This document discusses obesity and provides information on its epidemiology, burden, pathophysiology, evaluation, management, diet, physical activity, behavioral therapy, pharmacotherapy, and various anti-obesity drugs. It notes that obesity results from a long-term positive energy imbalance and is increasing worldwide. Management involves lifestyle modifications like reduced calorie diets, increased physical activity, and behavioral therapy, while anti-obesity drugs like sibutramine, orlistat, and bupropion may aid weight loss when used along with lifestyle changes.

1. DR.BASAVANAGOWDA
PRINCIPAL
J.S.S MEDICAL COLLEGE,MYSORE
J.S.S UNIVERSITY

2. OBESITY
 RESULT OF A LONG –TERM POSITIVE
IMBALANCE BETWEEN ENERGY INTAKE &
ENERGY EXPENDITURE

4. Epidemiology
 The WHO estimates that a billion people
worldwide are overweight (BMI greater than
25), and 300 million people are obese (BMI
greater than 30).
 Over 66% of US population is either
overweight or obese
 Prevalence is increasing throughout most of
the industrialized world

5. The burden
 5% of Indian population are obese
 Toppers! – Punjab: 30.3% Males 37% Females
Kerala : 24% Males 34% Females,
Goa : 20.8%Males & 27% females
 Our study : MYCOS: 43000 Children
 3.7% Girls & 2.9% Boys in 90th percentile
 4.8% overweight,( 85th percentile of BMI )

6. >50%
40-50%
30-40%
20-30%
10-205
5%
UW
NBMI-VISFAT
World obesity prevalence among Females (TOP) and Males (DOWN)

9. HAPPY MEN

13.  1.
 Carol Yager (1960 - 1994) of Flint, MI; 5 ft 7 in, estimated to have
weighed more than 1600 lbs at her peak. She had been fat since
childhood. In 1993, she was measured at 1189 lbs when admitted to
Hurley Medical Center, suffering from cellulitis. She lost nearly 500
lbs on a 1200-calorie diet, but most of that weight was thought to be
fluid, and she regained all of it and more soon after being discharged.
Her teenage daughter, a boyfriend, and a group of volunteers helped
take care of her. Despite extravagant promises by diet maven
Richard Simmons and talk-show host Jerry Springer, Yager received
little practical assistance in return for her media exposure (though
Springer continues to profit from her appearance on his show, having
rebroadcast that episode at least four times). She was refused further
hospitalization on the grounds that her condition was not critical,
despite massive water retention and signs of incipient kidney failure,
and these problems led to her death a few weeks later.

15. Abdominal obesity and waist
circumference thresholds
 New IDF criteria(2006):
Men Women
Europid >94 cm (37.0 in) >80 cm (31.5 in)
South Asian >90 cm (35.4 in) >80 cm (31.5 in)
Chinese >90 cm (35.4 in) >80 cm (31.5 in)
Japanese >85 cm (33.5 in) >90 cm (35.4 in)
Current NCEP ATP-III criteria
>102 cm (>40 inches) in men, >88 cm (>35 inches) in
women

16. ASIAN INDIAN PHENOTYPE-
PARADOX
 Increased visceral adiposity for a given BMI
 Increased insulin resistance for given V.fat
 SNP-Near MC4R gene-mostly associated
with visceral adiposity & waist circumference
 MYVISFAT-Study

17. PATHOPHYSIOLOGY
 PRIMARY-

 SECONDARY-

18. OBESITY PATHOPHYSIOLOGY
 Multifactorial Genetic factor
ENERGY ENERGY
CONSUMED SPENT
DIETARY
HABITS PHYSICAL SEDENTARY
EATING ACTIVITY LIFE
BEHAVIOR

20. EVALUATION & MANAGEMENT
1. Obesity Focused history taking
2. Physical examination to determine
the degree and type of obesity /
Sec.cause
3. Co-morbid conditions
4. Fitness level &
5. Pts readiness to adopt lifestyle
changes

21. Non-drug therapy-DIET
 The NIH recommends the following diet for
obese patients:
 Class I: 500 kcal/day energy deficit to produce a
1-lb weight loss per week and a 10% weight
loss over 6 months
 Classes II and III: 500 to 1000 kcal/day energy
deficit to produce a 1- to 2-lb weight loss per
week and a 10% weight loss over 6 months

22. Diet
As many diets as there are
physicians and dieticians and
self-proclaimed healers!!!!

23. Diet therapy
 Different types of weight loss diets exist.
 They all share the same goal of reducing total
energy intake.
 The most popular include
1. Low calorie (eg, Weight Watchers International,
Inc)
2. Very low calorie diet
3. High protein and low carbohydrate (eg, Atkins
Nutritionals, Inc)
4. Low fat diets

24. Low Calorie Diet
 Provide Weight loss upto 500 Cal/day.
 The hallmark of the program is that the group
support is facilitated by an individual who has
lost weight and maintained their weight loss
using the Weight Watchers program.
- Heshka S, Greenway F, Anderson JW, et al. Self-help
weight loss versus a structured commercial program after 26 weeks: A
randomized controlled study. Am J Med 2000;109:282-7

25. Very low calorie diet (VLCD)
 Total daily calorie intake of less than or equal
to 800 kcal/day.
 The weight loss mechanism is secondary to
severe calorie restriction.
 VLCDs are usually implemented by replacing
a patient’s regular food choices with specific
foods or liquid diets.

26.  VLCDs in weight loss maintenance is
inconsistent
 VLCDs are not recommended beyond16 weeks
after which point a LCD should be initiated.
 Weight is regained when the diet is stopped
 Due to VLCDs resulting in rapid weight loss,
they can be associated with a number of medical
risks and patients should be medically
supervised.

27. Diet
Diet Calorie content Comment
Very low calorie diet < 800 Kcal/day Poor maintenance of
weight loss
Low calorie diet 800 – 1500 Kcal/ day May cause actual
weight gain
Balanced Deficit Diet > 1500 Kcal /day Better reduction with
both fat and calorie
content reduc tion

28. Low-carbohydrate
Low-fat
 Low-carbohydrate diets restrict carbohydrate
intake to 20 to 100 g/day, depending on the
dietary program and stage. Low-fat diets
restrict intake of fat to less than 25% to 35%
of daily energy intake.

29. Low-carbohydrate
Low-fat
 The A TO Z Weight Loss Study is a 12-month
randomized trial evaluating the effects of
different diets on weight loss in 311 overweight
or obese, non-diabetic premenopausal women.
Intervention consisted of the Atkins, Zone,
Ornish, or LEARN diets for 2 months, with 10
month follow-up. The women on Atkins lost 4.7
kg, those on Zone 1.6 kg, those on LEARN 2.6 kg,
and those on Ornish 2.2 kg.Level of Evidence:
Moderate
 Gardner C, Kiazand A, Alhassan S. Comparison of the Atkins, Zone, Ornish and LEARN diets for change in weight
and related risk factors among overweight premenopausal women. JAMA. March 2007;297(9):969-977

30. Atkins diet
 The Atkins diet uses a low-carbohydrate
approach. Individuals are initially restricted to
20 g of carbohydrates for 2 weeks, after which
carbohydrates are gradually reintroduced until
the person maintains a diet consisting of 40 to
90 g of carbohydrates per day.

31. Atkins diet
 Studies done comparing the Atkins diet to a
traditional low-fat diet show similar weight
loss for both groups. The Atkins group,
however, showed a decrease in triglyceride
levels and an increase in high-density
lipoprotein-cholesterol (HDL-C).

34. Diet
 Recent large-scale trial concluded –
 how –how-much than
what you eat

35. PHYSICAL ACTIVITY

36. Customer Profiles - Driving Change
obesity
obesity
Yesterday
today
Average Age: 50 Average Age: 35
obese
overweight
Lifestyle physically
moderately
mobile inactive
Technology Aware but
indifferent
Economics
better informed/
low “quick-fix” “connected”
awareness remedies
not well informed
Low motivation consumer power

37.  A starting program of 30 min to 45 min of
moderate exercise (eg brisk walking) at least 3
days per week is recommended.
 Expends approximately 150 kcal/day (500 to
1000 calories per week).
 Some individuals require 2000Kcal per week to
ensure weight loss maintenance.
 Walking is the most common, safe and
accessible mode of exercise that is prescribed

38. Physical Activity
 Diet alone is not enough to modify
weight.
 Exercise should also be incorporated
into the program.
 Physical activity of 30 to 60 minutes a
day for 5 to 7 days per week has been
shown to result in a 2% to 3% weight
loss.

39. 39

41. Physical Activity
 Exercise when added to diet is effective in
long-term maintenance of weight loss and
prevention of weight gain.
 Daily exercise of 30 minutes of strenuous
activity (eg, aerobics, brisk walking) or
 60 minutes of less intense activity (eg,
normal walking, household chores) is
recommended.

42. BEHAVIORAL THERAPY
• Cognitive therapy
a • Reinforce new dietary, activity behaviors
• Self monitoring techniques
b • Stimulus control
• Social support
c • Problem solving-when,where,what,how

44. Behavioral Therapy
 Behavioral therapy, together with diet and
exercise, has been shown to lead to a 10%
weight loss over 4 months to 1 year.

45. Transtheoretical Model (TTM )
 is a randomized controlled trial in 1277 overweight or
obese adults with 24-month follow-up. The
intervention consisted of home-based, stage-
matched multiple behavior interventions for up to
three behaviors related to weight management versus
control. Effects were found for healthy eating (47.5%
versus 34.3%), exercise (44.9% versus 38.1%),
managing emotional distress (49.7% versus 30.3%),
and unlimited fruit and vegetable intake (48.5%
versus 39.0%). Multiple behavior interventions had
greater than three times the impact of single
interventions.Level of Evidence: Moderate
 Johnson DB, Gerstein DE, Evans AE, et al. Preventing obesity: a life cycle perspective.
J Am Diet Assoc. January 2006;106(1):97-101

47. PHARMACOTHERAPY IN OBESITY
USFDA Approved Other drugs used
Sibutramine Fluoxetine
Orlistat Bupropion
Phentermine Sertraline
Diethylpropion Topiramate
Zonisamide

49. SIBUTRAMINE
Reductil, Meridia, Sibutrex
Obirax
Dose: 10-15 mg daily
Cost: 10 tablets – Rs.84

50. Combined norepinephrine and
serotonin reuptake inhibitor.
 Weight loss is attributed to appetite
suppression and increased thermo-genesis
secondary to stimulation of brown adipose tissue.
 Sibutramine was approved for use in
conjunction with a low calorie diet as an aid to
weight loss in 1998
- National Library of Medicine/National Institutes of Health.
Sibutramine. Medline Plus Drug Information. available at URL:
www.nlm.nih.gov/medlineplus/druginfo/medmaster /a697012.html. Accessed 5/14/2004.

51. Arterburn DE, Crane PK, Veenstra DL. The efficacy and safety
of sibutramine for weight loss: a systematic review. Arch Intern
Med 2004;164(9):994-1003.
 Sibutramine with lifestyle
modification was more effective
than placebo with an average of
4.5 kg greater weight loss at one
year and a 20 to 30% greater
likelihood of achieving a weight
loss of 5% or more (compared to
placebo).

52. Dose of Sibutramine?
 1,047 patients were given instructions on diet,
physical activity, and lifestyle changes and then
randomized to received placebo or sibutramine at 1
mg, 5 mg, 10 mg, 15 mg, 20 mg, or 30 mg a day.
Weight loss at 24 weeks was dose-dependent, with
a mean weight loss above placebo equal to 4.9% for
10mg and 8.2% for the 10 mg & 30 mg doses.
 Side effects such as dry mouth, insomnia, and nausea
also increased in a dosedependent manner

54. Safety
 Sibutramine increases blood pressure
levels in normotensive patients or
 prevents the decrease that might
have occurred with weight loss.

55. ORLISTAT
Reeshape, Orlica,
Obelit, Xenical
Dose:120 mg TID with each
meal
Cost: 10 tablets-Rs.381

56. ORLISTAT-Lipase inhibitor
 Weight loss by reversibly binding to the active
center of the enzyme lipase, preventing the
digestion and absorption of some dietary fats.
 Orlistat was approved in the late 1990s and is
currently the only lipase inhibitor approved for
weight loss.
 Orlistat inhibits approximately 30 percent of fat
absorption, including the absorption of fat soluble
vitamins.

60. Safety
 Orlistat is not absorbed to any significant
degree, and its side effects are thus related to
the blockade of triglyceride digestion in the
intestine.
 Fecal fat loss and related gastrointestinal
symptoms are common initially, but they
subside as patients learn to use the drug.
 Orlistat can cause small but significant decreases
in fat-soluble vitamins.

61. Rimonabant
 Rimonabant is not approved by the US FDA
for the treatment of obesity.

63.  Zimulti in the United States
 Accomplia in Europe
 In June 2007, the European Commission
authorized the sale of Rimonabant for use in
treating obese patients
1. BMI>30 or more
2. BMI of at least 27 who also have type
2 diabetes or dyslipidemia.

64.  That same month, an FDA advisory
committee unanimously recommended against
approval of rimonabant because of a safety
concern related to an increased risk of
suicide during treatment.
 The manufacturer, sanofi aventis, then
announced that their application to the FDA
would be withdrawn.

65. Fluoxetine
 SSRI
 In a 2-week placebo-controlled trial,
fluoxetine at a dosage of 60 mg/d produced a
27% decrease in food intake.

66. Fluoxetine
 Fluoxetine, although not a good drug
for long-term treatment of obesity, may be
preferred for the treatment of depressed
obese patients over some of the tricyclic
antidepressants that are associated with
significant weight gain.

67. Phentermine
 Phentermine is approved by
the US FDA only for short-term
management of obesity
(approximately 12 weeks)

68. Bupropion
 Nor-epinephrine- and dopamine-
reuptake inhibitor

69. Bupropion
 The study in uncomplicated overweight subjects randomized 327 subjects to bupropion
at a dosage of 300 mg/d, bupropion at a dosage of 400 mg/d, or placebo in equal
proportions. At 24 weeks, 69% of those randomized remained in the study and the
percent losses of initial body weight were -5 ± 1%, minus;7.2 ± 1%, and -10.1 ± 1% for the
groups that received placebo, bupropion at a dose of 300 mg, and bupropion at a dose of
400 mg, respectively (P<.0001). The placebo group was randomized to the group
receiving bupropion at a dose of 300 mg or the group receiving bupropion at a dose of
400 mg at 24 weeks, and the trial was extended to week 48. By the end of the trial, the
dropout rate was 41% and the weight losses in the groups receiving bupropion at a dose
of 300 mg and bupropion at a dose of 400 mg were -6.2 ± 1.25% and -7.2 ± 1.5% of initial
body weight, respectively. Thus, it seems that nondepressed subjects may respond to
bupropion with weight loss to a greater extent than those with depressive
symptoms.
 Jain A.K., Kaplan R.A., Gadde K.M., et al: Bupropion SR vs. placebo for weight loss in obese patients with depressive symptoms. Obes
Res 10. (10): 1049-1056.2002;
 Anderson J.W., Greenway F.L., Fujioka K., et al: Bupropion SR enhances weight loss: a 48-week double-blind, placebo-controlled trial. Obes
Res 10. (7): 633-641.2002;

70. Topiramate
 The modulation of GABAA receptors
may provide one potential
mechanism to reduce food intake.

71. Metformin
 Metformin is a biguanide that is approved for the
treatment of diabetes mellitus.
 This drug reduces hepatic glucose production,
decreases intestinal absorption from the
gastrointestinal tract, and enhances insulin
sensitivity.
 In clinical trials in which metformin was compared
with sulfonylureas, it produced weight loss.

72. Exenatide
 GLP-1 is derived from the processing of the
proglucagon peptide, which is secreted by L
cells in the terminal ileum in response to a
meal.
 Increased GLP-1 inhibits glucagon secretion,
stimulates insulin secretion, stimulates
gluconeogenesis, and delays gastric
emptying.

73. Exenatide
 Exenatide (exendin-4) is a 39–amino acid peptide
that is produced in the salivary gland of the Gila
monster lizard. It has 53% homology with GLP-1,
but it has a much longer half-life.
 Exenatide is approved by the FDA for treatment
of type 2 diabetics who are inadequately
controlled while being treated with metformin or
sulfonylureas.

74. Exenatide
 In one trial with 377 type 2 diabetic subjects
who were failing maximal sulfonylurea
therapy, exenatide produced a decrease of
0.74% more in HgbA1c than placebo. Fasting
glucose also decreased, and there was a
progressive weight loss of 1.6 kg.The
interesting feature of this weight loss is that
it occurred without lifestyle change, diet, or
exercise.
 Buse J.B., Henry R.R., Han J., et al: Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2
diabetes. Diabetes Care 27. (11): 2628-2635.2004;

75. Exenatide
 Extracted from the venom of the Gila monster
(Heloderma suspectum).
 GLP receptor 1 agonist and is resistant to DPP-IV
breakdown in the plasma.
 Initial data from open-label extension studies in
diabetic patients have shown that a weight loss of
4.4 kg can be achieved by 82 weeks.

76. Liraglutide
 Arne Astrup et al. Effects of liraglutide in the
treatment of obesity: a randomized, double-
blind, placebo-controlled study The Lancet,
Volume 374, Issue 9701, Pages 1606 - 1616, 7
November 2009.
 Conclusion: Liraglutide treatment over 20 weeks
is well tolerated, induces weight loss, improves
certain obesity-related risk factors, and reduces
prediabetes.

77. Amylin
 Amylin is co-secreted with insulin from the alpha
cells of the pancreas.
 Pramlintide (Symlin, Amylin Pharmaceuticals), a
novel treatment for diabetes that has recently been
granted FDA approval.
 Reduces food intake and has been shown to result in
a 1.8-kg reduction in body weight over 26 weeks in
overweight diabetic subjects in addition to glycemic
control.
- Hollander P, Maggs DG, Ruggles JA, Fineman M, Shen L, Kolterman
OG, Weyer C: Effect of pramlintide on weight in overweight and obese insulin-treated
type 2 diabetes patients. Obes Res 12:661– 668, 2004

78. DPP IV inhibitors
 Sitagliptin & Vildagliptin
 The evidence from clinical trials to date
suggests that these therapies were well
tolerated with few adverse effects, but also
have little effect on weight
- Green BD, Flatt PR, Bailey CJ Dipeptidyl
peptidase IV (DPP IV) inhibitors: a newly emerging drug class for the
treatment of type 2 diabetes. Diab Vasc Dis Res 3:159–165, 2006

79. Drugs in clinical trial
 Serotonin 2C Receptor Agonists
 Multiple Monoamine-Reuptake Inhibitor
Tesofensine
 CP-945598-Cannabinoid-1 receptor antagonist
 Pfizer in phase 3 trials for obesity and
prevention of weight gain in obese subjects.31
 Growth hormone-increase protein & decrease fat
 Leptin
 Oxyntomodulin-reduce body fat & appetite

80. Ghrelin
 This 28–amino acid peptide is synthesized
principally in the stomach.
 It acts via the growth hormone secretagogue
receptor to increase food intake in humans.
 Antagonists to Ghrelin have been used in
preclinical studies, however, paving the way for
possible future evaluation as a therapy for obesity
in human
- Beck B, Richy S, Stricker-Krongrad A: Feeding
response to ghrelin agonist and antagonist in lean and obese Zucker rats.
Life Sci 76:473– 478, 2004

81. MK-0364 Taranabant
 CB-1 receptor inverse agonist (which binds to the
receptor and inhibits baseline activity at the
receptor).
 Merck Group of company.
 Demonstrated weight loss versus placebo in early
clinical studies
 Phase 3 clinical trials.
Addy C, Li S et al. Safety, tolerability, pharmacokinetics, and
pharmacodynamic properties of taranabant, a novel selective
cannabinoid-1 receptor inverse agonist, for the treatment of obesity:
results from a double-blind, placebo-controlled, single oral dose study in
healthy volunteers. J Clin Pharmacol. 2008;48(4):418-27.

82. Oleoylestrone
 Oleoylestrone is a weakly estrogenic compound
that is produced in fat cells, carried in the blood on
HDL particles, and feeds back to the central
nervous system to reduce food intake while
maintaining energy expenditure.
 Oleoylestrone is orally active and has been used to
treat one morbidly obese male without an
accompanying weight-loss program.

83. Melanin concentrating
hormone receptor-1
antagonist
 A number of other MCH-1 antagonists reduce
food intake and body weight in experimental
animals. No human studies have been
reported.
 Handlon A.L., Zhou H.: Melanin-concentrating hormone-1 receptor antagonists for the treatment of obesity. J Med Chem 49. (14): 4017-
4022.2006;

84. LORCASERIN
 Selective agonist of the 5-HT2C serotonin
receptor in the hypothalamus, which helps
regulate satiety and the metabolic rate.
 104-fold greater selectivity for the 5-
HT2Creceptor relative to the 5-HT2B receptor and
18-fold greater selectivity relative to the 5-HT2A
receptor.
- Thomsen WJ et al. Lorcaserin, a novel selective
human 5-HT2C agonist: in vitro and in vivo pharmacological
characterization. J Pharmacol Exp Ther. 2008;325(2):577-87.

85.  Less side effects (Valvular heat disease and
pulmonary hypertension) as seen with
Fenfluramine – non selective serotonin
receptor agonist
- Miller KJ. Serotonin receptor agonists: potential for the
treatment of obesity. Mol Interv. 2005;5(5):282-91.

86.  Lorcaserin is being developed by Arena
Pharmaceuticals and is in Phase III clinical trails
- http://clinicaltrials.gov/ct2/show/NCT00603902 [cited 2008 Mar
23].

87. Cetilistat
 Lipase blocker that will block breakdown and
absorption of dietary triglycerides.
 This drug is currently being prepared for phase
3 clinical development.
 The manufacturer-Alizyme Therapeutics, Ltd.
 Fewer gastrointestinal side effects when
compared to Orlistat.
- Kopelman P et al. Cetilistat (ATL-962), a novel lipase inhibitor: a 12-week
randomized, placebo-controlled study of weight reduction in obese patients.
Int J Obes (Lond). 2007;31(3):494-9.

88. PYY 3-36
 Development of a nasal spray formulation for
PYY 3-36 has undergone Phase I clinical trials.
Based on the reviews, Merck and Company
severed its commercial relationship with
Nastech on March 1, 2006. Nastech, the
developer of the nasal formulation, plans to
continue developing this product.

89. Bariatric Surgery
 Malabsorptive Surgery
 Restricitve Surgery

90. Surgery
 Surgical therapy provides the most successful
treatment in morbidly obese patients with a
BMI of 40 or higher or BMI of 35 or
higher with comorbidity. Surgery
candidates are those who have exhausted
numerous nonsurgical weight reduction
therapies and must be carefully selected.

92. Laparoscopic Adjustable Gastric Band

95. Jejunoileal bypass
 This was the first surgical procedure used to
treat obesity. The proximal jejunum (14
inches from the ligament of Treitz) is
attached to the terminal ileum (4 inches from
the ileocecal valve), excluding a loop from
passage of food

97. Patient Education
 Maintenance of weight loss may prove to be
more difficult than losing weight itself,
particularly in patients treated with calorie
restriction. Maintenance requires a lifelong
commitment to lifestyle changes and dietary
practices.

98. ALGORITHM FOR TREATMENT OF OBESITY
Patient encounter
Measure weight ,height & waist circumference
BMI > 30 or
BMI > 25 or Assess risk WC > 90 (M)
WC > 90 (M) factors >80 (F)
>80 (F)
& more than 2 risk factors
DIET
PHYSICAL ACTIVITY

99. ALGORITHM FOR TREATMENT OF OBESITY
BMI > 25 or
WC > 90 (M) & > 80 (F)
No risk factors With risk factors
Diet & Physical activity Diet & Physical activity
+
Behavioral therapy
Periodic monitoring & +
Re-inforcement Correction of risk factors

100. ALGORITHM FOR TREATMENT OF OBESITY
BMI > 30 - 35 BMI > 35 - 40 BMI > 40
Diet Risk Factors &
+ Physical activity - Co-morbidities +
+ Behavioral therapy
+ Pharmacotherapy All measures +
correct risk factors Bariatric surgery

101. Summary
 Medications can significantly increase weight
loss compared with placebo in most trials. In
general, patients can expect a weight loss of
8% to 10% from baseline provided they
adhere to the weight-loss program and take
medications regularly.

102. summary
 Obesity is an outcome of chronic positive
energy balance
 Rule out secondary cause
 Diet, physical activity & behavioral therapy
are the baseline in all types of obesity
 Pharmacotherapy-not many highly effective
medication
 Newer molecules are under evaluation

103. Summary
 All medications have side effects that need to be
considered before initiating treatment, however. For
sibutramine, there is an increase in blood pressure and
heart rate that may require discontinuation of the drug in
a small percentage of patients. For orlistat, the principal
side effect is gastrointestinal in origin resulting from the
increased activity of the lower bowel. Cannabinoid
receptor antagonists, once a promising target, are no
longer under study. Other medications are in clinical
trials and on their way.

105. Thank You
Thank you