Marijuana's side effect of Cannabinoid Hyperemesis Syndrome is well known to us, as is use of Marinol to enhance appetite in the chronically ill, but are there other high points in the use of medical marijuana?  What about the possible use of CBD oil for chronic pancreatitis or intractable abdominal pain? Studies have shown cannabis' effect on GI motility, inflammation and immunity, intestinal and gastric acid secretion, nociception and emesis pathways, and appetite. Let's weed through the available data on the medical use and side effects of medicinal cannabis in gastroenterology.

3. Hash It Out:
The Role of Medical Marijuana in GI
Patricia Raymond MD FACG
Rx For Sanity/ EatWell.MD

4. Disclosures
The presenter has identified no relevant relationships
with commercial interest organizations whose
products are related to the program content.
(Really?? You’d ask that?)
The Society of Gastroenterology Nurses and Associates,
Inc. is accredited as a provider of continuing nursing
education by the American Nurses Credentialing
Center’s (ANCC) Commission on Accreditation.

5. [Marijuana] doesn’t have a high potential for abuse,
and there are very legitimate medical applications.
In fact, sometimes marijuana is the only thing that works…
[I]t is irresponsible not to provide the best care we can
as a medical community,
care that could involve marijuana.
We have been terribly and systematically misled
for nearly 70 years in the United States,
and I apologize for my own role in that.
– Dr. Sanjay Gupta / Neurosurgeon

6. Objectives
• Explore the epidemiology of cannabis use
• Summarize current legal standing of cannabis in the US
• Analyze the cautions and side effects of cannabinoids, including
Cannabinoid Hyperemesis, Cannabinoid Use Disorder, and
Cannabinoid Psychosis
• Inventory the physiology of cannabinoid receptors in the
gastrointestinal tract
• Discuss what is known of efficacy of marijuana and extracts for
gastrointestinal disorders

7. Cannabis AKA
Aunt Mary, BC bud, blunt (cannabis within tobacco), boom, chronic,
dope, gangster, ganja, grass, hash, herb, hydro, indo, joint (cannabis
cigarette), kif, Mary Jane, mota, pot, reefer, roach, sinsemilla, skunk,
smoke, weed, and yerba
Synthetic cannabinoids have street or “brand” names that include
synthetic weed, legal high, spice, K2, Blaze, RedX Dawn, Paradise,
Demon, Black Magic, Spike, Mr. Nice Guy, Ninja, Zohai, Dream,
Genie, Sence, Smoke, Skunk, Serenity, Yucatan, Fire, and Crazy
Clown

9. Cannabis botany:
Three species
C. sativa and C. indica contain significant amounts
of psychoactive phytocannabinoids (eg, delta-9-
tetrahydrocannabinol [THC]), so are cultivated for
recreational and medicinal use
Psychoactive phytocannabinoids are generally found
only in the female plant, although in some varieties
the male plant may contain significant
amounts. THC is found chiefly in the flowering
heads (“buds”), with much less in the leaves and
stems
C. ruderalis contains negligible amounts of
psychoactive compounds, is cultivated for seeds and
fiber (hemp), and is not considered an illegal
substance.

10. Cannabis forms
• Delta-9-tetrahydrocannabinol (THC) as measure of cannabis potency
• Marijuana usually refers to an unsorted mixture of dried flowers, leaves,
and stems (typical THC content around 6%
• Sinsemilla refers to the unpollinated female plant (THC content around
13%)
• Hashish refers to the compressed resinous secretion of the plant (THC
around 40 %)

11. Cannabis forms
• Hash oil refers to the oil derived from the resin (THC around 50 %).
• Cannabis concentrates containing up to 80 percent THC (“dabs,” “earwax”) are
produced by solvent-based extraction (often butane) of THC from plant material
• Results in a dense oil or wax-like substance that can be readily vaporized in a
table-top vaporizer, “e-cigarette” or by placing a dab at the tip of a glass or
metal rod that is heated

12. Cannabidiol (CBD)
• Cannabidiol is a phytocannabinoid without psychoactive effects, so has little or no
abuse liability
• Question that CBD attached to CB2 receptors
• Appears that CBD does not attach directly to either CB1 or CB2
• Directs the body to use more of its own cannabinoids
• Not FDA-approved for pain relief
• Advantage of CBD oil is that it is not psychoactive (no ‘high’)
• Under updated hemp legislation in the 2018 U.S. Farm Bill, CBD is sold in all 50
states
• Legal hemp plants under the Farm Bill must contain less than 0.3% THC

13. More on that 2018 Farm Bill
• For decades, federal law did not differentiate hemp from other cannabis plants
• Hemp was effectively made illegal in 1937 (Marihuana Tax Act)
• Formally made illegal in the 1970 Controlled Substances Act
• Banned all cannabis
• Section 12619 of the 2018 Farm Bill removes hemp-derived products from its Schedule I
status under the Controlled Substances Act
• Legislation does not legalize CBD generally
• Any cannabinoid extract will be legal, if and only if that hemp is produced in a manner
consistent with the Farm Bill, associated federal regulations, association state regulations,
and by a licensed grower
• All other cannabinoids, produced in any other setting, remain a Schedule I substance
under federal law and are thus illegal

14. Of course I know
how to roll a joint.
-Martha Stewart
Of course I know how to
roll a joint.
-Martha Stewart

15. Who uses cannabis?
•Most commonly used illegal psychoactive substance
worldwide
•192 million world wide, 3.9% ages 15 to 64
•Past-year cannabis use in US >12 years old of
13.9%
•Past-month use of 8.9%
•10% of users develop CUD

16. Image good little girl
Not me!

17. Who uses cannabis?
Highest past-year prevalence is among young adults (18 to 25 years old)
(33%)
•Lowest prevalence is among early adolescents (0.5% among 12 year olds
and 2.8% among 13 year olds)
•Past year prevalence is 11% among those 26 years or older
•Rare in those 65 years or older (3.3%)
In 2016, the mean age of first-time cannabis users was 19.4 years
Men are almost twice as likely as women to have used cannabis over the past
month, 11.3 versus 6.7 percent, respectively
•Men and women start cannabis use in roughly comparable numbers and at
roughly comparable mean ages

18. Who uses cannabis?
•Cannabis use over the past month is more prevalent among those of mixed race
(17.7%)
•Blacks or African Americans (11.1 percent),
•Native Americans (13.6 percent)
•Compared with the overall non-Hispanic United States population (9.1 percent)
•Less prevalent among Asians (3.3 percent)
•Caucasian (9.0 percent), Pacific Islanders (8.6 percent), and Hispanics (7.7
percent
•College graduates have a lower cannabis use during the past month (6.6%)
•Less education (8.3 to 11.3 percent)
•Full-time college students have the same rate of current use as do their non-
student peers
•More use if socially unhappy, ‘bad crowd’, failing grades

19. Who uses cannabis?
• Full time or out of labor force
(7.5%, 4.8%)
• Part time 11.6%
• Unemployed 15%
•Income < $20 K 15.6%
•Income > $70 K 5.9%
•Unmarried 21%
•Married 5.5%
•Widowed /separated 8.3%

21. Legal status of cannabis
•33 US states, the District of Columbia, Puerto Rico, and Guam authorize
medical use of cannabis
•An additional 15 states have limited programs that authorize use of high
cannabidiol/low delta-9-tetrahydrocannabinol (THC) cannabis formulations
for treatment of childhood epilepsy, especially refractory seizures.
•Nabiximols (Sativex) is approved for medical use in 27 countries (including
Canada), but not in the United States, for treatment of pain and muscle
spasticity due to multiple sclerosis.
•Epidiolex FDA approved 2018 for the treatment of intractable childhood
epilepsy (Lennox-Gastaut syndrome (LGS) or Dravet syndrome), available
from specialty pharmacies
2020 data

22. • News, February 2021:
Virginia lawmakers approved a bill Saturday that would legalize
the sale and recreational use of marijuana — but not until 2024.
The move makes Virginia the first Southern state to vote to
legalize recreational marijuana, joining 15 other states and the
District of Columbia. The legislation now goes to Democratic Gov.
Ralph Northam, who supports legalization, for his signature.

23. https://disa.com/map-of-marijuana-legality-by-state
as of 02/2021

24. I couldn’t find a single
confirmed overdose death.
—Dr. Sanjay Gupta

25. Cannabinoid
hyperemesis syndrome
• Seen with chronic THC use
• Patients are almost always daily
cannabis users for at least one year and
symptoms resolve within one to two
days of cessation of cannabis use
• Episodic abdominal pain, vomiting, nausea
• Typically relieved by hot showers or
baths
• Hydration, antiemetics (latter not very
useful)
• Capsaicin cream to abdominal wall
• Pathophysiology remains unknown

26. Cannabis use disorder
•10 percent of regular cannabis users
•13.1 million individuals world-wide had moderate-severe
cannabis use disorder in 2010, a point-prevalence of 0.19
percent
•Young adult (20 to 24 years old) males living in high-income
regions
•Cognitive impairment
•Poor school or work performance
•Mood disorders and psychosis

28. Cannabis Psychosis
•Review of 35 longitudinal studies
•Increased risk of psychosis for those who ever used cannabis compared with those who did
not (adjusted odds ratio 1.41, 95% CI 1.20-1.65)
•Dose-response relationship, twofold increased in those with most frequent use (odds
ratio 2.09, 95% CI 1.54-2.84)
•Prospective longitudinal study of 6534 individuals born in northern Finland in 1986
•Evaluated at age 15 to 16 years and again at age 30 years
•Increased risk of psychosis for those who used cannabis at least five times by age 15 to
16 years
•Compared with those who had never used (adjusted hazard ratio 3.02, 95% CI 1.14-
7.98)
•No increased risk for those who used cannabis one to four times
•Adjusted for several known confounding factors (eg, prodromal psychosis
symptoms at baseline, parental psychosis, frequent alcohol use, daily tobacco
smoking) and excluded individuals with a psychosis diagnosis at first evaluation
Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review.
Moore TH, Zammit S, Lingford-Hughes A, et al. Lancet. 2007;370(9584):319.
Adolescent cannabis use, baseline prodromal symptoms and the risk of psychosis.
Mustonen A, NiemeläS, Nordström T, et al. Br J Psychiatry. 2018;212(4):227.

29. Cannabis induced psychosis and schizophrenia
• Danish national registry study 1492 patients who received a diagnosis of cannabis-
induced psychosis between 1994 and 2014 and followed to August 2014
• 41.2 percent (95% CI 36.6-46.2) conversion rate to schizophrenia
• 50 % men converted within 2.0 years , 50 % women within 4.4 years
• The hazard ratio for conversion to schizophrenia, compared with matched
comparison subjects without a history of substance-induced psychosis,
was 101.7 (95% CI 74.1-139.7)
• Young age was associated with a higher risk of converting to schizophrenia
• Self-harm after a substance-induced psychosis was significantly linked to a
higher risk of converting to both schizophrenia and bipolar disorder
Rates and Predictors of Conversion to Schizophrenia or Bipolar Disorder Following Substance-Induced Psychosis.
Starzer MSK, Nordentoft M, Hjorthøj C Am J Psychiatry. 2018;175(4):343. Epub 2017 Nov 28.

31. Physiology 101 for cannabis
•Cannabis plant contains more than 100 unique terpenophenolic compounds
known as (phyto)cannabinoids
•Psychoactive properties are due to delta-9-tetrahydrocannabinol (THC)
•THC is a partial agonist at cannabinoid receptors: CB1 and CB2
•CB1 receptors in the brain and vascular endothelium, liver, and adipose tissue
•CB2 receptors are present on immune cells throughout the body (including
brain microglia) and on some neurons
•TRPV channels: effects on TRPV3 and TRPV4
•Thermosensitive transient receptor potential (TRP) channels of vanilloid
type-3 or -4
•THC stimulates or inhibits
•Important in pain perception and colitis

33. “The American Nurses Association (ANA)
recognizes that patients should have safe
access to therapeutic marijuana/cannabis.
Cannabis or marijuana has been used
medicinally for centuries. It has been shown to
be effective in treating a wide range of
symptoms and conditions.”
– American Nurses Association

34. Gastrointestinal system disorders
•Irritable bowel syndrome
•Inflammatory bowel diseases
•Crohn’s disease, ulcerative colitis
•Diseases of the liver
•Hepatitis, fibrosis, steatosis, ischemia-reperfusion injury, hepatic
encephalopathy
•Metabolic syndrome, obesity, diabetes

35. https://www.canada.ca/content/dam/hc-sc/documents/services/drugs-medication/cannabis/information-medical-practitioners/information-
INFORMATION FOR HEALTH CARE PROFESSIONALS
Cannabis (marihuana, marijuana) and the cannabinoids
Dried or fresh plant and oil administration by ingestion or other means Psychoac
Spring 2018
The following GI information is (mainly) from:

36. For other potential uses,
please review the Health Canada document
•Palliative Care
•Pain management
•Hypertension
•Glaucoma
•Neurologic conditions

37. Cannabinoids and the gastrointestinal tract
•Cannabinoids have many functions in the digestive system
•Inhibition of gastric acid production
•GI motility
•Secretion and ion transport
•Attenuation of visceral sensation and inflammation
•Alterations in the levels of various components of the ECS have been noted in
experimental animal models of GI disorders, as well as in clinical studies

38. Endocannabinoid system
•CB1 and CB2 receptors
•Both detected in the enteric nervous system of the GI tract (enteric neurons, nerve fibers and
terminals)
•CB1 only in human colonic epithelium and gastric parietal cells
•CB2 expression is up-regulated in colon segments of patients with IBD
•Regional variations
•CB1 and CB2 pancreas
•CB1 NOT CB2 liver
•Endocannabinoid degradation enzymes FAAH and MAGL (animal studies)
•FAAH stomach, large and small intestine, myenteric plexus
•MAGL duodenal wall muscles and myenteric plexus, proximal and distal colon, enteric nervous system

39. IBS and cannabinoids

40. Dronabinol (Marinol)
• Man-made compound that contains cannabinoids found in the marijuana
plant (Cannabis sativa )
• Contains tetrahydrocannabinol (THC) in standardized concentrations
• Does not contain other compounds found in street marijuana
• Activates cannabinoid receptors causing a wide range of effects in the brain,
including short-term memory loss, euphoria, enhanced sensation, and
increased appetite.
• Prevents nausea and vomiting by inhibiting the vomiting center in the brain
• Approved by the FDA in May 1985.

41. IBS and dronabinol in humans
• Delay in gastric emptying in female subjects
• Increase in colon compliance
• Reduced pre and post prandial colon motility
• Tendency toward constipation
• No reduction in sensory perception
• Side effects drowsiness, dry mouth, dizziness, disturbed mental
concentration, nausea

42. IBS and cannabinoid references
Esfandyari T, Camilleri M, Ferber I, Burton D, Baxter K, Zinsmeister AR. Effect of a cannabinoid agonist on gastrointestinal transit
and postprandial satiation in healthy human subjects: A randomized, placebo-controlled study. Neurogastroenterol Motil 2006
09;18(1350-1925; 1350-1925; 9):831-8.
Esfandyari T, Camilleri M, Busciglio I, Burton D, Baxter K, Zinsmeister AR. Effects of a cannabinoid receptor agonist on colonic
motor and sensory functions in humans: A randomized, placebo-controlled study. Am J Physiol Gastrointest Liver Physiol
Wong BS, Camilleri M, Busciglio I, Carlson P, Szarka LA, Burton D, Zinsmeister AR. Pharmacogenetic trial of a cannabinoid
agonist shows reduced fasting colonic motility in patients with nonconstipated irritable bowel syndrome. Gastroenterology 2011
11;141(1528-0012; 0016-5085; 5):1638-47.

43. IBD and cannabinoids

44. IBD and cannabinoids
•May limit inflammation by activation of CB1 and CB2 receptors
•Many mouse model colitis studies, few human studies
•10 - 12% of patients with IBD are active cannabis users
•10-50% use cannabis for disease control (pain, nausea,
diarrhea)
•44 - 51% of patients with IBD have used cannabis at some time in
their lives

45. CBD Oil and IBD
• Descriptive study of IBD patients 13 to 23 years of age seen January 2015 - December
2017 at Children's Hospital Colorado.
• 15 users and 67 non-users were similar for clinical characteristics and pain and
appetite scores.
• 9 of 15 (60%) CO users had used in the past 30 days, an average of 22 ± 9
times; and 4 used daily. A variety of strengths and CBD:THC ratios were
reported.
• Most common perceived effect of use was on sleep quality, nausea, and
increase in appetite
• Of the 15 users, 6 used only CO and no additional forms of cannabis
• Of these 6 CO only users, 5 medical use, most commonly pain relief
J Pediatr Gastroenterol Nutr. 2019 Mar;68(3):348-352. doi: 10.1097/MPG.0000000000002189.
Cannabis Oil Use by Adolescents and Young Adults With Inflammatory Bowel Disease.Hoffenberg EJ, McWilliams S, Mikulich-Gilbertson S,et al.

46. Crohns and cannabis
•Retrospective, observational study of 30 patients with Crohn’s disease
•Indication: lack of response to conventional treatment in the majority of the patients,
and chronic intractable pain in most of the other patients.
•Duration of disease was 11 years (range: 1 – 41 years)
•20 patients terminal ileum; 5 patients proximal ileum; 8 patients Crohn’s colitis
•Most patients smoked cannabis as joints (0.5 g cannabis/joint), a few inhaled the
smoke through water, and one patient consumed cannabis orally
•1-3 joints per day (maximum 7)
•Duration 2 years average
•All reported improvements in Harvey-Bradshaw index
•Small study, limited by method

47. Crohns and cannabis (2)
• 8 week double-blind placebo trial, N= 21 patients
• Patients smoked joints containing 0.5 g dried cannabis flowers containing 11.5 mg Δ -THC (23%
THC, < 0.5% CBD), BID x 8 weeks followed by a 2 week “washout” period
• Primary objective: induction of remission (Crohn’s disease activity index (CDAI) score of < 150
after 8 weeks cannabis
• Secondary objectives:
• Response (defined as a 100 point reduction in the CDAI),
• Reduction of at least 0.5 mg/dl in C-reactive protein (CRP) levels
• Improvement in QoL of at least 50 points as measured by SF-36.
• All patients were cannabis-naïve and had failed at least one form of medical treatment for the
disease, including mesalamine, corticosteroids, thiopurines, methotrexate, or anti-TNF-α.
Patients were concomitantly taking other medications during the study period (5-aminosalicylic
acid (5-ASA), corticosteroids, purine analogue, methotrexate, opioids, and anti-TNF-α).

48. Crohns and cannabis (2)
• 45% of patients in the study group achieved full remission (CDAI score <150) compared to
10% of patients in the placebo group (NS)
• Response rate (CDAI reduction > 100 points) was 90% in the cannabis group and was
significantly different from the placebo group
• During the two-week washout period, the CDAI score returned to pre-study baseline
levels
• Patients taking corticosteroids or opioids and assigned to the cannabis group were able
to stop using the drugs during cannabis treatment
• Statistically significant increase in QoL, measured using the SF-36 QoL instrument, was
associated with cannabis treatment but not with placebo
• Statistically significant improvements for pain, appetite and in patient satisfaction were
reported with cannabis treatment but not with placebo
• No significant changes were observed for CRP levels

49. Crohns and Cannabis- don’t get too excited (2)
• Reported improvements in disease activity appeared to be
symptomatic, with no apparent objective evidence of reduction in
inflammatory activity
• Principal limitations of this study were the small sample size
and a high probability of treatment unblinding
• No significant side effects associated with cannabis treatment
• No withdrawal symptoms were reported during the two-week
washout period

50. Crohns and cannabis references
Naftali T, Lev LB, Yablecovitch D, Half E, Konikoff FM. Treatment of crohn's disease
with cannabis: An observational study. Isr Med Assoc J 2011 08;13(1565-1088;
8):455-8.
Naftali T, Bar-Lev Schleider L, Dotan I, Lansky EP, Sklerovsky Benjaminov F,
Konikoff FM. Cannabis induces a clinical response in patients with crohn's disease: A
prospective placebo-controlled study. Clin Gastroenterol Hepatol 2013
Oct;11(10):1276,1280.e1.

51. Cannabinoids IBD
“Modulating the endocannabinoid system using pharmacological
receptor agonists, genetic knockout models, or inhibition of degradative
enzymes have largely shown improvements in colitis in vivo. Despite
these promising experimental results, this has not translated into
meaningful benefits for human IBD in the few clinical trials which have
been conducted to date, the largest study being limited by poor
medication tolerance due to the Δ9-tetrahydrocannabinol component. “
J Crohns Colitis. 2019 Mar 30;13(4):525-535. doi: 10.1093/ecco-jcc/jjy185.
Cannabis, Cannabinoids, and the Endocannabinoid System-Is there Therapeutic Potential for Inflammatory Bowel Disease?
Ambrose T1,2, Simmons A1,2.

52. Cochrane review of cannabis and Crohns
“The effects of cannabis and cannabis oil on Crohn's disease are
uncertain. Thus no firm conclusions regarding the efficacy and safety of
cannabis and cannabis oil in adults with active Crohn's disease can be
drawn. The effects of cannabis or cannabis oil in quiescent Crohn's
disease have not been investigated. Further studies with larger numbers
of participants are required to assess the potential benefits and harms of
cannabis in Crohn's disease. “
Cochrane Database Syst Rev. 2018 Nov 8;11:CD012853. doi: 10.1002/14651858.CD012853.pub2.
Cannabis for the treatment of Crohn's disease.Kafil TS1, Nguyen TM, MacDonald JK, Chande N.

53. Cochrane review of cannabis and UC
• Only two studies to review, one flawed
• Second study, N = 60 compared 10 weeks of cannabidiol capsules with up to 4.7% D9-
tetrahydrocannabinol (THC) with placebo capsules in participants with mild to moderate UC.
• The starting dose of cannabidiol was 50 mg twice daily increasing to 250 mg twice daily if tolerated.
• Clinical remission at 10 weeks was achieved by 24% (7/29) cannabidiol group compared to 26%
(8/31) in the placebo group (RR 0.94, 95% CI 0.39 to 2.25; low certainty evidence).
• Clinical response at 10 weeks was achieved in 31% (9/29) of cannabidiol participants compared to
22% (7/31) of placebo patients (RR 1.37, 95% CI 0.59 to 3.21; low certainty evidence).
• Serum CRP levels were similar in both groups after 10 weeks of therapy
• Mean CRP in the CBD group was 9.428 mg/L compared to 7.638 mg/L in the placebo group
(MD 1.79, 95% CI -5.67 to 9.25; moderate certainty evidence).
• There may be a clinically meaningful improvement in QOL at 10 weeks, measured with the IBDQ
scale (MD 17.4, 95% CI -3.45 to 38.25; moderate certainty evidence).
Cochrane Database Syst Rev. 2018 Nov 8;11:CD012954. doi: 10.1002/14651858.CD012954.pub2.
Cannabis for the treatment of ulcerative colitis. Kafil TS1, Nguyen TM, MacDonald JK, Chande N..

54. Cochrane review of cannabis and UC
• Adverse events were more frequent in cannabidiol participants compared to placebo
• 100% (29/29) CBD
• 77% (24/31) placebo (RR 1.28, 95% CI 1.05 to1.56; moderate certainty evidence)
• Adverse events mild or moderate in severity
• Adverse events included dizziness, disturbance in attention, headache,
nausea and fatigue
“The effects of cannabis and cannabidiol on UC are uncertain, thus no firm conclusions
regarding the efficacy and safety of cannabis or cannabidiol in adults with active UC can
be drawn.There is no evidence for cannabis or cannabinoid use for maintenance of
remission in UC. Further studies with a larger number of patients are required to assess
the effects of cannabis in UC patients with active and quiescent disease.”
Cochrane Database Syst Rev. 2018 Nov 8;11:CD012954. doi: 10.1002/14651858.CD012954.pub2.
Cannabis for the treatment of ulcerative colitis. Kafil TS1, Nguyen TM, MacDonald JK, Chande N..

55. Motility and cannabinoids

56. Cannabis and GI motility (review article)
• Cannabinoid hyperemesis
• Dronabinol (a non-selective cannabinoid agonist), slows gastric emptying and
inhibits colonic tone and phasic pressure activity.
• Decreased enteric FAAH activity is associated with colonic inertia in slow
transit constipation
• Orphan G protein-coupled receptor, GPR55, is overexpressed in
streptozotocin-induced gastroparesis, suggesting it is involved in inhibition of
antral motility
• Activated by THC
• Suggestion that GPR55 should be reclassified as CB3
Neurogastroenterol Motil. 2018 Sep;30(9):e13370. doi: 10.1111/nmo.13370. Epub 2018 May 10.
Cannabinoids and gastrointestinal motility: Pharmacology, clinical effects, and potential therapeutics in humans.
Camilleri M1.

57. Liver and cannabinoids

58. Liver and cannabis
Pre-clinical studies suggest :
• CB1 receptor activation is detrimental in liver diseases
• promotes steatosis, fibrosis
• CB2 receptor activation appears to have some beneficial effects
Pre-clinical studies also suggest that CBD, THCV (tetrahydrocannabivarin) and ultra-low doses of
THC may have protective effects in hepatic ischemia-reperfusion injury and hepatic encephalopathy
• CB1 and CB2 play opposing roles in the liver

59. Liver and cannabis
• Mouse studies only
• Vaporized or IV cannabis prevents reperfusion injury in ischemic liver
• Both preventative and treatment
• Intraperitoneal cannabis improves hepatic encephalopathy
• Locomotor, cognitive and neurological

60. Metabolic syndromes
and cannabinoids

61. Metabolic syndromes and cannabinoids
Pre-clinical studies suggest acute CB1 receptor activation results in increased fat
synthesis and storage while chronic CB1 receptor activation (or CB1 receptor
antagonism) results in weight loss and improvement in a variety of metabolic indicators
Observational studies suggest an association between chronic cannabis use and an
improved metabolic profile, while pre-clinical and very limited clinical evidence suggests
a potential beneficial effect of THC on glycemic control (in patients with type II diabetes)

62. Regulation of energy balance by the ECS
• Centrally- CNS, especially hypothalamus
• Peripherally - white adipose tissue, skeletal muscle, pancreas, liver, and small intestine
• Overactivity of the ECS (e.g. CB1 receptor activation) - classic munchies
• Increased nutrient intake (i.e. increased motivation for palatable food, increase in hedonic
properties of palatable food, increased fat preference and intake, increased neural
responses to sweet taste, increased odor sensitivity, increased food-seeking behaviour),
enhanced energy storage (i.e. increased adipogenesis, decreased fatty acid oxidation,
increased glucose uptake, increased insulin secretion, increased liver lipogenesis,
decreased liver insulin clearance, decreased liver insulin-induced signaling), reduced
energy expenditure (i.e. decreased white adipose tissue lipolysis, decreased
mitochondrial biogenesis), reduced thermogenesis (brown adipose tissue)
• Central and peripheral inhibition of CB1 receptor activity: beneficial for the treatment of
obesity and metabolic syndrome

63. Cannabis and metabolism (1)
• Cross-sectional, case-control study 30 cannabis smokers and 30 control subjects
• Median self-reported duration of cannabis use was 12 years (range: 2 – 38 years)
• Median number of joints smoked per day was 9.5 (range: 3 – 30).
• Chronic cannabis smoking was associated with a statistically significant lower total
abdominal fat area and a lower subcutaneous abdominal fat area while no difference
was noted for abdominal visceral fat area
• Chronic cannabis users had significant increase in percentage of visceral fat
compared to controls
• Percentage of visceral fat was not related to age, frequency or duration of
cannabis use
• Chronic cannabis smoking was not associated with hepatic steatosis, insulin
insensitivity, impaired pancreatic β-cell function or glucose intolerance

64. NHANES III on diabetes and cannabis
• NHANES III, (1988 – 1994), a cross-sectional survey of 10,896 adults
• Current marijuana users had a lower age-adjusted prevalence of diabetes
mellitus compared to non-marijuana using adults (OR = 0.42, 95% CI = 0.33
– 0.55)
• Elevated c-reactive protein was highest among non-marijuana users (18.9%)
• past marijuana users (13%),
• current light marijuana users(16%)
• heavy (9%) marijuana users
• The lower odds of diabetes mellitus among marijuana users was statistically
significant (OR = 0.36, 95% CI = 0.24 to 0.55).

65. Cannabis and weight and
diabetes management?
• Studies suggest an association between
chronic cannabis use and an improved
metabolic profile (i.e. lower BMI, lower
fasting insulin, lower insulin resistance
score, lower likelihood of obesity, lower
prevalence of diabetes mellitus)
• Mouse studies are underway

66. Cannabis and metabolism
Muniyappa R, Sable S, Ouwerkerk R, Mari A, Gharib AM, Walter M, Courville A, Hall
G, Chen KY, Volkow ND, et al. Metabolic effects of chronic cannabis smoking.
Diabetes Care 2013 Aug;36(8):2415-22.
Rajavashisth TB, Shaheen M, Norris KC, Pan D, Sinha SK, Ortega J, Friedman TC.
Decreased prevalence of diabetes in marijuana users: Cross-sectional data from the
national health and nutrition examination survey (NHANES) III. BMJ Open.
2012;2(2044-6055):e000494.

67. I now have absolute proof that smoking
even one marijuana cigarette
is equal in brain damage to
being on Bikini Island during an H-bomb blast.
—Ronald Reagan

68. Cannabinoids and GI

69. Johnny Stack

70. More potent cannabis
• Current commercialized cannabis is near 20% tetrahydrocannabinol (THC)
• In the 1980s, THC concentration was < 2%
• Cannabis oils, waxes, and dabs can reach 80–90% THC
• CDPHE show significant increases in hospitalizations in each phase of marijuana
legalization
• 575 per 100,000 hospitalizations in 2000
• 2413 in the 2014–June 2015 period
• Prevalence of mental illness was or patients with marijuana-related billing codes
compared to those without
• 5.07; (95% confidence interval [CI], 4.96 – 5.09) for ED visits
• 9.67; (95% CI, 9.59 – 9.74) for hospital admissions
Legalized Cannabis in Colorado Emergency Departments.Western Journal of Emergency MedicinePUBLISHED: JUNE 3, 2019 DOI:

71. THC and psychosis
Daily cannabis use was associated with increased odds of
psychotic disorder compared with never users (adjusted odds ratio
[OR] 3·2, 95% CI 2·2–4·1), increasing to nearly five-times
increased odds for daily use of high-potency types of cannabis
(4·8, 2·5–6·3).
(high-potency cannabis >10 percent THC)
The contribution of cannabis use to variation in the incidence of psychotic disorder across Europe (EU-GEI):
a multicentre case-control study Marta Di Forti, PhD Diego Quattrone, MD Tom P Freeman, PhD et al.
Lancet Psychiatry VOLUME 6, ISSUE 5, P427-436, MAY 01, 2019

73. THC and the developing brain
“Johnny Stack struggled with social anxiety and panic attacks in high school, which were
successfully managed with support, prescription medications, and therapy. He could have
been fine.
Then at about 16 years old (when he could drive), Johnny discovered marijuana and believed
it helped his anxiety. (Yes, we live in Colorado. Yes, it is everywhere. Yes, your kids can get it
too unless you chain them to their beds.) He started “dabbing” high-THC marijuana (they
smoke a very potent wax or shatter form), which triggered bizarre episodes of psychosis, a
first suicide attempt, and delusional thinking (the FBI was after him, the world “knew about
him,” the mob had it in for him, we were “in on it,” etc.).
We would dis-enroll him from his current university, admit him to mental hospitals, and they
would stabilize him with medications, and he’d recover…until he did the drugs again. He
would try other illicit drugs as well. “

74. THC and the developing brain
“Eventually, even when he stopped using marijuana, the psychosis did not
go away, and he developed full-blown schizophrenia. He was put on anti-
psychotics to control the delusion, but he didn’t like how “stupid” they made
him feel, because he was extremely intelligent. So, he would stop taking
them without telling us (a common problem with the disorder).
When he died, he had given up smoking, he wasn’t on drugs, and he wasn’t
depressed. But because he wouldn’t take the medications he now needed,
the paranoid delusions told him to stop the pain, and he jumped.”
~Laura Stack
shared with permission

76. My beloved son
Johnny Kenneth Stack
2/7/00 – 11/20/19

77. Q&A
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