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Medications used to control weight

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The following list represents a relatively complete list of medications that have been used to help patients control appetite and lose weight.  Some are not available yet, others may never be.  The first five represent agents I use regularly, then these are followed by those I use less regularly.  The last few are here for informational purposes.

In order really understand the role of these drugs, you should also read How the Brain Controls Appetite and the How we develop food addictions.  In addition to those article, reading about the causes of cravings will also help you understand how the following drugs work


Phentermine/Phendimetrazine
Buproprion (Wellbutrin)
Topiramate          
Zonisamide      
Naltrexone
Metformin
Exenetide(Byetta)
Liraglutide (Victoza)
Pramlintide (Symlin)
Orlistat
Tesofensine
Ribonovant
Locaserin
5HTP/carbidopa
Sibutramine (Meridia)

 
Phentermine/Phendimetrazine

Mechanism of Action- These drugs are considered to be in the family of amphetamine or stimulant drugs.  They work by increasing the strength certain types of neuro-transmitters: Norepinephrine and dopamine.  These neurotransmitters work by increasing activity in a certain neuron tract (the CART/POMC) which then suppresses appetite.
Efficacy-  These medications have been the workhorse medications of weight loss treatment.  They are often result in weight loss of more than 10%.  The problem has been that the weight loss has plateaued after a few months.  Therefore, they have been approved for short term use only.  Nevertheless, when the medications are combined with other medications-such as Topamax and Naltrexone, the benefit can be prolonged.  This results in greater, longer-lasting weight loss.  One study showed an average weight loss of 37 lbs with weight continuing to be lost for one year.  Remember, the stimulant drugs may suppress appetite, but food cravings can be caused by other processes and need to be treated separately.
Side Effects-  The bigggest concern is that there is a potential for addiction.  I have read one study that looked at this and found no evidence of drug misuse.  When I look back at my experience in addiction medicine, I cannot think of anyone presenting to me to be detoxified from these medications.  There has not been any history that these drugs led to use of other drugs.  So these drugs may be safer than we think.  
    One reason these drugs may be safer than many other stimulants is because their effects are more targeted to norepinephrine; dopamine is far  less activated with these drugs than  when cocaine, ampthetamine, and ritalin are used.  Dopamine is a key neurotransmitter involved with addiction.   Of course, I still would not treat patient with these drugs if there is history of addiction.  I would also avoid use if a patient's BMI was less than 30.  After maximal weight loss is obtained, then these medicines should be titrated off. 
    Even discounting the risk for addiction, there are still other side effects such as anxiety, palpitations, high blood pressure, tremors, irritability and insomnia.  These limit the drug's usage.  To increase tolerability, at least one program combines this medication with a low dose of a tranquilizer.  

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Wellbutrin

Mechanism of Action- This is an anti-depressant that is also used for its' anti-craving effects; it has long been known to reduce  tobacco use.  It has been used to reduce other drug use as well.  It is difficult to be exactly how it works.  It can  facilitate norepinephrine activity which increases activity in the CART/POMC.  It can also increase Dopamine in the Nucleus Accumbens which  has an anti-craving effect.
Efficacy- It is known, since the initial studies, that the use of this medication led to weight loss.  However, weight loss when solely using this drug is only a few pounds.  Recently, its' use in combination with Naltrexone has been looked at and it was found to be effective.  I have often used this combination of medications in my practice for patients who are tring to stop alcohol; many have lost weight.  I have also used these drugs in patients who presented solely for weight loss.  They lost weight about 1/3 of the time.
Side effects- It also can cause irritability and insomnia.  In high doses, it has been reported to cause seizures but none of my patients have ever had a seizure

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Topamax

Mechanism of Action  Topamax (topiramate) has been used for many years in several ways.  It is used for seizures, headaches and for a variety of psychiatric problems.  It reduces alcohol consumption.  It is unclear how it works. It has multiple effects in the brain and therefore, its mechanism of action is difficult to discern.  Perhaps, it related to its effect on gluatamate and/or GABA receptors.  Yet, other medications with similar mechanisms of action are not asociated with weight loss
Efficacy  Like many other drugs, its' effects as a solitary agent is modest.  Yet, in combination, it is more effective.  It was used with phentermine to induce weight loss that averaged 37 pounds.  It will work with other medications as well.
Side effects Nausea and fatigue can often be seen.  Kidney stones have been reported.  In about 10%, there seems to be a mental slowing; this may occur no matter how slowly the dose is increased.  Liver and blood testing need to be performed periodically; however, few patiets have problems here.

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Zonisamide

Mechanism of Action-This is another anti-seizure drug that has two relevant effects.  It increases dopamine in the Nucleus Accumbens and it increases seratonin in the hypothalamus.  This will reduce normal appetite as well as food cravings.
Efficacy- at least one study showed  a 13 lb vs 2 lb weight loss over a 4 month period.  It was felt to have significant benefit in both binge eating disorder as well as preventing the weight gain seen with atypical anti-psychotics (Zyprexa and/or Seroquel)
Side Effects-nausea and fatigue are coomon as are other mild nerologic symptoms

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Naltrexone

Mechanism of action  Naltrexone blocks opiod receptors.  Opiod receptors are widely distributed though the hypothalmus and Nucleus Accumbens.  The nucleus accumbens is where appetite and reward take place.  There are two separate mechanisms through which this drug can work.  As stated in the paper on  how the brain controls appetite , the CART/POMC receptors are inhibited by endorphins.  When this effect is blocked, CART activity is increased and appetite is decreased.  Additionally, by blocking endorphins in the nucleus accumbens, we minimize the desire to continue eating.
Efficacy    There has some studies showing benefit when used in combination with Wellbutrin.  This is the basis for the drug Contrave.   The FDA is considering this for weight loss.  I have used this combination and seen patients benefit.
Side effects  There is an incidence of nausea and a very small incidence (0.3%) of liver abnormalities.   It cannot be used if someone is taking pain medication or is anticipated to be taking pain medications in the near future. 

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Metformin

Mechanism of action  Many overweight patients have glucose intolerance; sugars can get high after a meal.  The sugars than fall - even to very low levels at times.  The hypothalmus can sense sugar levels and seems to be sensitive to their fluctuations.  Metformin reduces the magnitude of the sugar swing.  Appetite is less.
Efficacy  I am not aware of any controlled studies showing  the magnitude of weight loss but I have seen several patients lose more than 10 pounds.  It is an inexpensive  medication that can only help.
Side effects There are no serious side effects unless someone has underlying kidney disease.  Some patients get stomach upset (which may also help with weight loss)

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Byetta 

Mechanism of action Byetta is available as an injectible medicine for diabetes.  It works by mimicking GLP-1.  This is a hormone intimately involved with sugar metabolism.  It also directly inhibits appetite by stimulating the CART/POMC cells in the hypothalmus.
Efficacy It has produced profound weight loss in many diabetics.  There is little data outside of that looking at diabetic treatment but the medication makes a nice addition for any diabetic or pre-diabetic condition.  It is costly however, and often needs a pre-certification for insurance coverage
Side effects It is taken before meals and can lead to nausea and other stomach upset.  There have been reports of pancreatitis with the drug; however, these are rare occurences.  Cause and effect have not yet been established

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Victoza (liraglutide)

Mechanism of Action- Similar to Byetta-it is a injectible medication used for diabetes.  It works by mimickiking GLP-1, a hormone involved with sugar metabolism.  It inhibits appetite by stimulating CART/POMC cells in the hypothalamus
Efficacy-It has resulted in significan weight loss in diabetics but has little data for weight loss outside of a diabetic population.  It has an advantage over byetta in that it can be used once daily.  It is expensive and may require pre-certification.
Side Effects-There is some concern about rare types of thyroid tumors as well as pancreatitis as well but theses events are rare, cause and effect is uncertain.  Nausea is more common

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Symlin (pramlintide)

Mechanism of Action-This is also an injectible medication recently approved for use in diabetes.  It works by mimicking amylin, a hormone secreted by the pancreas that tells us we are fed.  It  effects  the hypothalamus and will inhibit appetite
through it effects on the CART/POMC neurons.  It also slows stomach emptying and makes us feel more full
Efficacy- It has been shown to lose wight in diabetics.  In one study of non-diabetics-40% of patients lost 10% of their weight at one year.  (This was as a sole agent and not in combination)
Side effects-nausea occurs up to 30% of the time

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Orlistat

Mechism of Action  This is a fat blocker that prevents the absorption of fat from the intestine.  It has been marketed under the prescription name of Xenical and is available over the counter as Alli
Efficacy Modest weight  is seen.  It would likely work well with other medications but my experience, and the literature, is limited.  After all, we are blocking the absorbption of 30% of our calories from fat
Side effects  We are creating a situation of fat malabsobtion with resulting cramping, diarrhea, foul smelling stools and incontinence.  These effects are mild  if one follows an appropriate diet but may worsen the more fat one eats

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Tesofensine    (an investigational drug)

Mechanism of action- This is a drug which inhibits the reuptake of all three neurotransmitters: seratonin, dopamine and norepinephrine.  This will increase their availability.  Elevated seratonin will decrease appetite, elevated norepinephrine will do the same via another mechanism and elevated dopamine will reduce our tendencies to want to eat to relax.  In one drug, we have multiple mechanisms of action.
Efficacy- It seems very promising with the treatment group losing 20-25 lbs vs 5 lbs in the placeo group
Side effects It is to soon to say.  One might expect irritibility, nause and perhaps incresed pulse and blood pressure

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Ribonovant 

Mechanism of Actiom  This is a medication that blocks the endocannibinoid receptor.  The endocannibinoid  receptor  interacts with marijuana; therefore, the drug causes the anti-munchies.  This receptor is in the lateral hypothalmus where it likely boosts the hunger signal coming from there.  It is also in the Nucleus Accumbens where it can increase dopamine release.  This last effect is important in the biology of motivation. 
Efficacy It was effective leading to a weight loss of 10 lbs (over placebo) after one year of use although when the drug was stopped after one year, no benefit was seen at two years.  Additionally, a variety of improvements was seen in various metabolic factors such as lipids.
Side effects It was found to have an significant psychiatric side effects- such as depression.  This would be expected given its' ability to reduce the "motivational" tone in the Nucleus Accumbens.  It was not approved in the US for this reason.  The FDA may have been concerned that the drug would be used willy nilly by a variety of doctors unfamiliar with the risks.  It is available in Europe and can be obtained on-line.

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Lorcaserin (a new medication recently denied for approval)

Mechanism of Action This medication will stimulate the 5HT2C seratonin receptor which will stimulate the CART/POMC neurons
Efficacy Weight loss as a sole sdrug is modest.  About 30% of patients lost 5% of weight
Side effects This is difficult to say because the drug is not yet on the market.  Headache and nausea were issues but there have been reports of cancers in lab animals.

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5HTP/Carbidopa

Mechanism of Action   This is a proprietary drug which I include for completeness.  The idea is to give a precurser to Seratonin (5HTP) to increase seratonin in the brain.  The Carbidopa helps to target the effect to the brain and minimize side effects
Efficacy The combination of this with Phentermine was slightly more effective than Phentermine alone
Side effects Difficult to know seconary to lack of widespread reports of use.  I have little experience with this medicine.

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Meridia (sibutramine)-removed from the market recently by the FDA 

Mechanism of Action  This medication works in a process similar to most anti-depressants and increases both norepinephrine and seratonin in the brain
Efficacy- modest weight loss seen when used as a solitary agent in order of 5-10%
Side effects Removed secondary to cardiovascular effects

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