Marijuana as Medicine for Metabolic Syndrome?
Fascinating new research uses masses of data from NHANES to find that current cannabis users have less insulin resistance, smaller waists, and higher HDL, than former or non-users.
THE STUDY
Article published online May 16 in the American Journal of Medicine.
Data from NHANES between 2005 and 2010
Incl drug-use questionnaire, Fasting serum labs in 4k+ individuals
N=4657 participants
579 = current users (self-reported smoking marijuana or hashish in the past month)
1975 = had smoked marijuana in the past but were not current users
2103 = had never inhaled or ingested marijuana
Fasting insulin and glucose measured in serum after nine-hour fast
Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated
NHANES
National Health and Nutrition Survey
cross-sectional, continuous survey, observational
administered annually by the National Center for Health Statistics
data are released in 2-year increments
complex, multistage probability sampling design-->nationally representative US sample
uses interview, physical examination, and laboratory components
11,335 persons aged 20 to 59 years completed the drug questionnaire (2005-2010)
4657 participants provided a fasting blood sample
QUESTIONS ON ILLICIT DRUG QUESTIONNAIRE
used to distinguish current, past, or never ever users
•“Have you ever, even once, smoked marijuana or hashish?” (yes, no, refused, don’t know);
•“How long has it been since you last used marijuana or hashish?” (answers were given as number of days, weeks, months, or years); and
•“During the past 30 days, on how many days did you use marijuana or hashish?”
RESULTS
Lower glucose among current users than never evers
Not significant following multivariate adjustment
No sig assoc: triglyceride levels, systolic or diastolic blood pressure.
Current users had 16% lower levels of fasting insulin and 17% lower HOMA-IR
Remained significant even after multivariate adjustment
1.63-mg/dL-higher HDL-cholesterol levels (sig)
Lower waist circumferences (sig)
If adjusted for BMI, associations attenuated but still statistically significant
Same results when diabetics excluded
No tolerance seen, current users seem to have the effects
In unadjusted analyses, past and current marijuana use were associated with lower levels of fasting insulin, glucose, HOMA-IR, BMI, and hemoglobin A1c (Table 2). Current marijuana use also was found to be inversely associated with waist circumference. Models adjusted for age and sex demonstrated statistically significant associations between past and current use of marijuana with lower levels of fasting insulin, glucose, HOMA-IR, and BMI. Also, current use was associated with higher HDL-C levels and lower waist circumference (Table 3). In multivariable-adjusted models, the associations of current marijuana use with lower levels of fasting insulin and HOMA-IR, as well as with higher HDL-C levels and lower waist circumference, remained statistically significant (Table 3). Compared with participants reporting never having used marijuana in their lifetimes, current use was associated with 16% lower fasting insulin levels (95% CI, −26 to −6), 17% lower HOMA-IR (95% CI, −27 to −6), and 1.63 mg/dL higher HDL-C levels (95% CI, 0.23-3.04) in multivariable adjusted models. Among current users, we found no significant dose-response relationship and no evidence for a U- or J-shaped curve. We did not find any significant associations between marijuana use and triglyceride levels, systolic blood pressure, or diastolic blood pressure.
In an analysis adjusting for BMI, a potential mediator of the associations between marijuana use and the cardiometabolic outcomes, the associations between current marijuana use and fasting levels of insulin, HOMA-IR, and waist circumference were attenuated, but remained statistically significant (Table 3). In addition, the results were not materially different in analyses that excluded participants with diabetes mellitus (Table 3).
CHARACTERISTICS OF CURRENT MJ USERS
(from this study and previous)
lower levels of fasting insulin
(similar results found with cannabidiol in mice)
less likely to be insulin resistant
true even when diabetics excluded
smaller waist circumferences
higher HDL cholesterol than never users
lower prevalence rates of obesity and diabetes mellitus
acute increase in caloric intake with use
higher average caloric intake levels than nonusers
Mixed results on BMI
Some studies have found no significant trend between marijuana use and BMI
2 large national surveys found lower BMI and decreased prevalence of obesity
MECHANISM?
Relationship between cannabinoids and peripheral metabolic processes?
Rimonabant = cannabinoid type 1 receptor antagonist
R improves insulin sensitivity in wild-type mice, but not in adiponectin knockout mice
Blocking type 1 receptor in mice without adiponectin does not change insulin sensitivity
Adiponectin has been reported to improve insulin sensitivity
THEORY: Adiponectin at least partially mediates the improvement in insulin sensitivity
Rimonabant-induced improvement in insulin resistance confirmed in human studies
Rimonabant sig assoc w incr plasma adiponectin, wt loss, decr waist circ
Obese rats given cannabis-->wt loss, incr in wt of pancreata, implying beta-cell protection
Cannabinoid type 1 knockout mice resistant to diet-induced obesity
This receptor mb central in the metabolic processes leading to obesity
Adiponectin mb mediator: 2 of the main active phytocannabinoids in marijuana, (-)-trans-Δ9-tetrahydrocannabinol and cannabidiol, agonize these receptors
CONCERNS
Long-term effects of this agent
Need a lot more research
Most research looks at CNS effects of marijuana and addiction potential
LEGALIZATION
Recent legalization of medical marijuana use in the form of THC in 19 states and DC
Recreational use in 2 states
PREVALENCE OF MJ USE
Estimated 17.4 million current users of marijuana in the United States
Approx 4.6 million of these smoking it daily or almost daily
2010 National Survey on Drug Use and Health
2007-->2010 use in 12+ persons incr from 5.8% to 6.9%
SOURCES
Am J Med. 2013. Article, Editorial
http://www.amjmed.com/article/S0002-9343(13)00200-3/fulltext
CANNABINOIDS
1) Much studied: (-)-trans-Δ9-tetrahydrocannabinol
acts as a partial agonist at both the cannabinoid type 1 and 2 receptors
2) cannabidiol, lower affinity for the cannabinoid receptors, appears to antagonize both cannabinoid type 1 and 2.12
Repeated administration of cannabinoids reduces cannabinoid type 1 receptor density
(receptor type 1 gets downregulated-->tolerance)
EDITORIAL
Marijuana for Diabetic Control
Joseph S. Alpert, MD (Editor-in-Chief, The American Journal of Medicine)
http://www.amjmed.com/article/S0002-9343(13)00313-6/fulltext
For centuries, cannabis sativa, more commonly known as marijuana, has been used as a folk remedy to relieve pain, improve mood, and increase appetite.
In 1937, Franklin D. Roosevelt signed the US Marijuana Tax Act that made it illegal to sell or use this herb. Nevertheless, cannabis continued to be used by a small number of citizens in the United States, including jazz musicians, entertainers, and cognoscenti desiring an altered state of mind.
During the 1960s, cannabis use became a symbol for the youth revolution. It was widely used as a mild euphoric on college campuses and among counterculture youth. I remember well coming to parties in Cambridge, Massachusetts, during that heady era and being offered the choice of an alcoholic beverage or a hand-rolled marijuana cigarette. Since then, social use of this herb has continued at a more moderate pace.
In recent years, a synthetic form of its active ingredient, delta-9-tetrahydrocannabinol (THC) (6aR-trans-6a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H dibenzol(b,djpyran-a-01) has been approved by the Food and Drug Administration and is being prescribed to combat chemotherapy and acquired immunodeficiency syndrome-induced anorexia and nausea. This approved agent is named “dronabinol,” with several trade names, including Marinol (AbbVie Inc, North Chicago, Ill). On occasion, I have prescribed it to stimulate appetite and improve mood in apathetic, anorexic, and frail elderly patients, in whom it seemed to have a positive effect.
As a result of the 1937 law, as well as further criminalizing legislation passed during the Nixon administration, marijuana has become a major source of income for illegal drug smugglers. A major site of illegal drug importation is the United States-Mexico border. Hardly a week goes by here in Arizona without news reports involving seizures of large quantities of cannabis by US Border Patrol and Drug Enforcement Administration agents, who work constantly to impede the flow of this agent into the United States. The Drug Enforcement Administration has at this time spent more than 100 billion dollars trying to stop the flow of illegal drugs, including marijuana, into the United States. Unfortunately, the country continues to be flooded with illegal pharmaceuticals and marijuana courtesy of powerful drug cartels.
In recent years, 18 states and the District of Columbia, following California's lead in 1996, have passed legislation allowing physicians to prescribe marijuana for patients with severe and difficult to control pain or nausea. Similar legislation is pending approval in 10 more states. Marijuana continues to be widely consumed in the United States. Indeed, I can attest from clinical experience that many patients continue to abuse the use of this herb often alongside more dangerous compounds, such as methamphetamine. Anyone working on the inpatient service of a hospital in the United States today sees a daily stream of patients who admit to marijuana use or who are found to have THC in their “tox screen.”
A 2010 ABC news poll found that 81% of Americans favored medical marijuana use and its decriminalization for this purpose. Many other individuals lobby for repeal of the 1937 law forbidding marijuana sale and use. These citizens argue that marijuana should be regulated, sold, and taxed in a manner similar to tobacco and alcohol products.
Despite the ongoing debate, legislation, and current medical use of cannabis, there is a dearth of scientific, pharmacologic, and clinical studies with this agent. I reviewed more than 2070 articles catalogued by PubMed under the heading of medical marijuana and found little about the effect of THC on the metabolome.2, 3 However, there is a modest literature on the cardiovascular effects of THC, but the overwhelming number of investigations involved central nervous system effects and potential addiction.4
Much of what we know about cannabis comes from folktales and limited clinical observation. It was in this context that I was pleased to receive the submission published in this edition of The American Journal of Medicine, entitled “The Impact of Marijuana Use on Glucose, Insulin, and Insulin Resistance Among US Adults.”5 This epidemiologic, observational study demonstrated that among diabetic patients who admitted to using marijuana, insulin resistance was decreased and diabetic control was improved. Penner et al5 analyzed data obtained during the National Health and Nutrition Survey between 2005 and 2010. They studied data from 4657 patients, of whom 579 were current users of cannabis, 1975 used cannabis in the past but were not current users, and 2103 had never inhaled or ingested marijuana. These patients had fasting insulin and glucose levels measured along with a test for insulin resistance. Remarkably, fasting insulin levels were reduced in current cannabis users but not in former or never users. Two additional observations were that waist circumference was smaller and high-density lipoprotein cholesterol blood levels were higher in current cannabis users. These are indeed remarkable observations that are supported, as the authors note, by basic science experiments that came to similar conclusions.
Is it possible that THC will be commonly prescribed in the future for patients with diabetes or metabolic syndrome alongside antidiabetic oral agents or insulin for improved management of this chronic illness? Only time will answer this question for us. Nevertheless, what is very clear is that we desperately need a great deal more basic and clinical research into the short- and long-term effects of this agent in a variety of clinical settings, such as cancer, diabetes, and frailty of the elderly. I would like to call on the National Institutes of Health and the Drug Enforcement Administration to collaborate in developing policies to implement solid scientific investigations that would lead to information assisting physicians in the proper use and prescription of THC in its synthetic or herbal form.
As always, I welcome comments about this editorial and the article referred to on our blog at http://amjmed.blogspot.com.
SOURCES/LINKS
http://www.amjmed.com/article/S0002-9343(13)00200-3/fulltext
Article on Medscape: Pot Luck: Could Marijuana Be Used to Treat Diabetes?
by Lisa Nainggolan, May 16, 2013
http://www.medscape.com/viewarticle/804281?src=wnl_edit_tp10&uac=89474MT
Mj users appear to have better blood glucose control than never or former users
Editorial: Marijuana for Diabetic Control
Joseph S. Alpert, MD (Editor-in-Chief, The American Journal of Medicine)
http://www.amjmed.com/article/S0002-9343(13)00313-6/fulltext
THE STUDY
Article published online May 16 in the American Journal of Medicine.
Data from NHANES between 2005 and 2010
Incl drug-use questionnaire, Fasting serum labs in 4k+ individuals
N=4657 participants
579 = current users (self-reported smoking marijuana or hashish in the past month)
1975 = had smoked marijuana in the past but were not current users
2103 = had never inhaled or ingested marijuana
Fasting insulin and glucose measured in serum after nine-hour fast
Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated
NHANES
National Health and Nutrition Survey
cross-sectional, continuous survey, observational
administered annually by the National Center for Health Statistics
data are released in 2-year increments
complex, multistage probability sampling design-->nationally representative US sample
uses interview, physical examination, and laboratory components
11,335 persons aged 20 to 59 years completed the drug questionnaire (2005-2010)
4657 participants provided a fasting blood sample
QUESTIONS ON ILLICIT DRUG QUESTIONNAIRE
used to distinguish current, past, or never ever users
•“Have you ever, even once, smoked marijuana or hashish?” (yes, no, refused, don’t know);
•“How long has it been since you last used marijuana or hashish?” (answers were given as number of days, weeks, months, or years); and
•“During the past 30 days, on how many days did you use marijuana or hashish?”
RESULTS
Lower glucose among current users than never evers
Not significant following multivariate adjustment
No sig assoc: triglyceride levels, systolic or diastolic blood pressure.
Current users had 16% lower levels of fasting insulin and 17% lower HOMA-IR
Remained significant even after multivariate adjustment
1.63-mg/dL-higher HDL-cholesterol levels (sig)
Lower waist circumferences (sig)
If adjusted for BMI, associations attenuated but still statistically significant
Same results when diabetics excluded
No tolerance seen, current users seem to have the effects
In unadjusted analyses, past and current marijuana use were associated with lower levels of fasting insulin, glucose, HOMA-IR, BMI, and hemoglobin A1c (Table 2). Current marijuana use also was found to be inversely associated with waist circumference. Models adjusted for age and sex demonstrated statistically significant associations between past and current use of marijuana with lower levels of fasting insulin, glucose, HOMA-IR, and BMI. Also, current use was associated with higher HDL-C levels and lower waist circumference (Table 3). In multivariable-adjusted models, the associations of current marijuana use with lower levels of fasting insulin and HOMA-IR, as well as with higher HDL-C levels and lower waist circumference, remained statistically significant (Table 3). Compared with participants reporting never having used marijuana in their lifetimes, current use was associated with 16% lower fasting insulin levels (95% CI, −26 to −6), 17% lower HOMA-IR (95% CI, −27 to −6), and 1.63 mg/dL higher HDL-C levels (95% CI, 0.23-3.04) in multivariable adjusted models. Among current users, we found no significant dose-response relationship and no evidence for a U- or J-shaped curve. We did not find any significant associations between marijuana use and triglyceride levels, systolic blood pressure, or diastolic blood pressure.
In an analysis adjusting for BMI, a potential mediator of the associations between marijuana use and the cardiometabolic outcomes, the associations between current marijuana use and fasting levels of insulin, HOMA-IR, and waist circumference were attenuated, but remained statistically significant (Table 3). In addition, the results were not materially different in analyses that excluded participants with diabetes mellitus (Table 3).
CHARACTERISTICS OF CURRENT MJ USERS
(from this study and previous)
lower levels of fasting insulin
(similar results found with cannabidiol in mice)
less likely to be insulin resistant
true even when diabetics excluded
smaller waist circumferences
higher HDL cholesterol than never users
lower prevalence rates of obesity and diabetes mellitus
acute increase in caloric intake with use
higher average caloric intake levels than nonusers
Mixed results on BMI
Some studies have found no significant trend between marijuana use and BMI
2 large national surveys found lower BMI and decreased prevalence of obesity
MECHANISM?
Relationship between cannabinoids and peripheral metabolic processes?
Rimonabant = cannabinoid type 1 receptor antagonist
R improves insulin sensitivity in wild-type mice, but not in adiponectin knockout mice
Blocking type 1 receptor in mice without adiponectin does not change insulin sensitivity
Adiponectin has been reported to improve insulin sensitivity
THEORY: Adiponectin at least partially mediates the improvement in insulin sensitivity
Rimonabant-induced improvement in insulin resistance confirmed in human studies
Rimonabant sig assoc w incr plasma adiponectin, wt loss, decr waist circ
Obese rats given cannabis-->wt loss, incr in wt of pancreata, implying beta-cell protection
Cannabinoid type 1 knockout mice resistant to diet-induced obesity
This receptor mb central in the metabolic processes leading to obesity
Adiponectin mb mediator: 2 of the main active phytocannabinoids in marijuana, (-)-trans-Δ9-tetrahydrocannabinol and cannabidiol, agonize these receptors
CONCERNS
Long-term effects of this agent
Need a lot more research
Most research looks at CNS effects of marijuana and addiction potential
LEGALIZATION
Recent legalization of medical marijuana use in the form of THC in 19 states and DC
Recreational use in 2 states
PREVALENCE OF MJ USE
Estimated 17.4 million current users of marijuana in the United States
Approx 4.6 million of these smoking it daily or almost daily
2010 National Survey on Drug Use and Health
2007-->2010 use in 12+ persons incr from 5.8% to 6.9%
SOURCES
Am J Med. 2013. Article, Editorial
http://www.amjmed.com/article/S0002-9343(13)00200-3/fulltext
CANNABINOIDS
1) Much studied: (-)-trans-Δ9-tetrahydrocannabinol
acts as a partial agonist at both the cannabinoid type 1 and 2 receptors
2) cannabidiol, lower affinity for the cannabinoid receptors, appears to antagonize both cannabinoid type 1 and 2.12
Repeated administration of cannabinoids reduces cannabinoid type 1 receptor density
(receptor type 1 gets downregulated-->tolerance)
EDITORIAL
Marijuana for Diabetic Control
Joseph S. Alpert, MD (Editor-in-Chief, The American Journal of Medicine)
http://www.amjmed.com/article/S0002-9343(13)00313-6/fulltext
For centuries, cannabis sativa, more commonly known as marijuana, has been used as a folk remedy to relieve pain, improve mood, and increase appetite.
In 1937, Franklin D. Roosevelt signed the US Marijuana Tax Act that made it illegal to sell or use this herb. Nevertheless, cannabis continued to be used by a small number of citizens in the United States, including jazz musicians, entertainers, and cognoscenti desiring an altered state of mind.
During the 1960s, cannabis use became a symbol for the youth revolution. It was widely used as a mild euphoric on college campuses and among counterculture youth. I remember well coming to parties in Cambridge, Massachusetts, during that heady era and being offered the choice of an alcoholic beverage or a hand-rolled marijuana cigarette. Since then, social use of this herb has continued at a more moderate pace.
In recent years, a synthetic form of its active ingredient, delta-9-tetrahydrocannabinol (THC) (6aR-trans-6a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H dibenzol(b,djpyran-a-01) has been approved by the Food and Drug Administration and is being prescribed to combat chemotherapy and acquired immunodeficiency syndrome-induced anorexia and nausea. This approved agent is named “dronabinol,” with several trade names, including Marinol (AbbVie Inc, North Chicago, Ill). On occasion, I have prescribed it to stimulate appetite and improve mood in apathetic, anorexic, and frail elderly patients, in whom it seemed to have a positive effect.
As a result of the 1937 law, as well as further criminalizing legislation passed during the Nixon administration, marijuana has become a major source of income for illegal drug smugglers. A major site of illegal drug importation is the United States-Mexico border. Hardly a week goes by here in Arizona without news reports involving seizures of large quantities of cannabis by US Border Patrol and Drug Enforcement Administration agents, who work constantly to impede the flow of this agent into the United States. The Drug Enforcement Administration has at this time spent more than 100 billion dollars trying to stop the flow of illegal drugs, including marijuana, into the United States. Unfortunately, the country continues to be flooded with illegal pharmaceuticals and marijuana courtesy of powerful drug cartels.
In recent years, 18 states and the District of Columbia, following California's lead in 1996, have passed legislation allowing physicians to prescribe marijuana for patients with severe and difficult to control pain or nausea. Similar legislation is pending approval in 10 more states. Marijuana continues to be widely consumed in the United States. Indeed, I can attest from clinical experience that many patients continue to abuse the use of this herb often alongside more dangerous compounds, such as methamphetamine. Anyone working on the inpatient service of a hospital in the United States today sees a daily stream of patients who admit to marijuana use or who are found to have THC in their “tox screen.”
A 2010 ABC news poll found that 81% of Americans favored medical marijuana use and its decriminalization for this purpose. Many other individuals lobby for repeal of the 1937 law forbidding marijuana sale and use. These citizens argue that marijuana should be regulated, sold, and taxed in a manner similar to tobacco and alcohol products.
Despite the ongoing debate, legislation, and current medical use of cannabis, there is a dearth of scientific, pharmacologic, and clinical studies with this agent. I reviewed more than 2070 articles catalogued by PubMed under the heading of medical marijuana and found little about the effect of THC on the metabolome.2, 3 However, there is a modest literature on the cardiovascular effects of THC, but the overwhelming number of investigations involved central nervous system effects and potential addiction.4
Much of what we know about cannabis comes from folktales and limited clinical observation. It was in this context that I was pleased to receive the submission published in this edition of The American Journal of Medicine, entitled “The Impact of Marijuana Use on Glucose, Insulin, and Insulin Resistance Among US Adults.”5 This epidemiologic, observational study demonstrated that among diabetic patients who admitted to using marijuana, insulin resistance was decreased and diabetic control was improved. Penner et al5 analyzed data obtained during the National Health and Nutrition Survey between 2005 and 2010. They studied data from 4657 patients, of whom 579 were current users of cannabis, 1975 used cannabis in the past but were not current users, and 2103 had never inhaled or ingested marijuana. These patients had fasting insulin and glucose levels measured along with a test for insulin resistance. Remarkably, fasting insulin levels were reduced in current cannabis users but not in former or never users. Two additional observations were that waist circumference was smaller and high-density lipoprotein cholesterol blood levels were higher in current cannabis users. These are indeed remarkable observations that are supported, as the authors note, by basic science experiments that came to similar conclusions.
Is it possible that THC will be commonly prescribed in the future for patients with diabetes or metabolic syndrome alongside antidiabetic oral agents or insulin for improved management of this chronic illness? Only time will answer this question for us. Nevertheless, what is very clear is that we desperately need a great deal more basic and clinical research into the short- and long-term effects of this agent in a variety of clinical settings, such as cancer, diabetes, and frailty of the elderly. I would like to call on the National Institutes of Health and the Drug Enforcement Administration to collaborate in developing policies to implement solid scientific investigations that would lead to information assisting physicians in the proper use and prescription of THC in its synthetic or herbal form.
As always, I welcome comments about this editorial and the article referred to on our blog at http://amjmed.blogspot.com.
SOURCES/LINKS
http://www.amjmed.com/article/S0002-9343(13)00200-3/fulltext
Article on Medscape: Pot Luck: Could Marijuana Be Used to Treat Diabetes?
by Lisa Nainggolan, May 16, 2013
http://www.medscape.com/viewarticle/804281?src=wnl_edit_tp10&uac=89474MT
Mj users appear to have better blood glucose control than never or former users
Editorial: Marijuana for Diabetic Control
Joseph S. Alpert, MD (Editor-in-Chief, The American Journal of Medicine)
http://www.amjmed.com/article/S0002-9343(13)00313-6/fulltext