potential interactions with anticoagulant drugs and interference with absorption of other drugs.

17. Caffeine

                                                               i.      Mechanism; Caffeine stimulates fat breakdown via sympathetic receptors, [40] and is often added to weight loss products for its thermogenic effect. [41]

                                                             ii.      Efficacy:  Several studies document association of caffeine with fat breakdown [42] and thermogenesis. [43]   Some find metabolism is not necessarily increased. [44]   Most clinical studies include caffeine as a co-ingredient with agents such as ephedra.  This makes it hard to separate the independent effect of caffeine.  In 1991, the FDA banned caffeine as an additive to nonprescription weight loss products because it had not been proven effective. [45]

                                                            iii.      Safety:  Generally well tolerated with the most common complaints being insomnia and nervousness.  As with other drugs activating the sympathetic nervous system, caution is advised for cardiovascular, stimulation and blood sugar control.

18. Dehydroepiandrosterone (DHEA)

                                                               i.      Mechanism: A steroid hormone similar to testosterone that builds muscle mass.

                                                               i.      Efficacy:  Very limited research suggests a positive effect on increasing lean muscle mass and decreasing fat with a decrease [46] or no change [47] in body weight.

                                                             ii.      Safety: Risks of steroid abuse by body builders are described very well on the National Institute of Drug Abuse website:  (http://www.nida.nih.gov/DrugPages/Steroids.html.)  ”In boys and men, reduced sperm production, shrinking of the testicles, impotence, difficulty or pain in urinating, baldness, and irreversible breast enlargement (gynecomastia). In girls and women, development of more masculine characteristics, such as decreased body fat and breast size, deepening of the voice, excessive growth of body hair, and loss of scalp hair, as well as clitoral enlargement. In adolescents of both sexes, premature termination of the adolescent growth spurt, so that for the rest of their lives, abusers remain shorter than they would have been without the drugs. In males and females of all ages, potentially fatal liver cysts and liver cancer; blood clotting, cholesterol changes, and hypertension, each of which can promote heart attack and stroke; and acne. Although not all scientists agree, some interpret available evidence to show that anabolic steroid abuse-particularly in high doses-promotes aggression that can manifest itself as fighting, physical and sexual abuse, armed robbery, and property crimes such as burglary and vandalism.”

19. Germander (Teucrium chamaedrys)

                                                               i.      Mechanism: Unknown.

                                                             ii.      Efficacy: Unknown.

                                                            iii.      Safety: Serious risks including liver damage have caused some countries to ban its use.

20. Laxatives (cassia, senna, cascara) and Diuretics

                                                               i.      Mechanism: Laxatives limit absorption; diuretics cause loss of fluid.

                                                             ii.      Efficacy: Tissue wasting noted in animals poisoned with laxatives.  Diuretics cause temporary weight loss as fluid with no loss in body fat. 

                                                            iii.      Safety: Serious risks of electrolyte imbalance with reported human cases of seizures, permananet heart damage and death.  Products not recommended for weight loss.

21. Β-hydroxy-β-methylbutyrate (HMB)

                                                               i.      Mechanism:  A metabolite to the essential amino acid leucine it may act as a precurser to muscle.

                                                             ii.      Efficacy:  In non-obese humans, efficacy in increasing lean muscle mass. [48]   Not evaluated in overweight subjects.

                                                            iii.      Safety: Limited data available but adverse reactions not reported in 1-month studies.

22. Pyruvate

                                                               i.      Mechanism: Possibly increases metabolism.

                                                             ii.      Efficacy: Several small studies demonstrate a small reduction in weight and body fat. [49] ^{, [50]}  

                                                            iii.      Safety:  No side effects reported in above studies.

23. Nicotine

                                                               i.      Mechanism: Increases metabolism.

                                                             ii.      Efficacy: People who quit smoking often complain of weight gain.  Nicotine decreases food intake in rats. [51] [52]  It increases fat oxidation, [53] and energy expenditure [54] , an effect limited to time of exposure and more prominant in normal than overweight subjects.  Smokeless tobacco use has become a problem in female teens trying to lose weight. [55]

                                                            iii.      Safety:  Highly addictive.  Reliably leads to bronchitis, emphysema and pulmonary cancer.  Causes vasoconstriction with reduced blood supply to tissues.  Bad breath.    There are much safer ways to increase metabolism and lose weight.

6. Conclusions
1. Pharmaceutical or nutriceutical treatment can reduce body weight and fat.   These effects are modest, but are none-the-less associated with important physical and psychological benefits. Treatment is likely to be long-term as with other chronic diseases, and should be coupled with diet, exercise and behavioral therapies.  Few agents have been studied for long-term effectiveness and safety.  Guidelines for use of agents in children are needed.
2. There is good data to support efficacy and safety of the three major drugs available for weight management:  phentermine, sibutramine and orlistat.  Since orlistat has a different mechanism of action, there is theoretical reason to use it in conjunction with one of the other two drugs.  To date research has not supported this theory.
3. Dietary supplements include a large number of products many of which have a logical proposed mechanism of action.  These agents, however, may be marketed without research supporting efficacy and safety.  Consumers need to be vigilant in selecting and using these agents.

For more information on this topic try these CSUS courses, review abstracts linked from the above article (http://www.hhs.csus.edu/HomePages/NRS/Vancouwe/) or read one of these review articles:

• Nursing14.  General Pharmacology.
• HHS131-Introduction to Alternative Health Therapies
• Glazer G.  Long-term pharmacotherapy of obesity 2000.  A review of efficacy and safety.  Arch Intern Med. 2001; 161:1814-1824.
• Allison DB, Fontaine KR, Heshka S, Mentore JL, Heymsfield SB.  Alternative treatments for weight loss: A critical review.  Crit Rev in Food Sci and Nutr. 2001, 41(1):1-28.

References