Medical Marijuana Inservice - WordPress.com...Changes in menstrual cycle, ovulation suppression Health Canada. Information for Health Care Professionals: Cannabis (Marihuana, marijuana)

EVIDENCE AND USE OF MEDICAL MARIJUANAJennifer PitmanIsland Health Pharmacy Resident November 15th 2017

OUTLINE

• Background on medical marijuana• Pharmacology of medical marijuana• Evidence for the use if medical marijuana•Dosing, drug interactions, and adverse effects of

medical marijuana• How to get access to medical marijuana

BACKGROUND ON MARIJUANA

• Comes from cannabis sativa (a hemp plant)• Contains at least 489 distinct compounds from

18 chemical classes• Principle compounds are tetrahydrocannabinol

(THC) and cannabidiol (CBD)• Other cannabinoids:

• Cannabinol (CBN)• Cannabigerol (CBG)

• Average THC content:• 10% in illicit products• 12.5% in Health Canada products

HealthCanada.InformationforHealthCareProfessionals:Cannabis(Marihuana,marijuana)andthecannabinoids.2009;(888).

MEDICAL MARIJUANA• Health Canada products are composed of

the mature flowering heads of the female cannabis plant (highest THC content)

• The product is irradiated to remove contaminants such as toxic spores

• The finished lots are based on results of bacterial, fungal, and moisture testing

• Kept in sterile pouches in cold storage• Stability:

• Ideal storage is 2-6 degrees with shelf life of 12 months

• When kept >18 degrees 33% of THC content is lost over 5 years


THE CANNABINOIDS

• Tetrahydrocannabinol (THC)• Activates CB1 receptors• Responsible for psychoactive and therapeutic effects

• Cannabidiol (CBD)• Activates various ion channels, receptors and

enzymes (not CB1 or CB2)• Many possible therapeutic effects

• Cannabinol (CBN)• 10% of the activity of THC• Possible immunosuppressive effects

• Cannabigerol (CBG)• Partial activates CB1 and CB2 receptors• Possibly anti-inflammatory and pain relief properties


• CB1 Receptors• Most abundant in the central

and peripheral nervous system• Also expressed in fat tissues,

immune cells, spleen, heart, lungs, GI tract, kidney, bladder, reproductive organs, skeletal muscle, bone and joints

• CB2 Receptors• Most abundant in immune

system such as white blood cells and spleen

• Also found in bone, liver, and neurons


PRESCRIPTION CANNABINOIDS

• Dronanbinol (Marinol)• Oral capsule• Synthetic THC• Not available in Canada

• Nabilone (Cesamet)• Oral pill• THC analog (similar structure)• Indicated for nausea/vomiting in cancer

• Nabiximols (Sativex)• Buccal Spray• Contains THC and Cannabidiol extracts• Indicated for spasticity/neuropathic pain in

MS and adjunctive pain treatment in cancer

10

Figure 1. The Endocannabinoid System in the Nervous System (1) Endocannabinoids are manufactured ―on-demand‖ in the post-synaptic terminals: anandamide (AEA) is generated from phospholipase-D (PLD)-mediated hydrolysis of the membrane lipid N-arachidonoylphosphatidylethanolamine (NAPE); 2-AG from the diacylglycerol lipase (DAGL)-mediated hydrolysis of the membrane lipid diacylglycerol (DAG); (2) These endocannabinoids (AEA and 2-AG) diffuse retrogradely towards the pre-synaptic terminals and like exogenous cannabinoids such as THC (from cannabis), dronabinol, and nabilone, they bind and activate the pre-synaptic G-protein-coupled CB1 receptors; (3) Binding of phytocannabinoids and endocannabinoids to the CB1 receptors triggers the activation and release of the Gi/Go proteins from the CB receptors and inhibits adenylyl cyclase, thus decreasing the formation of cyclic AMP and the activity of protein kinase A; (4) Release of the Gi/Go proteins also results in the opening of inwardly-rectifying K+ channels (depicted with a ―+‖) causing a hyperpolarization of the pre-synaptic terminals, and the closing of Ca2+ channels (depicted with a ―-―), arresting the release of stored excitatory and inhibitory neurotransmitters (e.g. glutamate, GABA, 5-hydroxytryptamine (5-HT), acetylcholine, noradrenaline, dopamine, D-aspartate and cholecystokinin) which (5) once released, diffuse and bind to post-synaptic receptors; (6) Anandamide and 2-AG re-enter the post- or pre-synaptic nerve terminals (possibly through the actions of a specialized transporter depicted by a ―dashed‖ line) where they are respectively catabolized by fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL) to yield either arachidonic acid (AA) and ethanolamine (ETA), or arachidonic acid and glycerol. See text for additional details. Figure adapted from (51,52,53).

ENDOCANNABINOID SYSTEM• Endocannabinoids are made as needed from

post synaptic terminal lipid membranes • Primary endocannabinoids: Anandamide

and 2-AG• They diffuse retrograde to pre-synaptic

terminals to bind and activate CB1 receptors • The CB1 receptor activation triggers an

inhibitory response, preventing the release of excitatory and inhibitory neurotransmitters from the neuron

• The endocannabinoids then diffuse back to the post-synaptic neuron and are degraded by enzymes FAAH and MAGL to yield arachidonic acid and ethanolamine or glycerol


THC ON THE BRAIN

Output dopaminergic neuron locations:• Amygdala (emotion) & Hippocampus (memory)• Nucleus Accumbens (reward)• Ventral Tegmental Area (reward) Panlilio et al. Clin Pharmacol Ther. 2015 Jun;97(6): 616-27.

PHARMACOKINETICS OF THC

Absorption • Smoking: onset 5 mins, duration 2-4h, high peak concentration; F~25%• Vaporization: similar to smoking but faster onset• Oral: onset 30-60 min, duration 8-12h, lower peak blood levels; F~10-20%

Distribution • Taken up by fatty and highly perfused (brain, heart, lungs, liver) tissues• Heart and adipose reach 10 and 1000 x higher levels than plasma• VD=10 L/kg • Plasma protein binding 97%

Metabolism • Cannabinoid oxidation via CYP2C9, 2C19, 3A4• Polyaromatic hydrocarbons in smoke induce expression of CYP1A2• THC, CBD and CBN inhibit CYP1A1, 1A2, 1B1

Elimination • 65% Feces, 20% Urine• Terminal Half life estimate of 96 hours• Low levels detected in urine & feces for up to 5 weeks


HOW CANNABIS AFFECTS THE BODY System EffectsCNS Euphoria or dysphoria

AnxietyAggravation or precipitation of psychosisHeightened sensory perception, hallucinationsSedationImpaired cognition and motor functioningAnalgesiaAnti-emetic and anti-nausea; increased appetiteTolerance & dependence

Cardiovascular Tachycardia (tolerance develops), arrhythmias Peripheral vasodilationà hypotension, conjunctival reddening

Respiratory Histopathological lung changes (when smoked)CoughPhlegm productionBronchodilation

HOW CANNABIS AFFECTS THE BODY

System EffectsGastrointestinal Decreased motility and secretions

Hepatic steatosis (especially with Hepatitis C)Pancreatitis (heavy use)

Musculoskeletal Pain relief Eye Decreased IOPImmune Suppressive and stimulatory effectsReproduction Anti-androgenic properties

Decrease sperm count, motility and morphology Changes in menstrual cycle, ovulation suppression


COMMON MEDICAL INDICATIONS

• Severe refractory nausea and vomiting from chemotherapy• Loss of appetite and body weight in cancer and HIV patients• Pain and muscle spasms from multiple sclerosis• Chronic non-cancer pain (mainly neuropathic)• Severe refractory cancer associated pain• Insomnia and depression associated with chronic disease

(HIV, chronic non-cancer pain)• Palliation and end of life care

*All other indications have very limited evidence

HealthCanada.ConsumerInformation-Cannabis(Marijuana,marijuana).2007;29–76

OTHER STUDIED USES OF CANNABISSystem DiseaseCNS Amyotrophic lateral sclerosis (ALS)

Spinal Chord InjuryEpilepsyAcute PainHeadache and migraineAlzheimer’s Disease and DementiaMovement Disorders: Dystonia, Huntington’s Disease, Parkinson’s Disease, Tourette’s SyndromePsychiatric disorders: Anorexia Nervosa, Anxiety, depression, sleep disorders, PTSD, alcohol and opioid withdrawal symptoms, schizophrenia and psychosis

Musculoskeletal OsteoarthritisRheumatoid ArthritisFibromyalgiaOsteoporosis

GI IBS, IBDLiver disease, pancreatic diseaseMetabolic syndrome, obesity, diabetes

Other GlaucomaAsthmaHypertensionAnti-neoplastic properties

WHEN CANNABIS SHOULD NOT BE USED

• Under age 25• Allergy• Serious liver, kidney, heart or lung disease• Personal family history of mental illness such a schizophrenia, psychosis,

depression, bipolar disorder• History of substance abuse• Concomitant use of sedative-hypnotics • Pregnancy or breastfeeding• Both men and women attempting to conceive


Cochrane Database of Systematic Reviews

Cannabinoids for nausea and vomiting in adults with cancerreceiving chemotherapy (Review)

Smith LA, Azariah F, Lavender VTC, Stoner NS, Bettiol S

Smith LA, Azariah F, Lavender VTC, Stoner NS, Bettiol S.

Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy.

Cochrane Database of Systematic Reviews 2015, Issue 11. Art. No.: CD009464.

DOI: 10.1002/14651858.CD009464.pub2.

www.cochranelibrary.com

Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy (Review)

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

EVIDENCE: CHEMO INDUCED NAUSEA & VOMITING

• 23 RCTs between 1975-1991• Most were cross-over design • None compared cannabinoids to

newer anti-emetic drugs such as ondansetron

• Most at risk of bias due to allocation concealment or attrition

• Interventions included nabilone and dronabinol (use of THC cigarettes if oral dose was vomited in 2 studies)

SmithLA etal.CochranedatabaseSyst Rev.2015;11(11):CD009464.

Comparison 3. Cannabinoid plus other antiemetic agent versus other antiemetic monotherapy

Outcome or subgroup titleNo. ofstudies

No. ofparticipants Statistical method Effect size

1 Absence of nausea 1 Risk Ratio (IV, Random, 95% CI) Subtotals only2 Absence of vomiting 2 89 Risk Ratio (IV, Random, 95% CI) 1.47 [0.69, 3.13]3 Absence of nausea and vomiting 1 Risk Ratio (IV, Random, 95% CI) Subtotals only4 Depression 1 Risk Ratio (IV, Random, 95% CI) Subtotals only5 Dizziness 1 Risk Ratio (IV, Random, 95% CI) Subtotals only6 Dysphoria 1 Risk Ratio (IV, Random, 95% CI) Subtotals only7 Paranoia 1 Risk Ratio (IV, Random, 95% CI) Subtotals only8 Sedation 1 Risk Ratio (IV, Random, 95% CI) Subtotals only9 Withdrawal for any reason 1 Risk Ratio (IV, Random, 95% CI) Subtotals only

10 Withdrawal due to adverseevent

2 105 Risk Ratio (IV, Random, 95% CI) 6.97 [0.88, 55.19]

11 Withdrawal due to lack ofefficacy

1 Risk Ratio (IV, Random, 95% CI) Subtotals only

Analysis 1.1. Comparison 1 Cannabinoid versus placebo, Outcome 1 Absence of nausea.

Review: Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy

Comparison: 1 Cannabinoid versus placebo

Outcome: 1 Absence of nausea

Study or subgroup Cannabinoid Placebo Risk Ratio Weight Risk Ratio

n/N n/N IV,Random,95% CI IV,Random,95% CI

Chang 1979a 2/32 1/32 100.0 % 2.00 [ 0.19, 20.97 ]

Chang 1981 0/16 0/16 Not estimable

Total (95% CI) 48 48 100.0 % 2.00 [ 0.19, 20.97 ]Total events: 2 (Cannabinoid), 1 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.58 (P = 0.56)

Test for subgroup differences: Not applicable

0.05 0.2 1 5 20

Favours placebo Favours cannabinoid

64Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy (Review)



Analysis 1.2. Comparison 1 Cannabinoid versus placebo, Outcome 2 Absence of vomiting.

Review: Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy

Comparison: 1 Cannabinoid versus placebo

Outcome: 2 Absence of vomiting

Study or subgroup Cannabinoid Placebo Risk Ratio Weight Risk Ratio

n/N n/N IV,Random,95% CI IV,Random,95% CI

1 Nabilone

Levitt 1982 29/36 4/36 72.5 % 7.25 [ 2.84, 18.52 ]

Subtotal (95% CI) 36 36 72.5 % 7.25 [ 2.84, 18.52 ]Total events: 29 (Cannabinoid), 4 (Placebo)



2 Dronabinol

Chang 1979a 6/32 2/32 27.5 % 3.00 [ 0.65, 13.76 ]

Chang 1981 0/16 0/16 Not estimable

Subtotal (95% CI) 48 48 27.5 % 3.00 [ 0.65, 13.76 ]Total events: 6 (Cannabinoid), 2 (Placebo)



Total (95% CI) 84 84 100.0 % 5.69 [ 2.56, 12.64 ]Total events: 35 (Cannabinoid), 6 (Placebo)

Heterogeneity: Tau2 = 0.0; Chi2 = 0.93, df = 1 (P = 0.33); I2 =0.0%


Test for subgroup differences: Chi2 = 0.93, df = 1 (P = 0.33), I2 =0.0%

0.05 0.2 1 5 20

Favours placebo Favours cannabinoid

65Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy (Review)



Oncology Nursing Forum • Vol. 36, No. 3, May 2009 345

Journal Club Article

See page 352 for suggested questions to begin discussion in your journal club.

U sing marijuana as medicine is a contro-versial topic. One of the potential uses of marijuana is to decrease the incidence of chemotherapy-induced nausea and vomiting (CINV). Research on the topic

spans decades and may provide useful insight for at-tenuation of these symptoms. The purpose of this article is to synthesize the literature on the efficacy of crude, or “smoked,” marijuana and synthetic oral delta-9-tetrahy-drocannabinol (THC) as treatments for CINV.

Background

CINV is a significant, well-documented problem. The chemoreceptor trigger zone in the brain activates the emetic center secondary to chemical stimuli in the blood and cerebrospinal fluid. Chemotherapy stimulates the release of neurotransmitters such as dopamine, hista-mine, acetylcholine, and serotonin that are involved in the emetogenic pathways. The chemoreceptor trigger zone and the emetic center are rich in receptors for these neurotransmitters, resulting in CINV (Carrieri-Kohlman, Lindsey, & West, 2003). The risk for CINV is dependent on the drugs used for treatment. Chemotherapy drugs have varying levels of emetic, or vomit-inducing, po-tential. The emetogenicity of a chemotherapeutic agent is ranked on a scale of very low to very high and is as-sociated with incidence of vomiting described as a per-centage. Very low emetic potential has a less than 10% vomiting incidence, low emetic potential is 10%–30%, and moderately emetogenic is 30%–60%. High eme-togenicity is associated with a 60%–90% incidence of vomiting, and very high emetic potential is 90% (Itano & Taoka, 2005). Regimens with multiple drugs can lead to increased CINV because their emetic potentials are

Efficacy of Crude Marijuana and Synthetic Delta-9-Tetrahydrocannabinol as Treatment for Chemotherapy-Induced Nausea and Vomiting: A Systematic Literature Review

Jayme Cotter, RN, MS, OCN®

Purpose/Objectives: To synthesize the research to deter-mine whether oral delta-9-tetrahydrocannabinol (THC) and smoked marijuana are effective treatments for chemothera-py-induced nausea and vomiting (CINV) and to evaluate side effects and patient preference of these treatments.

Data Sources: Original research, review articles, and other published articles in CINAHL®, MEDLINE®, and Cochrane Library databases.

Data Synthesis: Cannabinoids are effective in controlling CINV, and oral THC and smoked marijuana have similar efficacy. However, smoked marijuana may not be acces-sible or safe for all patients with cancer. Also, these drugs have a unique side-effect profile that may include altera-tions in motor control, dizziness, dysphoria, and decreased concentration.

Conclusions: This synthesis shows that cannabinoids are more effective than placebo and comparable to antiemetics such as prochlorperazine and ondansetron for CINV.

Implications for Nursing: Nurses should feel supported by the literature to recommend oral synthetic THC as a treat-ment for CINV to their patients and physician colleagues. Nurses should be cognizant of the side-effect profile for this medication and provide appropriate patient education.

combined. Higher doses of the medications increase the emetic potential, resulting in more severe symptoms (Gullatte, 2001).

CINV is an undesirable side effect; it is distressing physically and may result in decreased quality of life (QOL). Patients may experience nausea, vomiting, or a combination. Nausea may precede vomiting or may oc-cur separately. The sensation of nausea may compromise patients physically by decreasing appetite, leading to poor nutrition or diminished movement that results in muscle decompensation. Nausea may restrict patients’ QOL by

Oncology Nursing Forum • Vol. 36, No. 3, May 2009 347

Table 1. Articles Reviewed

Source Purpose Sample Design Treatment Instrument Results

Sallan et al., 1975

Compared the effects of THC capsule versus p l a c e b o f o r CINV

22 patients with various neoplasms on high or very high emetogenic chemotherapy

Controlled, randomized, crossover, double-blind

THC or p lacebo two hours prior to chemotherapy and two and six hours after

Patient evaluation of antiemetic prop-erties

THC significantly better than placebo at controlling CINV

Chang et al., 1979

THC capsule versus placebo cap su l e and placebo versus marijuana ciga-rette for treat-ment of CINV

15 patients with osteogenic sarco-ma on high-dose methotrexate

Double-blind, randomized, placebo- controlled

Phase I: placebo three t imes and THC three times in three-paired trials

P lacebo or THC s ix hours before chemotherapy and every three hours for a total of five doses

I f v o m i t i n g o c -curred, pat ients were switched to marijuana or pla-cebo cigarette for remainder of trial.

THC blood levels were tested and, if patients vomited, frequency was not-ed.

THC blood levels less than 5 ng/ml: 44% vomited; be-tween 5–10 ng/ml: 21% vomited; and more than 10 ng/ml: 6% vomited

Placebo capsules: 72% vomited

THC significantly better than placebo

Frytak et al., 1979

Compared prochlorper-azine, THC, and placebo to treat CINV; compared tox-icities of each drug

116 patients with GI cancer receiv-i n g 5 - F U a n d semust ine; 18 patients dropped from the study on day 1 secondary to CNS toxicity or excessive vomit-ing.

Randomized, double-blind, placebo-con-trolled

Prochlorperazine, THC, or placebo

On day 1: treatment given two hours be-fore and two and eight hours after chemotherapy

On days 2–4: doses given three times daily before each regular mealtime

Patient interviews

Day 1: volunteered information

Day 2: Specific ques-tions were asked re-garding nausea and vomitting, appetite, mood, etc.

Number of times patient vomited was recorded.

THC and prochlor-perazine better than placebo but equally effective

More side effects noted with THC

Orr et al., 1980

Compared THC, prochlor-perazine, and placebo for severe CINV

55 patients with various malignancies receiving chemotherapy with moderate to high emetic potential

Double-blind, randomized, placebo-controlled, crossover

THC, compazine, or placebo prior to chemotherapy

Patient evaluations of nausea presence

No nausea in 73% receiving THC, 15% receiving prochlor-perazine, and 9% receiving placebo

THC more effective than prochlorpera-zine for moderate to high emetogenic chemotherapy

Michigan Cancer Foundation, 1982 as cit-ed in Musty & Rossi, 2001

Smoked mari-juana ver sus thiethylperazine for CINV

165 patients Randomized, crossover

Marijuana cigarette or thiethylperazine

If the treatment failed in 24 hours, patients were crossed over to the other treatment group.

Self-report and phy-sician and nurse ob-servations of nausea severity

No significant dif-ference between drugs

Ungerleider et al., 1982

THC versus prochlorper-azine for CINV

214 patients with a variety of malignancies re-ceiving different chemotherapies

Double-blind, cross-over

THC or prochlorper-azine one hour be-fore chemotherapy and then four hours thereafter for a total of four doses

Patient report of nausea, vomiting, and food intake

Both drugs equally effective in reducing CINV

(Continued on next page)

5-FU—5-fluorouracil; CINV—chemotherapy-induced nausea and vomiting; CNS—central nervous system; ECOG—Eastern Cooperative Oncology Group; GI—gastrointestinal; THC—delta-9-tetrahydrocannabinol

348 Vol. 36, No. 3, May 2009 • Oncology Nursing Forum

effect. The investigators determined that THC had antiemetic properties and was significantly better at reducing CINV than placebo (p < 0.001).

Chang et al. (1979) also published a study that com-pared oral THC and smoked marijuana to placebo. Fifteen patients with osteogenic sarcoma who were treated with high-dose methotrexate (high emetogenic potential) for 18 months after removal of their primary tumors participated in this double-blind, randomized, placebo-controlled study. Patients randomly received placebo three times and THC three times in three paired trials during six hospitalizations, which took approxi-mately five to six months. Each patient received a dose of either placebo or THC capsule starting six hours

prior to chemotherapy treatment and continuing every three hours for a total of five doses. If vomiting oc-curred, patients were switched to a random assignment of a placebo or marijuana cigarette for the remainder of that trial. Outcomes of treatment included blood levels of THC and number of vomiting episodes. The results showed that with THC blood levels less than 5 ng/ml, 44% of patients vomited; between 5–10 ng/ml, 21%; and with greater than 10 ng/ml, 6%. Seventy-two percent of patients who received the placebo vomited. The investigators concluded that THC was more effec-tive than placebo even with blood levels lower than 5 ng/ml; as THC blood levels rose, the efficacy of the drug increased. The investigators found that THC was

Table 1. Articles Reviewed (Continued)

Source Purpose Sample Design Treatment Instrument Results

New Mexico Health and Environment Department, 1983 as cited in Musty & Rossi, 2001

THC capsule ve r sus mar i -juana cigarette for treatment of CINV in patients re f ractory to traditional antiemetics

142 total patients Randomized THC capsule or mar-ijuana cigarette be-fore chemotherapy and for five days af-ter chemotherapy

Self-report using the Target Problem Rat-ing Scale

Both effective at de-creasing CINV, but no significant differ-ence between the two treatments

Vinciguerra et al., 1988

Smoked mari-juana for CINV in patients re-fractory to stan-dard antiemet-ics; patients’ acceptance of inhalation route

74 patients par-ticipated; 56 were evaluated.

Nonrandom-ized, no pla-cebo

Marijuana starting six to eight hours pri-or to chemotherapy and every four to six hours thereafter for a total of four doses

Patient evaluations using scales 1–5 to evaluate nausea, vomiting, appetite, and mood

Marijuana found to be effective for CINV; 24% of pa-tients dropped out of the study because they did not accept the inhalation route.

Lane et al., 1991

Compared dronabinol and prochlorpera-zine alone and in combination for prevention and reduction of CINV

62 patients with breast, colon, lung, lymphoma, or miscellaneous malignancies receiving both low and high emetogenic chemotherapy

Random-ized, dou-ble-blind, parallel group, multi-center

10 mg dronabinol plus placebo, 10 mg compazine plus placebo, or 10 mg compazine plus 10 mg dronabinol ev-ery six hours; treat-ment was started 24 hours prior to chemotherapy and continued 24 hours after chemotherapy completion.

Patient evaluation of feelings of nausea and number of times emesis occurred

The combination of dronabinol and c o m p a z i n e w a s found to be signifi-cantly more effec-tive in controlling chemotherapy-in-duced nausea and vomiting than either drug alone.

Meiri et al., 2007

Compared dronabinol, ondansetron, and combina-tion for delayed CINV

64 patients with various neoplasms not involving bone marrow receiv-ing moderate to highly emetogenic chemotherapy

Randomized, double-blind, paral-lel group, placebo-controlled

Dexamethasone and ondansetron prior to chemotherapy

Four groups: dronab-inol only, ondanse-tron only, dronabinol plus ondansetron, and placebo were dosed on a fixed schedule day 2 and flexible on days 3–5.

Patient report us-ing a visual analog scale, number of vomiting episodes, and ECOG

No significant differ-ence among three act ive t reatment groups; all were sig-nificantly better than placebo for CINV.

5-FU—5-fluorouracil; CINV—chemotherapy-induced nausea and vomiting; CNS—central nervous system; ECOG—Eastern Cooperative Oncology Group; GI—gastrointestinal; THC—delta-9-tetrahydrocannabinol

• Pts admitted after failing phenothiazine anti-emetics

• Smoked cannabis resulted in 70-100% relief of nausea & vomiting

• THC capsule resulted in 76-88% relief of nausea & vomiting

• Plasma THC levels >10 ng/mL were associated with best efficacy

CotterJ.Oncol Nurs Forum.2009;36(3):345–52.MustyREandRossiR.JCannabisTher.2001;1(1):29–56.

The medical use of cannabis for reducing morbidity andmortality in patients with HIV/AIDS (Review)

Lutge EE, Gray A, Siegfried N

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2013, Issue 4

http://www.thecochranelibrary.com

The medical use of cannabis for reducing morbidity and mortality in patients with HIV/AIDS (Review)


EVIDENCE: LOSS OF APPETITE & WEIGHT IN HIV/AIDS

• 7 randomized controlled trials included• Duration ranging from 21-84 days

Lutge EEetal.CochraneDatabaseSyst Rev.2013;(4)CD005175.

RESULTS• Haney 2007

• Population: N=10• Interventions: Marijuana cigarettes (0%, 2%, and 3.9% THC)and dronabinol (0mg, 5mg

and 10mg) x 37-42 days • Outcomes:

• Participants on marijuana 3.9% and dronabinol 10mg had significant weight increase vs those on lower doses (P<0.01)

• Higher doses also increased number of daily eating occasions and daily caloric intake

• Haney 2005• Population: N=30• Interventions: Marijuana cigarettes (0%, 1.8%, 2.9%, 3.9% THC) and dronabinol (0mg,

10mg, 20mg, 30mg) during 8 sessions over 3-4 weeks• Outcomes:

• Pts with significant wt loss showed increased daily caloric intake for both treatments

Lutge EEetal.CochraneDatabaseSyst Rev.2013;(4)CD005175.

RESULTS• Abrams 2003

• Population: N=62• Intervention: 3.95% THC marijuana cigarette or 2.5mg dronabinol capsule or

placebo TID before meals x 21 days • Outcomes:

• Marijuana arm gained median of 3kg (P=0.021), dronabinol arm gained median of 3.2kg(P=0.004), while placebo arm gained 1.1kg

• Beal 1995• Population: N=139• Intervention: 2.5mg dronabinol vs placebo1 hour before lunch and supper x 6

weeks • Outcomes:

• Dronabinol group gained mean of 0.1kg while placebo lost 0.4kg (P=0.14)• Significant increase in appetite in dronabinol group with 37% on VAS vs 17% in placebo

(P=0.05)Lutge EEetal.CochraneDatabaseSyst Rev.2013;(4)CD005175.

EVIDENCE: LOSS OF APPETITE & WEIGHT IN CANCER

• Effects of smoking cannabis on appetite and weight gain in this population have not been studied• Effects of THC capsules

(dronabinol) or oral cannabis have mixed results

• Population: N=243, average wt loss of 11.9%

• Intervention: Patients assigned to cannabis extract (CE) capsules (2.5mg THC + 1mg cannabidiol), THC capsules (2.5mg) or placebo BID x 6 weeks

• Outcome: Appetite, mood, and nausea were monitored daily with visual analog scale

• Results:• No significant difference in outcomes• Appetite increase was reported by 75%

in CE group, 60% in THC group, and 72% in placebo group (P=0.068)

Comparison of Orally Administered Cannabis Extract andDelta-9-Tetrahydrocannabinol in Treating Patients WithCancer-Related Anorexia-Cachexia Syndrome: AMulticenter, Phase III, Randomized, Double-Blind,Placebo-Controlled Clinical Trial From the Cannabis-In-Cachexia-Study-GroupFlorian Strasser, Diana Luftner, Kurt Possinger, Gernot Ernst, Thomas Ruhstaller, Winfried Meissner,You-Dschun Ko, Martin Schnelle, Marcus Reif, and Thomas Cerny

A B S T R A C T

PurposeTo compare the effects of cannabis extract (CE), delta-9-tetrahydrocannabinol (THC), and placebo(PL) on appetite and quality of life (QOL) in patients with cancer-related anorexia-cachexiasyndrome (CACS).

Patients and MethodsAdult patients with advanced cancer, CACS, weight loss (! 5% over 6 months), and EasternCooperative Oncology Group (ECOG) performance status (PS) " 2 were randomly assigned (2:2:1)to receive CE (standardized for 2.5 mg THC and 1 mg cannabidiol) or THC (2.5 mg) or PL orally,twice daily for 6 weeks. Appetite, mood, and nausea were monitored daily with a visual analogscale (VAS); QOL was assessed with the European Organisation for Research and Treatment ofCancer Quality of Life Questionnaire C30 (composite score: questions 29 and 30). Cannabinoid-related toxicity was assessed every 2 weeks.

ResultsOf 289 patients screened, 243 were randomly assigned and 164 (CE, 66 of 95 patients; THC, 65 of 100patients; and PL, 33 of 48 patients) completed treatment. At baseline, groups were comparable for age(mean, 61 years), sex (54% men), weight loss (32% ! 10%), PS (13% ECOG ! 2), antineoplastictreatment (50%), appetite (mean VAS score, 31/100 mm), and QOL (mean score, 30/100). Intent-to-treat analysis showed no significant differences between the three arms for appetite, QOL, orcannabinoid-related toxicity. Increased appetite was reported by 73%, 58%, and 69% of patientsreceiving CE, THC, or PL, respectively. An independent data review board recommended terminationof recruitment because of insufficient differences between study arms.

ConclusionCE at the oral dose administered was well tolerated by these patients with CACS. No differencesin patients’ appetite or QOL were found either between CE, THC, and PL or between CE and THCat the dosages investigated.

J Clin Oncol 24:3394-3400. © 2006 by American Society of Clinical Oncology

INTRODUCTION

Anorexia and weight loss contribute to cancer-relatedfatigue, functional loss, impaired survival, and intoler-ance of treatment.1,2 Efforts to palliate these condi-tions include studies of the endocannabinoid system,which modulates appetite3 through cannabinoid re-ceptor–related processes.4 Hyperphagic effects ofcannabinoids5 andhypophagicactionsofselectivecan-nabinoid receptor antagonists6 have been reported.

Cannabis sativa contains over 60 cannabinoids,including delta-9-tetrahydrocannabinol (dronabi-nol, THC) and cannabidiol (CBD).7 THC, its majorpsychoactive component, is an antiemetic medica-tion.8 CBD reportedly reduces the psychotropic ef-fects of THC and has anti-inflammatory effects.9

Cannabinoids reputedly stimulate appetite,both historically10 and in recent studies of humanvolunteers11-13 and AIDS patients.14 Studies of pa-tients with multiple sclerosis15-17 or pain18 have

From the Division of Oncology/Hematology, Department of InternalMedicine, Cantonal Hospital, St Gallen,Switzerland; Departments of MedicalOncology and Anesthesiology/PainManagement, University HospitalCharité, Central Campus; Institute forClinical Research, Berlin; Department ofAnesthesiology and Intensive Care,Friedrich-Schiller-University, Jena; andMedizinische Poliklinik, UniversityHospital, Bonn, Germany.

Submitted December 6, 2005; acceptedMay 4, 2006.

Supported by the Institute for ClinicalResearch (Berlin, Germany), whichprovided all funding for administrativeactivities related to the conduct of thetrial and for analysis of the data(www.ikf-berlin.de).

Presented in part at the 39th AnnualMeeting of the American Society ofClinical Oncology, Chicago, IL, May 31-June 3, 2003; and at the InternationalAssociation for Cannabis as Medicine2nd Congress on Cannabinoids inMedicine, Cologne, Germany,September 12-13, 2003.

Authors’ disclosures of potential con-flicts of interest and author contribu-tions are found at the end of thisarticle.

Address reprint requests to FlorianStrasser, MD, ABHPM, Oncology andPalliative Medicine, Section of Oncology/Hematology, Department Internal Medi-cine, Cantonal Hospital,Rorschacherstrasse, 9007 St Gallen,Switzerland; e-mail: [email protected].

© 2006 by American Society of ClinicalOncology

0732-183X/06/2421-3394/$20.00

DOI: 10.1200/JCO.2005.05.1847

JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

VOLUME 24 ! NUMBER 21 ! JULY 20 2006

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Downloaded from ascopubs.org by UBC Library Central Serials on November 13, 2017 from 142.103.160.110Copyright © 2017 American Society of Clinical Oncology. All rights reserved.

Strasser Fetal.JClin Oncol.2006;24(21):3394–400.

Spasticity is a common and disablingsymp tom that remains a substantial prob-lem for many patients with multiple scle-

rosis. Some patients have adverse effects fromconventional antispasticity medications; for oth-ers, spasticity persists despite treatment. A reportfrom the Institute of Medicine in the UnitedStates concluded that the active compounds ofcannabis (marijuana) are potentially effective intreating neurologic conditions and “should betested rigorously in clinical trials.”1 There is evi-dence that the cannabinoid receptors CB1 andCB2 may be involved in the control of spasticityin multiple sclerosis2 and that the endogenousligand of CB1, anandamide, is itself an effectiveantispasticity agent.3 CB1 receptors are primarilypresynaptic; their activation inhibits calciuminflux and glutamate release, and reduces neu-ronal excitability by activating somatic and den-dritic potassium channels.4

Although many patients with multiple sclerosisendorse smoking cannabis as therapy, evidencethat it relieves spasticity is largely anecdotal, asmost trials focus on orally ad min istered cannabi-noids. We sought to assess the safety and efficacyof smoked cannabis versus placebo in patientswith multiple sclerosis who have treatment-resistant spasticity.

Methods

ParticipantsWe recruited participants from a regional multi-ple sclerosis clinic and by referral from special-ists. Our eligibility criteria were spasticity and atleast moderate increase in tone (score ≥ 3 pointson the modified Ashworth scale5 at the elbow,hip or knee). Participants were allowed to con-tinue other treatments for spasticity, with theexception of benzodiazepines, if they had been

Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial

Jody Corey-Bloom MD PhD, Tanya Wolfson MA, Anthony Gamst PhD, Shelia Jin MD MPH, Thomas D. Marcotte PhD, Heather Bentley BA, Ben Gouaux BA

Competing interests: Nonedeclared.

This article has been peerreviewed.

Correspondence to: Dr. Jody Corey-Bloom,[email protected]

CMAJ 2012. DOI:10.1503/cmaj.110837

ResearchCMAJ

Background: Spasticity is a common andpoorly controlled symptom of multiple scle-rosis. Our objective was to determine theshort-term effect of smoked cannabis on thissymptom.

Methods: We conducted a placebo-controlled,crossover trial involving adult patients withmultiple sclerosis and spasticity. We re cruitedparticipants from a regional clinic or by refer-ral from specialists. We randomly assignedparticipants to either the intervention(smoked cannabis, once daily for three days)or control (identical placebo cigarettes, oncedaily for three days). Each participant wasassessed daily before and after treatment.After a washout interval of 11 days, partici-pants crossed over to the op posite group. Ourprimary outcome was change in spasticity asmeasured by patient score on the modifiedAshworth scale. Our secondary outcomesincluded patients’ perception of pain (as mea-sured using a visual analogue scale), a timedwalk and changes in cognitive function (asmeasured by patient performance on the

Paced Auditory Serial Addition Test), in addi-tion to ratings of fatigue.

Results: Thirty-seven participants were random-ized at the start of the study, 30 of whom completed the trial. Treatment with smokedcannabis resulted in a reduction in patientscores on the modified Ashworth scale by anaverage of 2.74 points more than placebo (p <0.0001). In addition, treatment reduced painscores on a visual analogue scale by an averageof 5.28 points more than placebo (p = 0.008).Scores for the timed walk did not differ signifi-cantly between treatment and placebo (p = 0.2).Scores on the Paced Auditory Serial AdditionTest decreased by 8.67 points more with treat-ment than with placebo (p = 0.003). No seriousadverse events occurred during the trial.

Interpretation: Smoked cannabis was superiorto placebo in symptom and pain reduction inparticipants with treatment-resistant spastic-ity. Future studies should examine whetherdifferent doses can result in similar beneficialeffects with less cognitive impact.

Abstract

© 2012 Canadian Medical Association or its licensors CMAJ, July 10, 2012, 184(10) 1143

EVIDENCE: MULTIPLE SCLEROSIS

• Placebo controlled cross over trial• Population: 30 adult patients with MS

and spasticity (Ashworth ≥3)• Intervention: smoked cannabis (800mg,

4% THC) vs placebo cigarettes once daily x 3 days with 11 day washout

• Outcome: Change in spasticity on modified Ashworth scale, pain perception by visual analog scale (VAS), timed walk, changes in cognition via Paced Auditory Serial Addition Test

Corey-Bloometal.CanMedAssoc J.2012;184(10):1143–50.

MODIFIED ASHWORTH SCALE

Authors combined ratings for elbows, hips, and knees for a total of 30 possible points.

Points were assed before and 45 minutes after treatment administration for 3 visits.


completed the study. (Seven patients withdrewbefore completion.)

Of the 30 patients who completed the proto-col, 63% were women (Table 1). The averageage of participants was about 50 years, and theaverage level of education was 15 years inschool. The mean score on the expanded dis-ability status scale was 5.3 (SD 1.5). Sixty-seven percent of participants required walkingaids, and 20% required the use of a wheelchair.The score on the modified Ashworth scale atthe initial screening visit was a mean of 9.3(SD 2.3). Seventy percent of participants wereundergoing disease -modifying therapy, and60% were taking antispasticity agents. Most ofthe participants (80%) had previous recre-ational experience with cannabis, and 33% ofparticipants had used cannabis within the pre-vious year.

Primary outcomeSmoking cannabis reduced patient scores on themodified Ashworth scale by an average of 2.74points (95% bootstrap CI 2.20 to 3.14) morethan placebo (p < 0.001) (Table 2 and Figure 2).The order of treatment (cannabis in phase 1 orphase 2) did not significantly affect the outcome(p = 0.8).

Secondary outcomesSmoking cannabis reduced patient scores on thevisual analogue scale by 5.28 points (95% boot-strap CI 2.48 to 10.01) more than placebo (p =0.008) (Table 2). The difference between timedwalk scores in the two conditions was not signif-icant (p = 0.2).

Participants in both conditions showed im -provement on the PASAT over the three visits,consistent with practise effects. However,within sessions, the group smoking cannabishad a consistent reduction in performance afterthe drug was administered versus before. Over-all, smoking cannabis re duced scores on thistest by 8.67 points (95% bootstrap CI 4.10 to14.31) more than placebo (p = 0.003) (Table 2).

Smoking cannabis did not significantly affectpatient perceptions of fatigue or deficits, nor didit increase symptoms, but it did increase patientperception of “highness” by 5.04 points morethan placebo (p < 0.001) (Table 3). Seventeenparticipants correctly guessed their treatmentphase for all six visits, and one participantguessed cannabis for all days (data not shown).For the remaining participants, cannabis wascorrectly guessed on 33/35 visits; they correctlyguessed placebo on 21/36 visits (data notshown).

Research

CMAJ, July 10, 2012, 184(10) 1147

Before treatment

After treatment

Mo

dif

ied

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wo

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om

bin

ed s

core

11

10

9

8

7

6

5

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1 2 3 1 2 3

Phase 1 visit Phase 2 visit

1 2 3 1 2 3

Visit (placebo) Visit (cannabis)

Placebo, before treatmentPlacebo, after treatment Cannabis, before treatmentCannabis, after treatment

Group 1 (placebo first)Group 2 (cannabis first)

Figure 2: Spasticity as measured by mean combined scores on the modified Ashworth scale, before and after treatment, on each day ofeach phase of the trial. (A) Change in scores by phase, before and after crossover. (B) Change in scores before and after treatment withplacebo versus cannabis.

RESULTS

• Smoked cannabis reduced Ashworth Score for spasticity by an average of 2.74 points (P<0.0001)

• Smoked Cannabis reduced pain scores on VAS by average 5.28 points (P=0.008)

• Scores for timed walk did not differ • Smoked Cannabis reduced Paced Auditory

Serial Addition Test for cognition by 8.67 points (P=0.003)


Research CMAJ

CMAJ • OCTOBER 5, 2010 • 182(14)© 2010 Canadian Medical Association or its licensors

E694

Chronic neuropathic pain has a prevalence of 1%–2%,1

and treatment options are limited.2 Pharmacotherapyincludes anticonvulsants, antidepressants, opioids and

local anesthetics,3,4 but responses vary and side effects limitcompliance.

Cannabis sativa has been used to treat pain since the thirdmillennium BC.5 An endogenous pain-processing system hasbeen identified, mediated by endogenous cannabinoid ligandsacting on specific cannabinoid receptors.6 These findings,coupled with anecdotal evidence of the analgesic effects ofsmoked cannabis,7 support a reconsideration of cannabinoidagents as analgesics.

Oral cannabinoids such as tetrahydrocannabinol, cannabid-iol and nabilone have, alone and in combination, shown effi-cacy in central8,9 and peripheral10 neuropathic pain, rheuma-toid arthritis11 and fibromyalgia.12

The analgesic effects of smoked cannabis remain contro-versial, although it is used by 10%–15% of patients withchronic noncancer pain13 and multiple sclerosis.14 Clinical tri-als are needed to evaluate these effects, given that the risksand benefits of inhaled cannabinoids may differ from oralagents. To date, three small clinical trials of the analgesicefficacy of smoked cannabis have been reported.15–17 All stud-ies were conducted in residential laboratories, and partici-pants smoked multiple doses of the drug at each time point.No study adequately reported data related to adverse events.

We conducted a clinical trial using a standardized single-dosedelivery system to explore further the safety and efficacy ofsmoked cannabis in outpatients with chronic neuropathic pain.

Methods

ParticipantsThe study was approved by the McGill University HealthCentre Research Ethics Committee, and all participants gavewritten informed consent. Participants were recruited at theMcGill University Health Centre.

Those eligible were men and women aged 18 years or olderwith neuropathic pain of at least three months in durationcaused by trauma or surgery, with allodynia or hyperalgesia,

DO

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4

Smoked cannabis for chronic neuropathic pain: a randomizedcontrolled trial

Mark A. Ware MBBS, Tongtong Wang PhD, Stan Shapiro PhD, Ann Robinson RN, Thierry Ducruet MSc,Thao Huynh MD, Ann Gamsa PhD, Gary J. Bennett PhD, Jean-Paul Collet MD PhD

See related commentary by McQuay at www.cmaj.ca

From the Department of Anesthesia (Ware), the Department of FamilyMedicine (Ware), the Department of Epidemiology, Biostatistics and Occu-pational Health (Wang, Shapiro), the Department of Medicine (Huynh) andthe Alan Edwards Centre for Research on Pain (Gamsa, Bennett), McGill Uni-versity, Montréal, Que.; Boreal Primum (Robinson, Ducruet), Montréal,Que.; and the Centre for Applied Health Research and Evaluation (Collet),University of British Columbia, Vancouver, BC

CMAJ 2010. DOI:10.1503/cmaj.091414

Background: Chronic neuropathic pain affects 1%–2% of theadult population and is often refractory to standard pharma-cologic treatment. Patients with chronic pain have reportedusing smoked cannabis to relieve pain, improve sleep andimprove mood.

Methods: Adults with post-traumatic or postsurgical neuro-pathic pain were randomly assigned to receive cannabis atfour potencies (0%, 2.5%, 6% and 9.4% tetrahydrocannabi-nol) over four 14-day periods in a crossover trial. Participantsinhaled a single 25-mg dose through a pipe three times dailyfor the first five days in each cycle, followed by a nine-daywashout period. Daily average pain intensity was measuredusing an 11-point numeric rating scale. We recorded effectson mood, sleep and quality of life, as well as adverse events.

Results: We recruited 23 participants (mean age 45.4 [stan-dard deviation 12.3] years, 12 women [52%]), of whom 21completed the trial. The average daily pain intensity, mea-sured on the 11-point numeric rating scale, was lower on theprespecified primary contrast of 9.4% v. 0% tetrahydro-cannabinol (5.4 v. 6.1, respectively; difference = 0.7, 95% con-fidence interval [CI] 0.02–1.4). Preparations with intermediatepotency yielded intermediate but nonsignificant degrees ofrelief. Participants receiving 9.4% tetrahydrocannabinolreported improved ability to fall asleep (easier, p = 0.001;faster, p < 0.001; more drowsy, p = 0.003) and improved qual-ity of sleep (less wakefulness, p = 0.01) relative to 0% tetrahy-drocannabinol. We found no differences in mood or qualityof life. The most common drug-related adverse events duringthe period when participants received 9.4% tetrahydro-cannabinol were headache, dry eyes, burning sensation inareas of neuropathic pain, dizziness, numbness and cough.

Conclusion: A single inhalation of 25 mg of 9.4% tetrahy-drocannabinol herbal cannabis three times daily for fivedays reduced the intensity of pain, improved sleep andwas well tolerated. Further long-term safety and efficacystudies are indicated. (International Standard RandomisedControlled Trial Register no. ISRCTN68314063)

Abstract

Previously published at www.cmaj.ca

EVIDENCE: CHRONIC NEUROPATHIC PAIN

• Population: 23 adults with post-traumatic or post surgical neuropathic pain for at least 3 months, average pain >4 pts

• Intervention: 25mg of smoked cannabis of varying potencies (THC 0%, 2.5%, 6% and 9.4%) three times daily x 5 days followed by 9 day washout (cross-over trial)

• Outcomes: Pain intensity on 11-point scale, mood, sleep, quality of life, adverse events

WareMAetal.CMAJ.2010;182(14).

RESULTS

• No difference in mood or quality of life• Most frequent AEs: headache, dry eyes, burning sensation, dizziness,

numbness, cough

Research

CMAJ • OCTOBER 5, 2010 • 182(14)E698

Table 3: Effects of smoked cannabis and secondary outcomes, by potency of tetrahydrocannabinol (THC) received

Potency of THC, %; outcome measure, mean (SD)*

Outcome 0 2.5 6.0 9.4

Pain intensity

Average daily pain 6.1 (1.6) 5.9 (1.9) 6.0 (1.8) 5.4 (1.7)†

Highest daily pain 7.1 (1.4) 7.0 (1.6) 7.0 (1.5) 6.5 (1.6)

Lowest daily pain 5.1 (2.1) 5.0 (2.4) 4.8 (2.4) 4.4 (2.2)

McGill Pain Questionnaire

Sensory 17.2 (10.5) 17.1 (9.9) 14.8 (9.2) 15.6 (8.7)

Affective 3.5 (3.0) 3.8 (3.6) 3.3 (3.4) 3.0 (3.1)

Evaluative 2.2 (1.5) 2.8 (1.3) 2.1 (1.5) 1.7 (1.5)

Miscellaneous 6.2 (4.3) 6.8 (4.4) 5.5 (2.9) 4.5 (3.6)

Total score 29.1 (17.0) 30.4 (18.1) 25.8 (14.5) 24.8 (14.7)

Present pain intensity 2.8 (1.2) 3.0 (1.0) 2.8 (1.0) 2.5 (1.1)

Leeds Sleep Evaluation Questionnaire‡

Getting to sleep

Harder — easier than usual 5.4 (1.5) 5.5 (1.6) 6.1 (1.5) 6.8 (1.8)†

Slower — faster than usual 5.3 (1.3) 5.6 (1.4) 6.2 (1.7) 6.9 (1.7)†

Less — more drowsy than usual 5.3 (1.1) 5.9 (1.4) 5.7 (1.3) 6.6 (1.5)†

Quality of sleep

More restless — more restful 5.5 (1.6) 5.4 (1.7) 5.9 (2.0) 6.5 (2.1)

More — less period wakefulness than usual 5.3 (1.5) 5.0 (1.5) 5.5 (1.7) 6.3 (1.8)†

Awakening this morning

More difficult — easier 4.6 (1.2) 4.4 (0.8) 4.7 (1.4) 4.8 (1.0)

Took longer — shorter 4.4 (0.8) 4.4 (0.9) 1.7 (1.1) 5.0 (1.0)

Feeling on waking-up

Tired — alert 4.3 (1.9) 4.0 (1.5) 5.2 (1.9) 4.9 (1.9)

Feeling now

Tired — alert 4.1 (1.5) 1.3 (1.7) 4.9 (2.0) 4.0 (1.7)

Sense of balance

More — less clumsy than usual 4.9 (0.4) 4.8 (0.4) 4.9 (0.4) 5.0 (1.2)

EQ-5D health outcomes§

Mobility, no. (%) 10 (48) 11 (52) 11 (52) 11 (55)

Self-care, no. (%) 14 (67) 12 (57) 15 (71) 14 (70)

Usual activities, no. (%) 3 (14) 3 (14) 4 (19) 5 (25)

Pain or discomfort, no. (%) 11 (52) 10 (48) 14 (67) 14 (75)

Anxiety or depression, no. (%) 4 (19) 5 (23) 7 (33) 9 (45)†

State of health, no. (%) 3 (14) 2 (9) 4 (19) 7 (35)

State of health (VAS) 54.1 (19.5) 48.6 (18.9) 52.9 (22.0) 56.3 (20.4)

Profile of Mood States (POMS)¶

Depression 10.6 (6.5) 10.4 (6.7) 9.3 (6.6) 9.4 (5.7)

Vigour 7.3 (4.3) 7.3 (5.4) 6.2 (4.6) 8.0 (4.6)

Anger 9.2 (7.0) 7.7 (6.3) 7.9 (7.6) 6.5 (6.0)

Tension 8.5 (5.1) 9.3 (4.6) 9.0 (5.6) 7.2 (5.2)

Confusion 6.3 (3.7) 6.7 (4.0) 6.0 (4.3) 5.7 (4.1)

Fatigue 11.9 (4.1) 11.1 (5.0) 11.1 (4.8) 10.5 (5.0)

Total mood disturbance 39.1 (22.7) 38.0 (24.5) 36.9 (25.9) 31.2 (22.4)

Note: EQ-5D = health outcome instrument,22 SD = standard deviation, VAS = visual analog scale. *Unless indicated otherwise. †p < 0.05 for the comparison with 0% THC. ‡Higher scores indicate improved sleep parameters. §Data are presented as a proportion of subjects reporting the most favourable responses; thus, a higher proportion suggests a better health outcome. ¶With the exception of vigour, lower scores represent better mood.

Research

CMAJ • OCTOBER 5, 2010 • 182(14)E698

Table 3: Effects of smoked cannabis and secondary outcomes, by potency of tetrahydrocannabinol (THC) received

Potency of THC, %; outcome measure, mean (SD)*

Outcome 0 2.5 6.0 9.4

Pain intensity

Average daily pain 6.1 (1.6) 5.9 (1.9) 6.0 (1.8) 5.4 (1.7)†

Highest daily pain 7.1 (1.4) 7.0 (1.6) 7.0 (1.5) 6.5 (1.6)

Lowest daily pain 5.1 (2.1) 5.0 (2.4) 4.8 (2.4) 4.4 (2.2)

McGill Pain Questionnaire

Sensory 17.2 (10.5) 17.1 (9.9) 14.8 (9.2) 15.6 (8.7)

Affective 3.5 (3.0) 3.8 (3.6) 3.3 (3.4) 3.0 (3.1)

Evaluative 2.2 (1.5) 2.8 (1.3) 2.1 (1.5) 1.7 (1.5)

Miscellaneous 6.2 (4.3) 6.8 (4.4) 5.5 (2.9) 4.5 (3.6)

Total score 29.1 (17.0) 30.4 (18.1) 25.8 (14.5) 24.8 (14.7)

Present pain intensity 2.8 (1.2) 3.0 (1.0) 2.8 (1.0) 2.5 (1.1)

Leeds Sleep Evaluation Questionnaire‡

Getting to sleep

Harder — easier than usual 5.4 (1.5) 5.5 (1.6) 6.1 (1.5) 6.8 (1.8)†

Slower — faster than usual 5.3 (1.3) 5.6 (1.4) 6.2 (1.7) 6.9 (1.7)†

Less — more drowsy than usual 5.3 (1.1) 5.9 (1.4) 5.7 (1.3) 6.6 (1.5)†

Quality of sleep

More restless — more restful 5.5 (1.6) 5.4 (1.7) 5.9 (2.0) 6.5 (2.1)

More — less period wakefulness than usual 5.3 (1.5) 5.0 (1.5) 5.5 (1.7) 6.3 (1.8)†

Awakening this morning

More difficult — easier 4.6 (1.2) 4.4 (0.8) 4.7 (1.4) 4.8 (1.0)

Took longer — shorter 4.4 (0.8) 4.4 (0.9) 1.7 (1.1) 5.0 (1.0)

Feeling on waking-up

Tired — alert 4.3 (1.9) 4.0 (1.5) 5.2 (1.9) 4.9 (1.9)

Feeling now

Tired — alert 4.1 (1.5) 1.3 (1.7) 4.9 (2.0) 4.0 (1.7)

Sense of balance

More — less clumsy than usual 4.9 (0.4) 4.8 (0.4) 4.9 (0.4) 5.0 (1.2)

EQ-5D health outcomes§

Mobility, no. (%) 10 (48) 11 (52) 11 (52) 11 (55)

Self-care, no. (%) 14 (67) 12 (57) 15 (71) 14 (70)

Usual activities, no. (%) 3 (14) 3 (14) 4 (19) 5 (25)

Pain or discomfort, no. (%) 11 (52) 10 (48) 14 (67) 14 (75)

Anxiety or depression, no. (%) 4 (19) 5 (23) 7 (33) 9 (45)†

State of health, no. (%) 3 (14) 2 (9) 4 (19) 7 (35)

State of health (VAS) 54.1 (19.5) 48.6 (18.9) 52.9 (22.0) 56.3 (20.4)

Profile of Mood States (POMS)¶

Depression 10.6 (6.5) 10.4 (6.7) 9.3 (6.6) 9.4 (5.7)

Vigour 7.3 (4.3) 7.3 (5.4) 6.2 (4.6) 8.0 (4.6)

Anger 9.2 (7.0) 7.7 (6.3) 7.9 (7.6) 6.5 (6.0)

Tension 8.5 (5.1) 9.3 (4.6) 9.0 (5.6) 7.2 (5.2)

Confusion 6.3 (3.7) 6.7 (4.0) 6.0 (4.3) 5.7 (4.1)

Fatigue 11.9 (4.1) 11.1 (5.0) 11.1 (4.8) 10.5 (5.0)

Total mood disturbance 39.1 (22.7) 38.0 (24.5) 36.9 (25.9) 31.2 (22.4)

Note: EQ-5D = health outcome instrument,22 SD = standard deviation, VAS = visual analog scale. *Unless indicated otherwise. †p < 0.05 for the comparison with 0% THC. ‡Higher scores indicate improved sleep parameters. §Data are presented as a proportion of subjects reporting the most favourable responses; thus, a higher proportion suggests a better health outcome. ¶With the exception of vigour, lower scores represent better mood.

WareMAetal.CMAJ.2010;182(14).

A�Randomized,�Placebo-Controlled,�Crossover�Trial�of�CannabisCigarettes�in�Neuropathic�Pain

Barth�Wilsey,*�Thomas�Marcotte,†�Alexander�Tsodikov,‡�Jeanna�Millman,§

Heather�Bentley,!�Ben�Gouaux,!�and�Scott�Fishman§

*VA�Northern�California�Health�Care�System,�Department�of�Anesthesiology�and�Pain�Medicine,�University�ofCalifornia,�Davis�Medical�Center,�Davis,�California.†Department�of�Psychiatry,�University�of�California,�San�Diego,�California.‡UC�Davis/VANCHCS�General�Clinical�Research�Center�and�Department�of�Public�Health�Sciences,�University�ofCalifornia,�Davis�Medical�Center,�Davis,�California.§Department�of�Anesthesiology�and�Pain�Medicine,�University�of�California,�Davis�Medical�Center,�Davis,�California.!University�of�California�Center�for�Medicinal�Cannabis�Research,�University�of�California,�San�Diego,�California.

Abstract:�The�Food�and�Drug�Administration�(FDA),�Substance�Abuse�and�Mental�Health�ServicesAdministration�(SAMHSA),�and�the�National� Institute�for�Drug�Abuse� (NIDA)�report�that�no�soundscientific�studies�support�the�medicinal�use�of�cannabis.�Despite�this�lack�of�scientific�validation,�manypatients�routinely�use�”medical�marijuana,”�and�in�many�cases�this�use�is�for�pain�related�to�nerveinjury.�We�conducted�a�double-blinded,�placebo-controlled,�crossover�study�evaluating�the�analgesicefficacy�of�smoking�cannabis�for�neuropathic�pain.�Thirty-eight�patients�with�central�and�peripheralneuropathic�pain�underwent�a�standardized�procedure�for�smoking�either�high-dose�(7%),�low-dose(3.5%),�or�placebo�cannabis.�In�addition�to�the�primary�outcome�of�pain�intensity,�secondary�outcomemeasures�included�evoked�pain�using�heat-pain�threshold,�sensitivity�to�light�touch,�psychoactive�sideeffects,� and� neuropsychological� performance.� A� mixed� linear� model� demonstrated� an� analgesicresponse�to�smoking�cannabis.�No�effect�on�evoked�pain�was�seen.�Psychoactive�effects�were�minimaland�well-tolerated,�with�some�acute�cognitive�effects,�particularly�with�memory,�at�higher�doses.Perspective:�This� study� adds� to� a� growing� body� of� evidence� that� cannabis� may� be� effective� atameliorating�neuropathic�pain,�and�may�be�an�alternative�for�patients�who�do�not�respond�to,�orcannot�tolerate,�other�drugs.�However,�the�use�of�marijuana�as�medicine�may�be�limited�by�its�methodof�administration�(smoking)�and�modest�acute�cognitive�effects,�particularly�at�higher�doses.

©�2008�by�the�American�Pain�SocietyKey�words:�Neuropathic�pain,�analgesia,�cannabis,�clinical�trial,�neuropsychological�testing.

The�case�for�the�clinical�utility�of�cannabis�as�an�an-algesic�derives�from�experimental�studies�as�well�asanecdotal�reports.�Activation�of�the�endocannabi-

noid� system� suppresses� behavioral� responses� to� acuteand� persistent� noxious� stimulation� through� both� cen-tral71�and�peripheral45�mechanisms.�Cannabinoid�recep-

tors�are� localized� in�neuroanatomic� regions� intimatelyinvolved�with�transmission�and�modulation�of�pain�sig-nals:�The�periaqueductal�gray�(PAG),�the�rostral�ventro-medial�medulla�(RVM),40,66� and�the�dorsal�horn�of�thespinal�cord.66�Animal�experimentation�has�clearly�dem-onstrated�that�synthetic�and�endogenous�cannabinoidsnot� only� produce� analgesia� but� also� interact� in� somemanner�to�potentiate�opioids,18,70�particularly�in�neuro-pathic�pain.41

Surveys� involving�the�use�of�medicinal�marijuana�re-veal�that�pain,�sleep,�and�mood�improve�with�only�mod-est�side�effects.72,73�In�one�human�pain�experiment,�sub-jects�had�a�significant�dose-dependent�antinociception(increased�finger�withdrawal�latency)�effect�that�was�notreversed�by�opioid�antagonism.31�In�a�somewhat�contra-dictory�manner,�hyperalgesic�activity�and�enhancement

Received June 25, 2007; Revised December 10, 2007; Accepted December18, 2007.Supported by grant C01-DA-114 from the University of California Centerfor Medicinal Cannabis Research.Alexander Tsodikov is currently at the School of Public Health, Universityof Michigan, Ann Arbor, MI.Address reprint requests to Dr. Barth L. Wilsey, Pain Academic Office, UCDavis Medical Center, 3020 Ellison Ambulatory Care Center, 4860 YStreet,�Sacramento,�CA�95817.�E-mail:�[email protected]/$34.00© 2008 by the American Pain Societydoi:10.1016/j.jpain.2007.12.010

The Journal of Pain, Vol 9, No 6 (June), 2008: pp 506-521Available online at www.sciencedirect.com

506

EVIDENCE: CHRONIC NEUROPATHIC PAIN

• Population: 38 patients with central and peripheral neuropathic pain (with previous cannabis exposure)• Interventions: 7%, 3.5%, or placebo

cannabis cigarettes x 3 six hour sessions• Outcomes: Pain intensity, evoked

pain using heat-pain threshold, sensitivity to light touch, psychoactive side effects, and neuropsychological performance

Wilsey Betal.JPain.2008;9(6):506–21.

PROCEDURES

DesignThe study used a randomized, double-blinded, placebo-

controlled, crossover design, using high-dose cannabis(7% delta-9-THC), low-dose cannabis (3.5% delta-9-THC), and placebo cigarettes. Two doses of medicationand a cumulative dosing scheme17,31 were used to deter-mine dosing relationships for analgesia and psychoactiveand cognitive effects.

The cannabis was harvested and machine-rolled intocigarettes at the University of Mississippi under the su-pervision of the National Institute on Drug Abuse (NIDA).NIDA routinely is able to provide cigarettes ($8 each)ranging in strength from 3% to 7% THC, subject to theavailability of current crop potency. Placebo cigarettesare made from whole plant with extraction of cannabi-noids. After overnight delivery, the cigarettes werestored in a freezer securely bolted to the floor of theSacramento Veterans Administration Research Phar-macy. Further precautions against theft of the studydrug included limited password access to the pharmacy,with a state-of-the-art entry detection system and a di-rect connection of the alarm system of the room housingthe freezer to the Sacramento Veterans AdministrationPolice Department. In addition to security precautionsfor storing the study drug, a background check of allmembers of the investigative team was performed bythe Drug Enforcement Agency during the process of ob-taining a Schedule I license.

ProceduresAfter informed consent was obtained, participants

were scheduled for 3, 6-hour experimental sessions atthe UC Davis/Sacramento VA Medical Center GeneralClinical Research Center (GCRC). The sessions were sepa-rated by at least 3 days to permit the metabolic break-down of residual cannabis. The intervals between ses-sions ranged from 3 to 21 days, with a mean (SD) of 7.8(3.4) days. Participants received either low-dose, high-

dose, or placebo cannabis cigarettes at each visit in acrossover design using a Web-based random number–generating program, ”Research Randomizer” (http://www.randomizer.org/). Each patient received eachtreatment once, in random order. The allocation sched-ule was kept in the pharmacy and concealed from otherstudy personnel. Patients were assigned to treatment af-ter they signed a consent form. Patients and assessorswere blinded to group assignments.

The cigarettes were stored in a freezer at !20°C untilthe day before use. At least 12 hours before each session,2 marijuana cigarettes were thawed and humidified byplacing them above a saturated NaCl solution in a closedhumidifier at room temperature. The cigarettes weresmoked under a standard laboratory fume hood withconstant ventilation in ambient room temperature at22°C and a humidity of 40% to 60%. A cued-puff proce-dure17 standardized the administration of the cannabis.Participants were verbally signaled to “light the ciga-rette” (30 seconds), “get ready” (5 seconds), “inhale” (5seconds), “hold smoke in lungs” (10 seconds), “exhale,”and to wait before repeating the puff cycle (40 seconds).A nurse continuously supervised the participant duringthe smoking session via a closed-circuit monitor in anadjoining room. Participants were observed constantlyand could signal that they wanted to stop smoking forwhatever reason by raising their hand. Participants com-pleted a standardized cued-puff procedure9,21 of 2 puffsafter baseline measurements, 3 puffs an hour later, and 4puffs an hour after that. The cumulative dose for eachsession was thus 9 puffs (Fig 1).

Hourly assessment periods were scheduled before andafter each set of puffs and for 2 additional hours duringthe recovery period (Fig 1). Plasma levels for delta-9-THC,cannabidiol (CBD), cannabinol (CBN), 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (11-nor-9-carboxy THC),and 11-hydroxy-tetrahydrocannabinol (11-hydroxy-THC)were measured at baseline, 5 minutes after the first puff

Figure 1. Experimental procedures. THC, tetrahydrocannabinol; VAS, visual analog scale.

508 Analgesic Response to Cannabis Cigarettes


RESULTS

• Significant response occurred only after a cumulative dose of 9 puffs at time 240 minutes (P=0.02)• No effect on evoked pain• Psychoactive effects were

minimal • Patients felt significantly more

high, stoned or impaired on the 7% THC marijuana cigarettes

T score ! 40 ! 0; no impairmentT score ! 35 to 39 ! 1; mild impairmentT score ! 30 to 34 ! 2; mild-to-moderate impairmentT score ! 25 to 29 ! 3; moderate impairmentT score ! 20 to 24 ! 4; moderate-to-severe impairmentT score " 20 ! 5; severe impairment.An arithmetic mean of the deficit scores was used to

create the GDS.

Statistical MethodologyA linear mixed model with a random intercept was

used to model pain intensity (the primary responsemeasure) and secondary outcomes (pain unpleasant-ness, global impression of change, neuropathic painscale, allodynia, quantitative sensory testing score,mood, subjective, and psychoactive effects, and neu-ropsychological tests). The random intercept term isused to model the subject-specific component of theresponse that is shared by measurement performed onthe same subject but differs between subjects. Time ismodeled as a continuous variable. To reproduce theU-shaped character of the response (recovery phase)noted toward the end of observation period on thesubjects (eg, Fig 2, which represents the primary out-come measure VAS pain intensity), a quadratic term intime was introduced. Treatment (high dose, low dose,and placebo) is modeled as a categorical variable witha simple contrast. The main effects of time (linear andquadratic terms) in this analysis model the responsepattern over time from the baseline values.

The main effect of treatment as well as treatment bytime interaction effects were considered in the model.The main effect of treatment models treatment differ-ences in mean response at any time point, including thebaseline measurement at hour 1 (Fig 1). If subjects do notshow any difference at this time, before the treatment isadministered, this term would not be significant with allof the possible treatment effect expressed as an interac-tion. This is the situation shown in Fig 2, which indicatesthat response curves start at the same point at the begin-ning of hour 1. Overall treatment difference modifica-tion over time as well as treatment differences at specific

time points over the course of treatment are modeledand tested using treatment by time interaction terms. Allavailable patient data, including information from pa-tients who did not complete all experimental sessions,was included in this model. # was set at 0.05, and all testswere 2-tailed. No adjustment for multiple statistical com-parisons was performed. Models were fitted using max-imum likelihood methods to enable Wald and likelihoodratio tests of statistical hypotheses. R statistics softwarewas used for all analyses.

Results

Recruitment and WithdrawalsOf 44 patients recruited between June 2004 and Feb-

ruary 2006, 23 were men and 21 were women. The meanage (range) was 46 years (21–71 years). Six subjects wereexcluded and did not receive study medication, 3 be-cause they withdrew consent before commencing thestudy and 3 because they were excluded after medicalevaluation. Of the remaining 38 patients (Table 1), 32completed all 3 study sessions, 1 completed 2 sessions,and 5 completed only 1 session; a total of 103 study ses-

Table 1. Demographics and Characteristics ofPatients (N ! 38)Sex (No.)

Male 20Female 18

Age (y)Median 46Range 21–71

Education level (y)Median 14Range 12–21

RaceCaucasian 33African American 1Hispanic 1Asian American 1American Indian 1Other 1

Cause of pain (No.)CRPS type I 22Spinal cord injury 6Multiple sclerosis 4Diabetic neuropathy 3Ilioinguinal neuralgia 2Lumbosacral plexopathy 1

Intensity of pain at baseline 5.6 $ 2.10Duration of pain

Mean (y) 6Range (mo) 10–290

Concomitant medications (No.)Opioids 31Antidepressants 19NSAIDS 9Anticonvulsants 22

Abbreviations: CRPS, complex regional pain syndrome; NSAIDS, nonsteroidalanti-inflammatory drugs.

Figure 2. Visual analog scale (VAS) pain intensity.

510 Analgesic Response to Cannabis Cigarettes


844 VOLUME 90 NUMBER 6 | DECEMBER 2011 | www.nature.com/cpt

ARTICLES nature publishing group

See COMMENTARY page 769

Selecting an appropriate treatment for chronic pain remains problematic. Although opioids are effective analgesics, dose-limiting side effects such as sedation, nausea and vomiting, and fear of dependence often limit their use at higher—and possibly more effective—doses. Of particular interest is the potential for enhanced analgesic effect with the use of cannabinoids and opio-ids in combination. Such a combination would allow for opioid analgesic effects to be achieved at lower dosages than are neces-sary when the opioids are used alone.1–4 As increasing numbers of patients turn to medicinal cannabis to augment the effects of opioid analgesics, the data on the potential pharmacokinetic interactions and clinical safety of the combination need to be evaluated.

Cannabinoids and opioids share several pharmacologic prop-erties, including antinociception; a tendency to induce hypo-thermia, sedation, and hypotension; and inhibition of intestinal motility and locomotor activity.1,5,6 Initially, investigators postu-lated that cannabinoids and opioids act on the same pathways to produce their pharmacological actions.7,8 Subsequent preclinical research conducted over the past decade has clarified the nature of the interaction; these data suggest the existence of independ-ent but related mechanisms of antinociception for cannabinoids and opioids.5

Synergy in analgesic effects between opioids and cannabinoids has been demonstrated in animal models. The antinociceptive effects of morphine are mediated predominantly by mu opioid

receptors but may be enhanced by delta-9-tetrahydrocannab-inol (THC) activation of kappa and delta opiate receptors.8 It has further been suggested that the cannabinoid–opioid interaction may occur at the level of their signal transduction mechanisms.9,10 Receptors for both classes of drugs are cou-pled to similar intracellular signaling mechanisms that lead to a decrease in cyclic adenosine monophosphate production via G protein activation.10–12 There is also some evidence that can-nabinoids increase the synthesis and/or release of endogenous opioids.2,3,12,13

In addition to these potential pharmacodynamic interactions, there is the potential for pharmacokinetic interaction between cannabinoids and other drugs. Cannabinoids have been shown to affect the kinetics of other drugs in several ways. They inhibit the CYP450-mediated metabolism of some drugs, slow the absorption of others, and may also enhance penetration of some drugs into the brain.14–16 Our prior study of oral delta-9-THC and smoked cannabis in patients with HIV on protease inhibitor therapies showed that oral THC had no effect on the pharma-cokinetics of the antiviral agents.17 However, smoked cannabis decreased the 8-h area under the plasma concentration–time curve (AUC) of both nelfinavir (−17.4%, P = 0.46) and indi-navir (−14.5%, P = 0.07). In a study involving 24 patients with cancer, cannabis administered as a medicinal tea did not alter the pharmacokinetics of the chemotherapy agents irinotecan and docetaxel.18

1Division of Hematology–Oncology, San Francisco General Hospital, University of California, San Francisco, San Francisco, California, USA; 2Center for AIDS Prevention Studies, University of California, San Francisco, San Francisco, California, USA; 3Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, San Francisco, California, USA. Correspondence: DI Abrams ([email protected])

Received 5 May 2011; accepted 12 July 2011; advance online publication 2 November 2011. doi:10.1038/clpt.2011.188

Cannabinoid–Opioid Interaction in Chronic PainDI Abrams1, P Couey1, SB Shade2, ME Kelly1 and NL Benowitz3

Cannabinoids and opioids share several pharmacologic properties and may act synergistically. The potential pharmacokinetics and the safety of the combination in humans are unknown. We therefore undertook a study to answer these questions. Twenty-one individuals with chronic pain, on a regimen of twice-daily doses of sustained-release morphine or oxycodone were enrolled in the study and admitted for a 5-day inpatient stay. Participants were asked to inhale vaporized cannabis in the evening of day 1, three times a day on days 2–4, and in the morning of day 5. Blood sampling was performed at 12-h intervals on days 1 and 5. The extent of chronic pain was also assessed daily. Pharmacokinetic investigations revealed no significant change in the area under the plasma concentration–time curves for either morphine or oxycodone after exposure to cannabis. Pain was significantly decreased (average 27%, 95% confidence interval (CI) 9, 46) after the addition of vaporized cannabis. We therefore concluded that vaporized cannabis augments the analgesic effects of opioids without significantly altering plasma opioid levels. The combination may allow for opioid treatment at lower doses with fewer side effects.

EVIDENCE: CHRONIC PAIN

• Population: 21 adult inpatients with chronic pain, on a regimen of BID sustained release morphine (MS Contin) or oxycodone (OxyContin)

• Intervention: Vaporized cannabis (3.56%, 0.9g) HS on day one, followed by TID on days 2-4, and the morning of day 5

• Outcomes: • Daily questionnaire evaluating:

• Pain, stimulation, anxiety, sedation, feeling down, hunger, mellowness, confusion, irritation, depression, withdrawn, dizziness, nausea, dry mouth (VAS 0-100)

• Pharmacokinetic parametersAbramsDIetal.Clin Pharmacol Ther.2011;90(6):844–51.

RESULTS

• Participants in both groups reported significant reductions in pain ratingsCLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 90 NUMBER 6 | DECEMBER 2011 845

ARTICLES

Inhalation of vaporized cannabis delivers levels of THC and other cannabinoids similar to those from smoked marijuana but without exposure to combustion products.19 Here we describe the disposition kinetics of sustained-release morphine and oxy-codone, as well as pain ratings and other subjective responses, before and after 4 days of treatment with vaporized cannabis.

RESULTSStudy participantsA total of 315 potential participants were assessed for eligibility between January 2007 and February 2009; most of them were deemed ineligible because they either did not have pain, were not taking the appropriate opioids, or were receiving opioids three times a day. A total of 24 participants were enrolled, 13 of whom were on morphine treatment and 11 on oxycodone. Of those on morphine, 3 participants did not complete the study, leaving 21 evaluable participants (10 on morphine, and 11 on oxycodone) (see Table 1). Most of the participants (11 men and 10 women) were white. The average age was 42.9 (range = 33–55) years in the morphine cohort and 47.1 (range = 28–61) years in the oxycodone cohort. The mean morphine dose was 62 mg twice a day (range = 10–200 mg) and the mean oxycodone dose was 53 mg twice a day (range = 10–120 mg). The origin of the participants’ pain was musculoskeletal (not otherwise specified) (seven); posttraumatic (four); arthritic (two); peripheral neu-ropathy (two); cancer, fibromyalgia, migraine, multiple sclerosis, sickle cell disease, and thoracic outlet syndrome (one each).

PainPain ratings on day 1 (before exposure to vaporized canna-bis) and on day 5 (after exposure to vaporized cannabis) are shown in Table 2. Participants on oxycodone had higher mean pain scores at baseline (mean = 43.8; 95% confidence interval

(CI) = 38.6, 49.1) compared with those on morphine (mean = 34.8; 95% CI = 29.4, 40.1). Participants in both groups reported statistically significant reductions in pain ratings on day 5 as compared with day 1. The mean percentage change in pain was statistically significant overall as well as for the patients on mor-phine, but not for those on oxycodone.

Opioid disposition kineticsMean plasma concentration–time curves for morphine and oxycodone with and without cannabis treatment are shown in Figure 1. There was no statistically significant change in the AUC12 for either of these opiates (see Table 3). There was a sta-tistically significant decrease in maximum concentration (Cmax) of morphine sulfate during cannabis exposure. The time to Cmax of morphine tended to be delayed during cannabis treatment, although this effect was not statistically significant. Cannabis had no significant effect on oxycodone kinetics. During cannabis treatment, there were no significant changes in the AUCs of the metabolites of either morphine or oxycodone or in the ratios of individual metabolites to the parent drug.

Plasma THC levelsMean plasma THC levels were 1.8 ng/ml (SD = 1.5) at base-line, 126.1 ng/ml (SD = 86.2) at 3 min, 33.7 ng/ml (SD = 28.9) at 10 min, 10.9 ng/ml (SD = 9.3) at 30 min, and 6.4 ng/ml (SD = 5.6) at 60 min. The peak THC concentration occurred at 3 min in all the participants. THC plasma levels did not vary significantly by opioid group.

Monitoring of effectsCannabis inhalation produced a subjective “high” that was not present with the use of opioids alone (see Figure 2). In addition, the participants in the morphine cohort felt significantly more stimulated and less hungry on day 5 than on day 1 (see Table 4), whereas those in the oxycodone group were less anxious on day 5 as compared with day 1. Other than these, there were no sig-nificant changes in the subjective effects measured. No clinically significant adverse events were reported. Pulse oximetry moni-toring did not reveal any episodes of lowered oxygen saturation after cannabinoids were added to the participants’ stable opioid regimens.

DISCUSSIONOur study findings support preclinical observations that cannabis augments the analgesic effects of opioids. We studied individuals with chronic pain who were taking stable doses of sustained-

Table 1 Participant characteristics

Morphine group Oxycodone group

n 10 11

Women 4 6

Caucasian 8 9

Mean age (range) 42.9 (33–55) 47.1 (28–61)

Mean opioid dose (mg) (range)

62 Twice daily (10–200) 53 Twice daily (10–120)

Mean pain score day 1 (95% CI)

34.8 (29.4, 40.1) 43.8 (38.6, 49.1)

CI, confidence interval.

Table 2 Pain by study day

n

Day 1 Day 5 Difference Percentage change

Mean (95% CI) Mean (95% CI) Mean (95% CI) Mean (95% CI)

Overall 21 39.6 (35.8, 43.3) 29.1 (25.4, 32.8) −10.7 (−14.4, −7.3) −27.2 (−45.5, −8.9)

Morphine 11 34.8 (29.4, 40.1) 24.1 (18.8, 29.4) −11.2 (−16.5, −6.0) −33.7 (−63.8, −3.5)

Oxycodone 10 43.8 (38.6, 49.1) 33.6 (28.5, 38.6) −10.3 (−14.8, −5.8) −21.3 (−47.0, 5.3)

CI, confidence interval.

AbramsDIetal.Clin Pharmacol Ther.2011;90(6):844–51.

EVIDENCE: CANCER PAIN

3.2.4 Cancer pain

Two SRs (Whiting et al., 2015; M€ucke et al., 2016)

covered the same two RCTs with 307 patients and a

study duration of 2 and 3 weeks (see Tables 2 and

6). One study each tested dronabinol (range: 5 to

20 mg/day) and THC/CBD oromucosal spray (range:

30/32 to 43/40 mg/day) versus placebo.

One study each had a moderate and high risk of

bias according to the Cochrane risk of bias tool.

Both reviews concluded from quantitative analysis

that cannabinoids were not statistically superior to

placebo in 30% and more pain relief.

Whiting et al. (2015) did not analyse adverse

events separately for the cancer pain studies. M€uckeet al. (2016) did not find statistically significant dif-

ferences in tolerabilty and safety between cannabi-

noids and placebo.

The SR did not perform subgroup analyses of

cannabinoids and dosages.

M€ucke et al. (2016) concluded that due to the sparse

amount of data, it is not possible to recommend a

favoured use of cannabis products for cancer pain.

Whiting et al. (2015) did not give a separate recommen-

dation for cannabis-based medicines for cancer pain.

2.3.5 Multiple sclerosis and paraplegia-associatedspasticity

One SR (Whiting et al., 2015) covered 14 studies

with 2280 participants (see Table 2; Supporting

Information Table S1) as a subgroup analysis, of

which 11 included patients with MS, while three

included patients with paraplegia. Cannabis-based

medicines tested were dronabinol (up to 10 mg/

day), nabilone (1 mg/day), plant-based THC (800 mg

cigarette) and THC/CBD oromucosal spray (maxi-

mum dosages ranged from 27/25 to 130/120 mg/

day). Study duration ranged between 2 and

52 weeks.

Study quality was assessed by the Cochrane ROB tool

(Whiting et al., 2015). Study quality ranged between

low and high (2, low; 5, unclear and 7, high risk).

Only MS trials reported data suitable for meta-

analysis. Whiting et al. (2015) found by quantitative

analysis that if the Asworth Scale for spasticity

(assessment by physician) was used with a WMD

!0.12 (95% CI: !0.24 to 0.01], cannabis-based med-

icines were not statistically superior to placebo, but

if self-reported spasticity was assessed using numeri-

cal rating scales (mean difference, !0.76 (95% CI:

!1.38 to !0.14) this was the case. Other measures

of change suggested a greater benefit of cannabis-

based medicines without reaching significance, with

the exception a greater global impression of change

score for nabiximols compared to placebo (OR 1.44

(95% CI: 1.07 to 1.94; 3 of 14 trials). The SR did not

present data on tolerability and safety separately for

patients with MS. The SR did not perform subgroup

analyses of cannabis-based medicines and dosages.

Whiting et al. (2015) concluded that there was

moderate-quality evidence to support the use of can-

nabis-based medicines for the treatment of spasticity.

4. Discussion

4.1 Summary of main findings

There were inconsistent findings of four SRs on the

efficacy of cannabis-based medicines compared to

placebo in chronic neuropathic pain. There were

Table 6 Results of the systematic reviews of randomized controlled trials of cannabis-based medicines for cancer pain included in the systematic reviews

Reference

Databases and period cov-

ered by

search of literature

Results for efficacy (95% CI)

Number of studies/patients in

case of quantitative synthesis

Results for tolerability and safety

(95% CI)

Number of studies/patients in case

of quantitative synthesis Conclusions of the authors

M€ucke

et al.

(2016)

Cochrane Central Register of

Controlled Trials

(CENTRAL), MEDLINE,

PsycINFO, PubMed, Scopus

and Clinicaltrials.gov up to

April 2015

RD 30% and more pain relief

0.07 (95% CI: 0.0 to 0.16)

2/387

RD Drop-out due to adverse events

1.15; 95% CI: 0.80 to 1.6)a; 4/825

RD Serious adverse events 1.12

(95% CI: 0.86 to 1.46) 4/825

Due to the sparse amount of

data, it is not possible to

recommend a favoured

use of cannabis or

cannabinoids at this time

Whiting

et al.

(2015)

Twenty-eight databases and

grey literature sources

were searched from

inception to April 2015

OR 30% and more pain relief

1.41 [95% CI: 0.99 to 2.00];

2/387

No separate analysis for cancer pain No separate statement for

cannabis-based medicines

in cancer pain

CO, confidence interval; OR, odds ratio; RD, risk difference.aTwo additional studies with cancer patients included which did not measure pain but other outcomes.

12 Eur J Pain "" (2017) ""–"" © 2017 European Pain Federation - EFIC!

Cannabinoids for chronic pain W. H€auser et al.

*No clinical trials with smoked marijuana WhitingPFetal.JAMA.2015;313(24):2456Mücke Metal.CochraneDatabaseSyst Rev.2016;2016(5).

EVIDENCE: CANCER PAIN

• One study tested dronabinol (range: 5 to 20 mg/day) vs placebo

• One study test THC/CBD oromucosal spray (Sativex) (range: 30/32 to 43/40 mg/day) versus placebo.

• Both reviews of this evidence concluded from quantitative analysis that cannabinoids were not statistically superior to placebo in 30% and more pain relief

WhitingPFetal.JAMA.2015;313(24):2456Mücke Metal.CochraneDatabaseSyst Rev.2016;2016(5).

Cannabinoids for epilepsy (Review)

Gloss D, Vickrey B



Cannabinoids for epilepsy (Review)


EVIDENCE: EPILEPSY• Four randomized trials (48 patients total) using

cannabidiol as an adjunct to anti-epileptic drugs • Cunha 1980: 15 pts with temporal lobe epilepsy with

secondary generalized seizures on cannabidiol 200-300mg daily vs placebo.

• Ames 1985: 12 pts with uncontrolled seizures on 300mg cannabidiol daily vs placebo x1 week, then 200mg daily. No difference found.

• Mechoulam 1978: 9 pts on cannabidiol 200mg daily vs placebo x 3 months. Two pts were seizure free vs none in placebo.

• Trembly 1990 (abstract): 12 pts on 300mg cannabidiol vs placebo x 6 months. Suggested reduction in seizures.

GlossDetal.CochraneDatabaseSyst Rev.2014;(3).

Cannabis and schizophrenia (Review)

McLoughlin BC, Pushpa-Rajah JA, Gillies D, Rathbone J, Variend H, Kalakouti E, KyprianouK



Cannabis and schizophrenia (Review)


EVIDENCE: SCHIZOPHRENIA

• Cannabidiol vs Amisulpride• No data reported for mental state

using BPRS and PANSS• No overall differences in mental

state• Conclusions: No evidence that

cannabidiol has antipyschotic effect

McLoughlin BCetal.CochranedatabaseSyst Rev.2014;(10):CD

EVIDENCE: PALLIATIVE CARE• Gaining ground in settings where the focus is on individual choice,

autonomy, empowerment, comfort and especially quality of life

• May be be useful in alleviating a wide variety of single concurrent symptoms often encountered in the palliative setting such as nausea and vomiting with chemo and radiation, anorexia, severe pain, depression, insomnia

• Effects on Quality of life:• RCT in adult patients with advanced cancer and anorexia

• Cannabis extract and THC did not provide any significant benefit • RCT in chronic neuropathic pain (post traumatic or post-surgical

etiology) • Smoked cannabis did not provide significant benefit


PATIENT WARNINGS/PRECAUTIONS• Can affect proper mental functioning• Use involves risks to health which are not fully known or understood• Does not meet standards required by Food and Drug regulations for

marketed drugs in Canada• Smoking cannabis is not recommended• Cannabis can impair concentration, decision making, coordination,

and reaction time, affecting your ability to drive• It can increase anxiety and cause panic attacks, and in some cases

paranoia and hallucinations• Cognitive impairment may be greatly increased when consumed with

alcohol or other psychoactive drugs


DOSING• Highly individualized and relies greatly on titration• Most individuals use < 3g /day of dried marijuana whether oral,

inhaled or combination of both• Max supply from health Canada is 150g per 1 month (5g/day)• Smoking/Vaporizing:

• Onset within minutes, shorter duration• Wait 30 min between puffs/ inhalations to gauge effect

• Edibles/oils:• Slow and erratic absorption, delayed onset• Dosing less well established (more overdoses)• Wait 2 h between administration of single doses of oral products to gauge effect


DOSING CONVERSION


OVERDOSE

• Signs and Symptoms:• Sleepiness, confusions, disorientation, loss of coordination, fainting,

dizziness, chest pain, fast or slow heart rate, panic attacks, loss of contact with reality, seizures

• Estimated lethal dose:• 30mg/kg (approx. 21g for 70kg person) • There is no documented evidence of death exclusively attributable

to cannabis overdose to date


INTERACTIONS

Drug That Increase THC Levels:• Antiretroviral drugs

• ritonavir• Antibiotics & Antifungals

• clarithromycin, erythromycin, itraconazole, fluconazole, ketoconazole, miconazole

• Certain antidepressants • fluoxetine, fluvoxamine, nefazodone

• Proton Pump Inhibitors• Omeprazole, cimetidine

• Certain heart meds• diltiazem, verapamil, amiodarone

Most Important Interaction:CNS Depressants (e.g. alcohol, sedative-hypnotics)

Drugs that Decrease THC Levels:• Antibiotics:

• Rifampicin, rifabutin• Anticonvulsants:

• Carbamazepine, phenobarbital, phenytoin, primidone

• Natural Health Products• St. John’s wort

Drugs Increased by THC:• Amitriptyline, theophylline, granisetron,

dacarbazine, flutamide


ADVERSE EFFECTSSystem Adverse Effect

CNS Dizziness, sedation, fatigue, headacheImpaired memory, concentration, decision makingDisorientation, confusion, feeling ”high”Anxiety, paranoid, hallucinationMotor skill impairment, fallsSeizures

Mouth & Throat Dry mouth, throat irritation, cough

CV TachycardiaGI Nausea/Vomiting

Cannabis Hyperemesis Syndrome

Copyright 2015 American Medical Association. All rights reserved.

Table 3. Summary Estimates From Meta-analyses for Each AE Assessed: Odds of Participants Experiencing AEWith Cannabinoid vs Placebo or Active Comparison

No. of Studies(No. of Patients) Summary OR (95% CI) I2, %

General AE categories

Any 29 (3714) 3.03 (2.42-3.80) 31

Serious 34 (3248) 1.41 (1.04-1.92) 0

Withdrawal due to AE 23 (2755) 2.94 (2.18-3.96) 2

MedDRA high-level grouping164

Gastrointestinal disorders 10 (1960) 1.78 (1.43-2.22) 0

Infections and infestations 7 (1681) 1.13 (0.87-1.46) 0

Psychiatric disorders 8 (1672) 3.10 (1.81-5.29) 55

Nervous system disorders 10 (1521) 3.17 (2.20-4.58) 46

Musculoskeletal and connective tissuesdisorders

7 (1310) 1.32 (0.75-2.32) 34

General disorders and administrationsite conditions

6 (1208) 1.78 (1.34-2.36) 0

Death 5 (929) 1.01 (0.51-2.00) 0

Ear and labyrinth disorders 3 (922) 2.72 (1.55-4.75) 0

Respiratory, thoracic, and mediastinal disorders 5 (851) 0.80 (0.46-1.39) 0

Cardiac disorders 7 (833) 1.42 (0.58-3.48) 0

Blood disorders 3 (543) 1.42 (0.20-10.25) 18

Injury, poisoning and procedural complications 3 (543) 1.18 (0.48-2.93) 0

Renal and urinary disorders 3 (470) 2.45 (2.27-2.65) 0

Investigations 2 (427) 1.55 (0.36-6.71) 0

Metabolism and nutrition 2 (427) 2.37 (1.00-5.61) 0

Neoplasms, benign, malignant, and unspecified 2 (427) 0.99 (0.47-2.08) 0

Skin and subcutaneous 3 (405) 0.85 (0.34-2.13) 0

Eye disorders 1 (339) 1.42 (0.46-4.33) NA

Reproductive system 1 (246) 1.55 (0.20-11.92) NA

Hepatobiliary disorders 1 (181) 3.07 (0.12-76.29) NA

Mental status change 3 (106) 2.49 (0.49-12.64) 0

Other body systems 1 (42) 2.59 (0.34-19.47) NA

Injection site pain 1 (32) 2.49 (0.92-6.68) NA

Individual AEs

Dizziness 41 (4243) 5.09 (4.10-6.32) 18

Dry mouth 36 (4181) 3.50 (2.58-4.75) 28

Nausea 30 (3579) 2.08 (1.63-2.65) 0

Fatigue 20 (2717) 2.00 (1.54-2.62) 0

Somnolence 26 (3168) 2.83 (2.05-3.91) 27

Euphoria 27 (2420) 4.08 (2.18-7.64) 49

Depression 15 (2353) 1.32 (0.87-2.01) 0

Vomiting 17 (2191) 1.67 (1.13-2.47) 0

Diarrhea 17 (2077) 1.65 (1.04-2.62) 15

Disorientation 12 (1736) 5.41 (2.61-11.19) 0

Asthenia 15 (1717) 2.03 (1.35-3.06) 0

Drowsiness 18 (1272) 3.68 (2.24-6.01) 44

Anxiety 12 (1242) 1.98 (0.73-5.35) 54

Confusion 13 (1160) 4.03 (2.05-7.97) 0

Balance 6 (920) 2.62 (1.12-6.13) 0

Hallucination 10 (898) 2.19 (1.02-4.68) 0

Dyspnea 4 (375) 0.83 (0.26-2.63) 0

Paranoia 4 (492) 2.05 (0.42-10.10) 0

Psychosis 2 (37) 1.09 (0.07-16.35) 25

Seizures 2 (42) 0.91 (0.05-15.66) 0

Abbreviations: AE, adverse event; I2,measures of heterogeneity; NA, notapplicable; OR, odds ratio; MedDRA,medical dictionary for regulatoryactivities.

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Table 3. Summary Estimates From Meta-analyses for Each AE Assessed: Odds of Participants Experiencing AEWith Cannabinoid vs Placebo or Active Comparison

No. of Studies(No. of Patients) Summary OR (95% CI) I2, %

General AE categories

Any 29 (3714) 3.03 (2.42-3.80) 31

Serious 34 (3248) 1.41 (1.04-1.92) 0

Withdrawal due to AE 23 (2755) 2.94 (2.18-3.96) 2

MedDRA high-level grouping164

Gastrointestinal disorders 10 (1960) 1.78 (1.43-2.22) 0

Infections and infestations 7 (1681) 1.13 (0.87-1.46) 0

Psychiatric disorders 8 (1672) 3.10 (1.81-5.29) 55

Nervous system disorders 10 (1521) 3.17 (2.20-4.58) 46

Musculoskeletal and connective tissuesdisorders

7 (1310) 1.32 (0.75-2.32) 34

General disorders and administrationsite conditions

6 (1208) 1.78 (1.34-2.36) 0

Death 5 (929) 1.01 (0.51-2.00) 0

Ear and labyrinth disorders 3 (922) 2.72 (1.55-4.75) 0

Respiratory, thoracic, and mediastinal disorders 5 (851) 0.80 (0.46-1.39) 0

Cardiac disorders 7 (833) 1.42 (0.58-3.48) 0

Blood disorders 3 (543) 1.42 (0.20-10.25) 18

Injury, poisoning and procedural complications 3 (543) 1.18 (0.48-2.93) 0

Renal and urinary disorders 3 (470) 2.45 (2.27-2.65) 0

Investigations 2 (427) 1.55 (0.36-6.71) 0

Metabolism and nutrition 2 (427) 2.37 (1.00-5.61) 0

Neoplasms, benign, malignant, and unspecified 2 (427) 0.99 (0.47-2.08) 0

Skin and subcutaneous 3 (405) 0.85 (0.34-2.13) 0

Eye disorders 1 (339) 1.42 (0.46-4.33) NA

Reproductive system 1 (246) 1.55 (0.20-11.92) NA

Hepatobiliary disorders 1 (181) 3.07 (0.12-76.29) NA

Mental status change 3 (106) 2.49 (0.49-12.64) 0

Other body systems 1 (42) 2.59 (0.34-19.47) NA

Injection site pain 1 (32) 2.49 (0.92-6.68) NA

Individual AEs

Dizziness 41 (4243) 5.09 (4.10-6.32) 18

Dry mouth 36 (4181) 3.50 (2.58-4.75) 28

Nausea 30 (3579) 2.08 (1.63-2.65) 0

Fatigue 20 (2717) 2.00 (1.54-2.62) 0

Somnolence 26 (3168) 2.83 (2.05-3.91) 27

Euphoria 27 (2420) 4.08 (2.18-7.64) 49

Depression 15 (2353) 1.32 (0.87-2.01) 0

Vomiting 17 (2191) 1.67 (1.13-2.47) 0

Diarrhea 17 (2077) 1.65 (1.04-2.62) 15

Disorientation 12 (1736) 5.41 (2.61-11.19) 0

Asthenia 15 (1717) 2.03 (1.35-3.06) 0

Drowsiness 18 (1272) 3.68 (2.24-6.01) 44

Anxiety 12 (1242) 1.98 (0.73-5.35) 54

Confusion 13 (1160) 4.03 (2.05-7.97) 0

Balance 6 (920) 2.62 (1.12-6.13) 0

Hallucination 10 (898) 2.19 (1.02-4.68) 0

Dyspnea 4 (375) 0.83 (0.26-2.63) 0

Paranoia 4 (492) 2.05 (0.42-10.10) 0

Psychosis 2 (37) 1.09 (0.07-16.35) 25

Seizures 2 (42) 0.91 (0.05-15.66) 0

Abbreviations: AE, adverse event; I2,measures of heterogeneity; NA, notapplicable; OR, odds ratio; MedDRA,medical dictionary for regulatoryactivities.

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WhitingPFetal.JAMA.2015;313(24):2456

LONG TERM EFFECTS

• Aggravation of psychiatric disorders• Risk of lung infections • Decrease in fertility (males and females)• Behavioral and cognitive development issues from exposure in utero• Reduced cognitive function• Tolerance and Withdrawal (physical dependence)• Addiction (psychologic dependence)

• Compulsive and continued used despite harm• Cravings


DSM-V: CANNABIS WITHDRAWAL• Cessation of cannabis use that has been heavy and prolonged • ≥3 of the follow signs and symptoms (within 1 week of cessation):

• Irritability, anger, or aggression• Nervousness or anxiety• Sleep difficulty (insomnia, disturbing dreams)• Decreased appetite/ weight loss• Restlessness• Depressed mood• At least one of the follow symptoms causing significant discomfort: abdominal

pain, shakiness/tremors, sweating, fever, chills, or headache

“Among adults and adolescents enrolled in treatment or heavy cannabis users, 50%–95% report cannabis withdrawal”

CANNABIS WITHDRAWAL SCALE • Commonly used in studies to

quantify cannabis withdrawal• Allsop 2014 & Levin 2011

• Developed from the “Marijuana Withdrawal Checklist” (Budney et al. 1999)

• Not yet a validated assessment tool, but in the works

Allsop et al. Drug Alcohol Depend 2011 Dec 1;119(1-2):123-9.

HOW TO GET ACCESS FROM HEALTH CANADA

1. Consult with Health Care Practitioner (Physician or Nurse Practitioner)

2. Obtain a medical document from your health care practitioner

3. Registered and order from a licensed producer (must submit document)

4. Cannabis is sent directly to patient from licensed producer via maila) Maximum allowable quantity is 150g/month

LICENSED PRODUCERS

Only licensed producers may sell or provide:• Dried marijuana• Fresh marijuana• Cannabis oil• Starting materials to eligible

persons

CANNABIS DISPENSARIES• Not operating under the government’s approved distribution system• Free Skype Consultation with a medical practitioner OR have a MMPR (Medical Marijuana

Purposes Regulation) Card• Marijuana and THC/CBD products are shipped to your address• Formulations:

• Cannabis Flowers• Concentrates

• Capsules• Phoenix Tears• Shatter• Hash• Cannabis Tinctures• THC Distillate• CO2 (for vaping)• Suppositories

• Pure CBD Products (including oils)• Topical Products

CANNABIS DISPENSARY PRODUCTS

QUESTIONS?

REFERENCES

1. AbramsDI,Couey P,ShadeSB,KellyME,Benowitz NL.Cannabinoid-opioidinteractioninchronicpain.Clin Pharmacol Ther [Internet].2011;90(6):844–51.Availablefrom:http://dx.doi.org/10.1038/clpt.2011.188/nature06264

2. ChangAE,Shiling DJ,Stillman RC,GoldbergNH,Seipp CA,Barofsky I,etal.Delta-9-TetrahydrocannabinolasanAntiemeticinCancerPatientsReceivingHigh-DoseMethotrexate:Aprospective,RandomizedEvaluation.AnnInternMed.1979;91(6):819–24.

3. Cirone S,Kahan M,WareM,Dubin R.AuthorizingDriedCannabisforChronicPainorAnxiety.CanFamPhysician.2014;(September).

4. Corey-BloomJ,WolfsonT,Gamst A,Jin S,Marcotte TD,BentleyH,etal.Smokedcannabisforspasticityinmultiplesclerosis:arandomized,placebo-controlledtrial.CanMedAssoc J.2012;184(10):1143–50.

5. CotterJ.EfficacyofCrudeMarijuanaandSyntheticDelta-9-TetrahydrocannabinolasTreatmentforChemotherapy-InducedNauseaandVomiting:ASystematicLiteratureReview.Oncol Nurs Forum[Internet].2009;36(3):345–52.Availablefrom:https://onf.ons.org/onf/36/3/efficacy-crude-marijuana-and-synthetic-delta-9-tetrahydrocannabinol-treatment-chemotherapy

6. GlossD,Vickrey B.Cannabinoidsforepilepsy.CochraneDatabaseSyst Rev[Internet].2014;(3).Availablefrom:http://doi.wiley.com/10.1002/14651858.CD009270.pub3

7. Häuser W,Petzke F,Fitzcharles M-A.Efficacy,tolerabilityandsafetyofcannabis-basedmedicinesforchronicpainmanagement- Anoverviewofsystematicreviews.Eur JPain[Internet].2017;Availablefrom:http://doi.wiley.com/10.1002/ejp.1118

8. HealthCanada.AccesstoCannabisforMedicalPurposesRegulationsRèglement surl’accès aucannabisà desfinsmédicales.2016

9. HealthCanada.ConsumerInformation-Cannabis(Marijuana,marijuana).2007;29–76.

10. HealthCanada.InformationforHealthCareProfessionals:Cannabis(Marihuana,marijuana)andthecannabinoids.2009;(888).

REFERENCES CONTINUED1. KramerJL.MedicalMarijuanaforCancer.CaCancerJClin.2015;65(2):109–22.2. Lutge EE,GrayA,SiegfriedN.ThemedicaluseofcannabisforreducingmorbidityandmortalityinpatientswithHIV/AIDS.Cochrane

DatabaseSyst Rev[Internet].2013;(4).Availablefrom:http://doi.wiley.com/10.1002/14651858.CD005175.pub33. Mücke M.,PhillipsT.,Radbruch L.,Petzke F.,Häuser W.Cannabinoidsforchronicneuropathicpain.CochraneDatabaseSyst Rev.

2016;2016(5).4. McLoughlin BC,Pushpa-Rajh JA,Gillies D,RathboneJ,Variend H,Kalakouti E.Cannabisandschizophrenia.CochranedatabaseSyst Rev.

2014;(10):CD.5. MustyRE,RossiR.EffectsofSmokedCannabisandOral∆9-TetrahydrocannabinolonNauseaandEmesisAfterCancerChemotherapy :

AReviewofStateClinicalTrials.JCannabisTher [Internet].2001;1(1):29–56.Availablefrom:http://files.iowamedicalmarijuana.org/science/clincal/Musty-RossiJCANT.pdf

6. SmithLA,Azariah F,LavenderVTC,StonerNS,Bettiol S.Cannabinoidsfornauseaandvomitinginadultswithcancerreceivingchemotherapy.CochranedatabaseSyst Rev.2015;11(11):CD009464.

7. Strasser F,Luftner D,Possinger K,ErnstG,Ruhstaller T,MeissnerW,etal.Comparisonoforallyadministeredcannabisextractanddelta-9- tetrahydrocannabinolintreatingpatientswithcancer-relatedanorexia-cachexiasyndrome:Amulticenter,phaseIII,randomized,double-blind,placebo-controlledclinicaltrialfromtheCannabis-In-Cachexia-Study-Group.JClin Oncol.2006;24(21):3394–400.

8. Tafelski S,Häuser W,Schäfer M.Efficacy,tolerability,andsafetyofcannabinoidsforchemotherapy-inducednauseaandvomiting—asystematicreviewofsystematicreviews.DerSchmerz [Internet].2016;30(1):14–24.Availablefrom:http://link.springer.com/10.1007/s00482-015-0092-3

9. WareMA,WangT,ShapiroS,RobinsonA,Ducruet T,HuynhT,etal.Smokedcannabisforchronicneuropathicpain:Arandomizedcontrolledtrial.Cmaj.2010;182(14).

10. WhitingPF,WolffRF,DeshpandeS,DiNisio M,DuffyS,HernandezAV.,etal.CannabinoidsforMedicalUse.Jama[Internet].2015;313(24):2456.Availablefrom:http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.6358

11. Wilsey B,Marcotte T,Tsodikov A,Millman J,BentleyH,Gouaux B,etal.ARandomized,Placebo-Controlled,CrossoverTrialofCannabisCigarettesinNeuropathicPain.JPain.2008;9(6):506–21.

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Medical Marijuana Inservice - WordPress.com...Changes in menstrual cycle, ovulation suppression Health Canada. Information for Health Care Professionals: Cannabis (Marihuana, marijuana)