Theresa Mallick-Searle, MS, RN-BC, ANP-BC Stanford Health Care: Division Pain Medicine

tmallick@stanfordhealthcare.org

Speakers Bureau: Allergan Pharmaceuticals Speakers Bureau: Depomed Pharmaceuticals

Examine the history of cannabinoids & current science.

Evaluate drug interactions, considerations, pharmacology of delta-9-tetrahydrocannabinol.

Objectively evaluate clinical applications of cannabinoids, supported by the research.

Verbalize the limitations of scientific research on cannabinoids/delta-9-tetrahydrocannabinol.

<1000 B.C. early writings in the Far and Middle East note the use of cannabis for medicinal purposes.

In 1545 the Spanish brought cannabis to the New World.

The late 1800’s William Brooke O’Shaughnessy, an Irish physician was the first to introduce the use of medicinal marijuana into Western Medicine.

Cannabis was listed in the United States Pharmacopeia from 1850 -1942.

A campaign conducted in the 1930s by the U.S. Federal Bureau of Narcotics sought to portray marijuana as a powerful, addicting substance that would lead users into narcotics addiction.

1937 Marijuana Tax Act

The Controlled Substances Act of 1970

The Compassionate Investigational New Drug Program (1978), federally sponsored program allowing a limited number of patients to use medical marijuana grown at the University of Mississippi. Closed to new entrants (1992), there were only seven surviving patients who were grandfathered into the program.

1999 IOM Report

2000 IOM Report

2011: Veterans Administration Marijuana Policy August 29, 2013: Memorandum For All US Attorneys, From The Office of the Deputy Attorney General - Guidance Regarding Marijuana Enforcement. December 2014: Congress Enacts Measure Protecting State-Sponsored Medi-Pot Programs. President Barack Obama signed spending legislation into law in December that included a provision limiting the Justice Department’s ability to take criminal action against state-licensed individuals or operations that are acting in full compliance with the medical marijuana laws of their states.

http://blog.norml.org/2014/12/30/2014-the-year-in-review-normls-top-10-events-that-shaped-marijuanapolicy/#sthash.E5q8vCzD.dpuf

http://www.justice.gov/iso/opa/resources/3052013829132756857467.pdf

http://www.va.gov/vhapublications/viewpublication.asp?pub_id=2362

States That Have Passed Medical-Marijuana Laws.

Washington State Maine New York New Mexico California

http://midlevelu.com/blog/scope-practice-all-time-high-nurse-practitioners-some-states

"For states that have enacted laws to authorize the production, distribution, possession & taxation of marijuana, The Department of Justice expects these states to establish strict regulatory schemes that protect the eight federal interests identified in The Department’s guidance."

Founded in 2010 as a collaboration among three MBAs, “Privateer” became the first private equity firm to invest in the cannabis industry in 2011 when it acquired “Leafly”.

Marijuana investing tops $100 million in two years

“Leafly” – website which allows consumers/users rate strains and dispensaries of cannabis. http://www.leafly.com/

https://thecannabisindustry.org/

1964 ∆9-THC synthesized and structure identified 1980s Synthetic cannabinoids 1988 CB1 receptor identified 1990 CB1 receptor cloned 1992 CB2 receptor 1992 Anandamide 1993 CB2 receptor cloned 1995 2-arachidonylglycerol (2AG) identified 1994-7 Receptor antagonists 1998 Endogenous ligands shown to be analgesic 2001 Noladin ether identified 2000+ Synthetic cannabinoids, more on the endogenous

system, biosynthesis and degradation, delivery systems.

The cannabis plant contains more than 400 chemicals. Approximately 60 are called cannabinoids. THC = delta-9-tetrahydrocannabinol CBD = cannabidiol 1964, Raphael Mechoulam discovered the chemical structure of the THC molecule.

1988 discovery of the cannabinoid receptor site in the brain @St. Louis University Medical School (Howlett & Devane). CB1 receptors: Expressed by central & peripheral neurons. Most abundant G-protein-coupled receptors in the brain.

CB2 receptors: Expressed mostly by cells of the immune system. Their activation modulates immune cell migration and cytokine release.

High density of receptor sites in the CNS, account for the effects seen by (THC): Euphoria Anxiety Anxiolysis Coordination Antinociception Cognitive disturbances

• Cognition and memory • Appetite • Stress response • Inflammation • Exploration, social

behavior, & anxiety • Immune/Endocrine

function • Autonomic nervous

system • Antinociception

The endocannabinoid system - Signaling system that includes CB1 & CB2 receptors, endogenous receptor ligands (endocannabinoids), and their synthesizing and degrading enzymes. 1992 Raphael Mechoulam discovered the existence of the first endogenous cannabinoid: anandamide. The exposure to phytocannabinoids (exogenous), (THC, CBD), can have similar effects on these systems.

Discovery of the endocannabinoid system and cannabindiol (non-psychoactive cannabinoid), that has driven much of the current research on cannabinoids (1990s). The endocannabinoid system is present and has important physiological functions not only in the central nervous system but also in peripheral tissues.

Our endocannabinoid system works to modulate the sensitivity of

our brain to many of the other neurotransmitters that are present, such as dopamine and serotonin.

Our experience of pain, especially from inflammation (the

endocannabinoid system interacts with our endorphin system to reduce pain) .

Our response to stress (the entire stress response, from brain

(hypothalamus) to endocrine glands (adrenal cortisol secretion) is regulated by the endocannabinoid system) .

• Cognition & Memory • Appetite • Stress response • Inflammation • Exploration, social

behavior and anxiety • Immune/Endocrine

function • Autonomic nervous

system • Antinociception

Phytocannabinoids (THC, CBD) can bind to the cannabinoid receptor sites (CB1, CB2), and mimic the physiological processes seen with binding of the endocannabinoids (anandamide, 2-AG).

Clinical Endocannabinoid Deficiency Syndrome (Russo, E. 2008).

http://youtu.be/QGKpbqXwg84

YouTube - Cannabinoid Receptors - Horizon: Cannabis - The Evil Weed

Highly lipophilic.

THC psychoactive cannabinoid.

Rapidly absorbed through lungs after inhalation, quickly reaching high serum concentration.

Systemic bioavailability is ~23-27% for daily users,

~10-14% occasional users.

Extensive liver (first pass) metabolism; cytochrome P450.

>65% excreted in the feces, ~20% urine.

t1/2 occasional users is 1-2 days, daily users up to 2 weeks.

Cannabinoids appear to effect the same reward systems as alcohol, cocaine and opioids.

Evidence for cannabis dependence is now available from epidemiological studies of long-term users. (Miller & Plant 1996; Malhotra & Parthasarathy 2006)

Tolerance to cannabis can occur in relation to mood, psychomotor performance, sleep, arterial pressure, body temperature and antiemetic properties.

Symptoms such as irritability, anxiety, craving and disturb sleep have been reported in 60 to 90% of cannabis users during abstinence.

Common adverse effects: blurred vision, dry mouth and eyes, tachycardia, hypo/hypertension, somnolence, urinary retention, cognitive dysfunction, hallucinations.

• Herb 3-22% THC • Hashish/Hash Oil 40-90% THC

• Synthetic: – Dronabinol (Marinol) CIII – Nabilone (Cesamet) CII – Nabiximols (Sativex)

Dronabinol : 2.5 mg, 5 mg, 10 mg Nausea/vomiting, chemo-related 5 mg oral q2-4hr x4-6 doses/day Anorexia, AIDS-associated 2.5-10 mg oral bid Nabilone: 1 mg Nausea/vomiting, chemo-related 1-2 mg oral bid

Nabiximol (Epidiolex) is a liquid formulation of highly purified CBD extract, as a treatment for various pediatric epilepsy syndromes.

Nabiximol (Sativex), is an oral spray which consists of a formulated extract of the cannabis sativa plant that contains the principal cannabinoids delta-9-tetrahydrocannabinol and cannabidiol.

Current available in UK and Canada. In clinical trials in the US.

http://www.gwpharm.com/FAQ.aspx

The two species of the Cannabis genus that are most commonly grown are: Cannabis indica & Cannabis sativa. A third species, Cannabis ruderalis is very short and produces only trace amounts of THC, and thus is not commonly grown for industrial, recreational or medicinal uses.

Wesley LT, et. al. – Auburn University, AL. The American Journal of Drug and Alcohol Abuse, 2012; 38(4): 334-343. Objective: Summarize the clinical literature on interactions between common illicit drugs and prescription therapies. Design: Systematic review of the literature: including Medline (1948-2011), International Pharmaceutical Abstracts (1970-2011), EBSCO Academic Search Premier (1975-2011). Findings: The interactions of illicit drugs with prescription therapies have the ability to potentiate or attenuate the effects of both the illicit agent and/or the prescription therapeutic agent, which can lead to toxic effects or a reduction in the prescription agent’s therapeutic activity.

Drug Interactions between Common Illicit Drugs and Prescription Therapies

Cannabinoid in pregnancy - Marinol category C.

Antibiotics - no direct interaction.

Cytochrome P450 - competitively inhibit the prescribed RX (e.g. warfarin, theophylline, antiretroviral, protease inhibitors)

General anesthesia - stop THC 2 weeks before.

CNS depressants (benzodiazepines, opioids, other sedatives/hypnotics, ETOH) - potentiate the CNS depressant effects.

Antidepressants, Antipsychotic & Atypical Antipsychotic Medications - depression, anxiety, mania, tachycardia, hypertension.

Other (Lithium & Valproate - increased serum levels, Disulfiram (Antabuse) - hypomania, agitation, trouble sleeping, and irritability, Sildenafil - myocardial infarction).

Largest body of literature

– Neurological & movement disorders: antispasmodic, epilepsy. – Cancer: chemotherapy induced nausea/vomiting, anti-

angiogenesis, pain. – Addiction & abuse potential, safety. – Pain

Emerging Clinical Applications For Cannabis & Cannabinoids A Review of the Recent Scientific Literature, 2000 — 2013

http://norml.org/component/zoo/category/recent-research-on-medical-marijuana

United States • Center for Medicinal Cannabis Research • National Center for Natural Products Research

(NCNPR) at the University of Mississippi • National Institute on Drug Abuse (NIDA) • National Institutes of Health (NIH)

Canada • Canadian Institutes of Health Research

Europe • The Medicinal Cannabis Research Foundation

(MCRF): a UK registered charity set up to promote and sponsor medicinal cannabis research and to raise public awareness

• Spain, Germany, Italy • ICRS: http:// www.cannabinoidsociety.org • Sanoti-Aventis, GW Pharmaceuticals, Pfizer

Purpose of the Center is to coordinate rigorous scientific studies to assess the safety and efficacy of cannabis for treating medical conditions

Funding is the result of SB 847 from the State of California Research focus on disease and conditions as specified by the National

Academy of Sciences, Institute of Medicine Report (1999) and the Workshop on the Medical Utility of Marijuana, NIH (1997) Severe appetite suppression, weight loss, and cachexia due to HIV

infection and other medical conditions Chronic pain, particularly neuropathic pain Severe nausea and vomiting associated with cancer and its treatment Severe muscle spasticity caused by diseases such as multiple sclerosis

www.cmcr.ucsd.edu/geninfo/research.htm

Clinical and Psychological Effects of Marijuana in Man

Weil, A., et al., Science 1968; 162:1234-1242.

• Early attempts to investigate marijuana in a formal double-blinded study model.

• Few early studies involving human subjects in US/Internationally.

• It is also the first attempt to collect basic clinical and psychological information on the drug by observing its effects on marijuana-naive human subjects in a neutral laboratory setting.

Design: Single center, randomized, double-blind, placebo controlled. N = 9 healthy male volunteers, 21-26 y/o, Daily tobacco smokers, marijuana naïve. N = 8 healthy male volunteers, 21-26 y/o, chronic marijuana smokers. All subjects smoked 2 standardized cigarettes per session. Naïve = placebo, low dose (4.5mg THC), high dose (18mg THC) Experienced = placebo, high dose (18mg THC) Randomized subjects 1 of 3 groups, all completing a series of 3 sessions (Naïve subjects required a 4th “practice session”). I High Placebo Low II Low High Placebo III Placebo Low High

Physiological Parameters Measured : heart rate, respiratory rate, pupil size, blood glucose level.

The Psychological Tests : Continuous Performance Test (CPT)-5 minutes, The Digit Symbol Substitution Test (DSST)-90 seconds, CPT with strobe light distraction-5 minutes, Self-rating bipolar mood scale-3 minutes, Pursuit rotor-10 minutes.

Findings: It is feasible and safe to study the effects of marijuana on human volunteers who smoke

it in a laboratory.

No significant changes in vital signs in young healthy adults.

Regular users of marijuana do not show the same degree of impairment of performance on the tests as do naive subjects. In some cases, their performance even appears to improve slightly after smoking marijuana.

In a neutral setting the physiological and psychological effects of a single, inhaled dose of marijuana appear to reach maximum intensity within 30 minutes of inhalation, to be diminished after 1 hour, and to be completely dissipated by 3 hours.

“I think it’s really dumb to grow cotton in Arizona, when growing hemp makes much more sense.”

Quality of evidence

High quality At least 2 high-quality, directly applicable randomized, controlled trials with consistent results.

Moderate quality

At least 1 high-quality randomized, controlled trial or 2 or more high-quality observational studies with consistent results, or reasonable extrapolation of 2 or more high-quality randomized, controlled trials.

Low quality Some evidence of effect, but conclusions limited by study design limitations, inconsistent results, or extrapolation of questionable reliability.

Oxford Center for Evidence-based Medicine levels of evidence

“Strong” recommendation FOR

Balance of desirable vs harmful effects substantially favors the desirable effects. Most patients would want and should receive the therapy.

“Weak” recommendation FOR

Balance of desirable effects vs harmful effects seems to favor the desirable effects. Most patients would want the therapy, but many would not; shared decision-making recommended.

“Inconclusive” Insufficient evidence to recommend for or against the therapy.

Recommendation AGAINST

At least fair evidence that the therapy is ineffective or anticipated harmful effects outweigh potential for benefit

GRADE (Grading of Recommendations, Assessment, Development & Evaluation) guidelines

Intervention Quality of evidence

Strength of recommendation Additional comments

Inhibition tumor growth High Inconclusive

1) In all studies included, cannabinoids were shown to exert anti-tumor activity. 2) Anti-tumor evidence included: reduction in tumor size, anti-angiogenic, anti-metastatic effects. 3) Normal cells used as controls were not effected. 4) More human trials are needed.

Pain management High Strong

THC:CBD has been shown to be a useful adjunctive treatment for relief of pain in patients with advanced cancer who experience inadequate analgesia despite chronic opioid therapy.

Antiemetic Moderate Against

The current American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) guidelines do not recommend cannabinoids as first-line therapies.

Anorexia Weak Inconclusive

The data for cannabinoids in cancer-associated anorexia based on three randomized studies are weak and the data for inhaled cannabis for cancer-associated cachexia are lacking.

Intervention Quality of evidence

Strength of recommendation Additional comments

Epilepsy Weak Inconclusive

No reliable conclusions can be drawn at present regarding the efficacy of cannabinoids as a treatment for epilepsy. Nabiximol (Epidiolex) is a liquid formulation of highly purified CBD extract, as a treatment for various pediatric epilepsy syndromes.

Multiple Sclerosis High Recommend Effective for spasticity, pain. Less effective tremor.

Neuropathic Pain High Weak

Replicated positive RCTs, but concerns about the RCT and about safety. Because of the concern regarding the risk of abuse and psychiatric adverse events, published guidelines as well as expert recommendations suggest using them as second-line therapy only.

Neuroprotective Weak Inconclusive Mostly in vivo studies. Anti-glutamatergic effects, calcium channel blockade, antioxidant effects & anti-inflammatory actions.

Intervention Quality of evidence

Strength of recommendation Additional comments

Addiction/ Withdrawal High Against

CB1 cannabinoid receptors are responsible for all the addictive properties of cannabinoids. Dopaminergic, Opioid, & Cannabinoid systems are involved in the neurochemical substrate of addiction. Cannabis w/d = irritability, increased anxiety, depressed mood, sleep disturbances, heightened aggressiveness, decreased appetite. Last 1-2 weeks.

Cognitive Functioning Low Inconclusive

Community controls performed significantly better than both drug-using groups; memory, learning, and executive components of memory. Sub-chronic use of THC = down regulation of the cannabinoid CB1 receptor. More human trials are needed.

Anxiety Moderate Inconclusive

Frequent cannabis users consistently have a high prevalence of anxiety disorders and patients with anxiety disorders have relatively high rates of cannabis use. Unclear if cannabis use increases the risk of developing long-lasting anxiety disorders.

The enactment of statewide medicinal marijuana laws is associated with significantly lower state-level opioid overdose mortality rates, according to data published in August in JAMA Internal Medicine. Researchers reported, “States with medical cannabis laws had a 24.8 percent lower mean annual opioid overdose mortality rate compared with states without medical cannabis laws.”

Fewer Opiate-Related Deaths In Medical Marijuana States

Intervention Quality of evidence

Strength of recommendation Additional comments

Neuropathic Pain High Strong Consensus statement and guidelines from the Canadian Pain Society: First-line treatments = gabapentinoids TCA & SNRI. Second-line = Tramadol & controlled-release opioid analgesics. Third-line = Cannabinoids.

Inflammatory Pain Low Inconclusive In the first ever controlled trial of a CBM in RA, a significant analgesic effect was observed and disease activity was significantly suppressed following Sativex treatment.

Chronic Pain High Strong

38 published RCTs = 71% (27) concluded that cannabinoids had empirically demonstrable and statistically significant pain relieving effects, whereas 29% (11) did not. Systematic review of 18 recent good quality randomized trials demonstrates that cannabinoids are a modestly effective and safe treatment option for chronic non-cancer (predominantly neuropathic) pain.

Experience from the United States suggests that medical marijuana practices tend to prescribe to large volumes of patient. In Colorado, 49% of more than 36,000 medical recommendation for medical marijuana were written by only 15 physicians. We believe that this could lead to potentially unsafe use. (Nussbaum AM (2011)).

• Patient has severe neuropathic pain interfering with function.

• Patient experiences inadequate analgesia or intolerable side effects with “first” and “second-line” treatments.

• Failed trial of oral or buccal cannabinoids (nabilone, nabiximols).

Consider Referral to Pain Specialist • Patient has no contraindications to cannabis use: age >25 y, no current substance use disorder, no clinical features of cannabis use disorder, no current mood or anxiety disorder, no family hx. of psychosis, not pregnant, no CV or respiratory dz.

• Provide the following warnings & advice: Use with vaporizer is preferable Do not drive for 3 hours after smoking Do not combine with tobacco Do not use with alcohol, opioids, sedating drugs Keep cannabis safely stored Start with 1 inhalation/d., to maximum 4 inhalations/d. Prescription: 1 inhalation qid as needed (maximum 400 mg/d)

Monitoring:

Analgesic response Side effects Signs of addiction or diversion

Consider referring to a pain or addiction specialist

Discontinue if patient experiences following: Inadequate pain relief (<2 points of improvement on

VAS) Substantial side effects Signs of addiction or diversion

• Current literature supports that the Endocannabinoid system is vital in the regulation of various physiological processes in brain and peripheral tissue, effecting multiple body systems.

• Effects of phytocannabinoids on EC system. • CBD v/s THC: safety, efficacy, addiction. • Stigma, legality. • Education/counseling. • Drug to drug interactions. • Keep abreast of the literature.

• On the horizon …

2013 - A total of seven new investigation new drug access sites have been granted by the FDA to independent investigators to allow treatment of approximately 125 pediatric epilepsy patients with this product.

April 30th 2014 - GW Pharmaceuticals announces that Sativex™ receives fast track designation from FDA in treatment of pain in patients with advanced cancer, who experience inadequate analgesia during optimized chronic opioid therapy. May 2014 - Department of Health and Human Services and the Food and Drug Administration have given their approval to a proposed study on whether medical marijuana can help with post-traumatic stress disorder.

Identification of compounds that retain therapeutic effects without the side effects.

Alternative methods of delivery: Oral THC preparations Microspheres Topical delivery Buccal mucoadhesive preparations Portable vapourizers/aerosols Rectal administration

Manipulation of the endocannabinoid system.

Some of the most important future directions in this field are: Developing peripherally restricted CB1 agonists.

Inventing new CB2 agonists.

Combining cannabinoids with other analgesics.

Elevating endocannabinoid levels by inhibition of

EC degrading enzymes.

Practicality of using cannabinoids intra-spinal.

Abrams, D.I., Couey P., Shade S.B., et al. (2011). Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Ther, 90:844-851. Aggarwal, SK. (2013). Cannabinergic pain medicine: a concise clinical primer and survey of randomized-controlled trial results. Clin J Pain, Feb;29(2):162-71. Aggarwal, S. K., Carter, G. T., Sullivan, M. D., ZumBrunnen, C., Morrill, R., & Mayer, J. D. (2009). Medicinal use of cannabis in the United States: historical perspectives, current trends, and future directions. J Opioid Manag, 5(3), 153-68.

Ashton, CH., Moore, PB. (2011). Endocannabinoid system dysfunction in mood and related disorders. Acta Psychiatr Scand, Oct;124(4):250-61. Basinski, H, Jensen, HB, Stenager, E. (2014). There is evidence for the use of cannabinoids for symptomatic treatment of multiple sclerosis. Ugeskr Laeger. 2014 Mar 17;176(12A).

Batalla, A., et al. (2013). Structural and Functional Imaging Studies in Chronic Cannabis Users: A systematic review of adolescent and adult findings. POLS ONE, 8(2):1-18. Benbadis, SR, Sanchez-Ramos, J, Bozorg, A, et al. (2014) Medical marijuana in neurology. Expert Rev Neurother. 2014 Dec;14(12):1453-65. Bifulco M, Laezza C, Gazzerro P, et al. (2007). Endocannabinoids as emerging suppressors of angiogenesis and tumor invasion (review). Oncol Rep. Apr;17(4):813-6.

Blake DR, Robson P, Ho M, Jubb RW, et al. (2006). Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology (Oxford).45:50–2. Bowles DW, O'Bryant CL, Camidge DR, Jimeno A. (2012)The intersection between cannabis and cancer in the United States. Crit Rev Oncol Hematol. Jul;83(1):1-10

Budney, A.J., Novy, P.L., & Hughes, J.R. (1999), Marijuana withdrawal among adults seeking treatment for marijuana dependence. Addiction, 94(9),1311-1322.

Burns, T.J., and Ineck, J.R. (2006), Cannabinoid analgesia as a potential new therapeutic option in the treatment of chronic pain. The Annuals of Pharmacotherapy, 40(2), 251-259. Campbell, F.A., Tramèr, M.R., Carroll, D., et al. (2001). Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review. BMJ, 323:13-16.

Cohen, P. J. (2010). Medical Marijuana 2010: It’s time to fix the regulatory vacuum. J Law Med Ethics, 38(3), 654-66. doi:10.1111/j.1748-720X.2010.00519.x.

Cohen, P. J. (2009). Medical Marijuana: The conflict between scientific evidence and political ideology. Part one of two. J Pain Palliat Care Pharmacother, 23(1), 4-25.

Collin, C., Davies, P., Mutiboko, I.K., & Ratcliffe, S. (2007). Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. Eur J Neurol, 14(3), 290-6. Collin, C., Ehler, E., Waberzinek, G., et al. (2010). A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis. Neurol Res, 32:451-459. doi: 10.1179/016164109X12590518685660. Crippa, JA., Zuardi, AW., Martín-Santos, R. et al. (2009). Cannabis and anxiety: a critical review of the evidence. Hum Psychopharmacol, Oct;24(7):515-23. Croxford, J. L. (2003). Therapeutic potential of cannabinoids in CNS disease. CNS Drugs, 17(3), 179-202. Davis MP. (2014). Cannabinoids in pain management: CB1, CB2 and non-classic receptor ligands. Expert Opin Investig Drugs, Aug;23(8):1123-40. Damiano, D.L., Quinlivan, J.M., Owen, B.F., Payne, P., Nelson, K.C. & Abel, M.F. (2002). What does the Ashworth scale really measure and are instrumented measures more valid and precise? Dev Med Child Neurol. 44(2):112-8. de Dios, M. A., Hagerty, C. E., Herman, D. S., Hayaki, J., Anderson, B. J., Budney, A. J., & Stein, M. (2010). General anxiety disorder symptoms, tension reduction, and marijuana use among young adult females. J Womens Health(Larchmt), 19(9), 1635-42.

de Lago, E., Gómez-Ruiz, M., Moreno-Martet, M., et al. (2009). Cannabinoids, multiple sclerosis and neuroprotection. Expert Rev Clin Pharmacol. 2009 Nov;2(6):645-60. Esposito, G., Filippis, D.D., Cirillo, C., et al. (2013). Cannabidiol in inflammatory bowel diseases: a brief overview. Phytother Res, 27:633-636. doi: 10.1002/ptr.4781. Fine, P.G., Rosenfeld, M.J. (2013). The endocannabinoid system, cannabinoids, and pain. Rambam Maimonides Med J. Oct 29;4(4):e0022 Gloss, D., Vickrey, B. (2012/2014 updated). Cannabinoids for epilepsy. Cochran Database Syst Rev. Jun 13;6. Gonzalez, R., Carey, C., Grant, I. (2002). Non-acute (residual) neuropsychological effects of cannabis use: A qualitative analysis and systemic review. Grotenhermen, F., Müller-Vahl, K. (2012). The therapeutic potential of cannabis and cannabinoids. Dtsch Arztebl Int, 109:495-501. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442177/#E74 Accessed July 25, 2013. Grant, I., Gonzalez, R., Carey, C.L., et al. (2003). Non-acute (residual) neurocognitive effects of cannabis use: a meta-analytic study. J Int Neuropsychol, 9(5), 679-89. Green, A. J., & De-Vries, K. (2010). Cannabis use in palliative care – an examination of the evidence and the implication for nurses. J Clin Nurs, 19(21-22), 3253-5.

Haney, M., Ward, A.S., Comer, S.D., et al. (1999). Abstinence symptoms following smoked marijuana in humans. Psychopharmacology (Berl) 141(4), 395-404. Hill, M.N., et al. (2010). Functional Interactions between Stress and the Endocannabinoid Syster: From Synaptic Signaling to Behavioral Output. Journal of Neuroscience, 30(45), 14980-14986. Hoffmann, D.E., & Weber, E. (2010). Medical Marijuana and the Law. N Engl J Med, 362(16), 1453-1457. Iskedjian M, Bereza B, Gordon A, et al. (2007). Meta-analysis of cannabis based treatments for neuropathic pain and multiple sclerosis-related pain. Curr Med Res Opin, 23(1):17-24. Izzo, A.A., Mascolo, N., Capasso, F. (2000). Marijuana in the new millennium: perspectives for cannabinoid research. TiPS, Vol. 21, August, 281-282. Johnson, JR., Burnell-Nugent, M., Lossignol, D. et al. (2010). Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. J Pain Symptom Manage, Feb;39(2):167-79. Kahan, M., Srivastava, A., Spithoff, S. et al. (2014). Prescribing smoked cannabis for chronic noncancer pain: Preliminary recommendations. Can Fam Physician, Dec;60(12):1083-1090 Karst, M., Salid, K., Burstein, S., Conrad I, et al. (2003). Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. JAMA, 290:1757-1762. http://jama.jamanetwork.com/article.aspx?articleid=197396 Accessed July 24, 2013.

Karst M, Wippermann S, Ahrens J. (2010). Role of cannabinoids in the treatment of pain and (painful) spasticity. Drugs, Dec 24;70(18):2409-38. Killestein, J., Polman, C., & Uitdehaag, B.M.J. (2002). Cannabinoids for multiple sclerosis (Intervention Protocol). Cochrane Database of Systematic Reviews, Issue 4. doi:10.1002/14651858.CD003981. Kondrad E., Reid A. (2013). Colorado family physicians' attitudes toward medical marijuana. J Am Board Fam Med, 26:52-60. http://www.medscape.com/viewarticle/777468 Accessed June 5, 2013. Koppel BS, Brust JC, Fife T, et al. (2014). Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology, Apr 29;82(17):1556-63. Leussink, V.I., Husseini, L., Warnke, C., et al. (2012). Symptomatic therapy in multiple sclerosis: the role of cannabinoids in treating spasticity. Ther Adv Neurol Disord, 5:255-266. doi: 10.1177/1756285612453972. Liu, W. M., Fowler, D. W., & Dalgleish, A. G. (2010). Cannibis-derived substances in cancer therapy – an emerging antiinflammatory role for the cannabinoids. Curr Clin Pharmacol, 5(4), 281-7. Lutge, E.E., Gray, A., Siegfried, N. (2013). The medical use of cannabis for reducing morbidity and mortality in patients with HIV/AIDS. Cochrane Database Syst Rev, 4: CD005715. Lyketsos, C.G., Garrett, E., Liang, K.Y., & Anthony, J.C. (1999). Cannabis use and cognitive decline in persons under 65 years of age. Am J Epidemiol, 149(9), 794-800.

Lynch, M.E. & Campbell, F. (2011). Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. BrJ Clin Pharmacol, Nov;72(5), 735-44. Maldonado, R., Berrendero, F., Ozaita, A., & Robledo, P. (2011). Neurochemical Basis of Cannabis Addiction. Neuroscience, 181:1-17. Martín-Sánchez E, Furukawa TA, Taylor J, Martin JL. (2009) Systematic review and meta-analysis of cannabis treatment for chronic pain. Pain Med, 10:1353-1368. Mechoulam, R., Peters, M., Murillo-Rodriguez, E., et al. (2007). Cannabidiol – Recent Advances. Chemistry & Biodiversity, 4, 1678-1692. Moore, B.A., Augustson, E.M., Moser, R.P., & Budney, A.J. (2005). J Gen Intern Med, 20(1), 33-7. Moulin, D., Boulanger, A., Clark, AJ. Et al. (2014). Pharmacological management of chronic neuropathic pain: Revised consensus statement from the Canadian Pain Society. Pain Res Manag, 2014 Nov-Dec;19(6):328-35. Musty, R.E., Reggio, P., & Consroe, P. (1995). A review of recent advances in cannabinoid research and the 1994 international symposium on cannabis and the cannabinoids. Life Sciences, 56(23/24), 1933-1940. Neuhaus, O., Kieseier, B.C., Klimke, A., Gaebel, W., Hohlfeld, R., & Hartung, H.P. (2004). Cannabinoids in multiple sclerosis. Opportunity or hazard? Nervenarzt, 75(10), 1022-6. Novotna A, Mares J, Ratcliffe S, et al. (2011). A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex(®) ), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Eur J Neurol. 2011 Sep;18(9):1122-31.

Nussbaum, A.M., Boyer, J.A, Kondrad, E.C. (2011). “But my doctor recommended pot”: medical marijuana and the patient-physician relationship. J Gen Intern Med. 26(11):1364-7. Podda, G., Constantinescu, C.S. (2012). Nabiximols in the treatment of spasticity, pain and urinary symptoms due to multiple sclerosis. Expert Opin Biol Ther, 12:1517-1531. ProCont.org. Legal Medical Marijuana States and DC Laws, Fees, and Possession Limits. http://medicalmarijuana.procon.org/view.resource.php?resourceID=000881 Accessed July 26, 2013. Robson, P. (2014). Therapeutic potential of cannabinoid medicines. Drug Test Anal, 6(1-2):24-30. Rog, D.J., Nurmikko, T.J., Friede, T., & Young, C.A. (2005). Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology, 65(6), 812-9. Russo, E., Mathre, M.L., Byrne, A., Velin, R., Bach, P. J., Sanchez-Ramos, J., & Kirlin, K. A. (2002). Chronic cannabis use in the compassionate investigational new drug program: An examination of benefits and adverse effects of legal clinical cannabis. Journal of Cannabis Therapeutics, 2(1), 3-57. doi:10.1300/J175v02n01_02. Sailler S., Schmitz K., Jäger E. et al. (2014). Regulation of circulating endocannabinoids associated with cancer and metastases in mice and humans. Oncoscience, Apr 30;1(4):272-82. eCollection Saito, V.M., Rezende, R.M., Teixeira, A.L. (2012). Cannabinoid modulation of neuroinflammatory disorders. Curr Neuropharmacol, 10:159-166.

Schreiner, A.M., Dunn, M.E. (2012). Residual effects of cannabis use on neurocognitive performance after prolonged abstinence: a meta-analysis. Exp Clin Psychpharmacol, 20:420-429. Scuderi, C., De Filippis, D., Iuvone, T., et al. (2009). Cannabidiol in Medicine: A Review of its Therapeutic Potential in CNS Disorders. Phytother. Research, 23, 597– 602. Skrabek, R.Q., Galimova, L., Ethans, K., Perry, D. (2008). Nabilone for the treatment of pain in fibromyalgia. J Pain, 9:164-173. Stella ., N. (2013). Chronic THC intake modifies fundamental cerebellar functions. J Clin Invest. Aug 1;123(8):3208-10. Strasser, F., Luftner, D., Possinger, K., et al. (2006). Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinal in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the cannabis-in-cachexia-study-group. Journal of Clinical Oncology 24 (21), 3394–3400. Takagi, M., Yücel, M., Cotton, SM., et al. (2011). Verbal memory, learning, and executive functioning among adolescent inhalant and cannabis users. J Stud Alcohol Drugs. Jan;72(1):96-105. Teitelbaum, S.A., DuPont, R.L., Bailey, J.A. (2009). Cannabis (marijuana) use disorders: treatment, prognosis, and long-term medical effects. UpToDate, 18.3: September.

Tetrault, J.M., Crothers, K., Moore, B.A., et al. (2007). Effects of marijuana smoking on pulmonary function and respiratory complications: a systemic review. Arch Intern Med, 167(3), 221-8. Thaera, G.M., Wellik, K.E., Carter, J.L., Demaerschalk, B.M., & Wingerchok, D.M. (2009). Do cannabinoids reduce multiple sclerosis related spasticity? Neurologist, Nov 15(6), 369-71. Tongtong, W., Collet, JP., Shapiro, S., et al. (2008). Adverse effects of medical cannabinoids: a systematic review. CMAJ, June 178(13), 1669-1678. Tramer, M.R., Carroll, D., Campbell, F.A., Reynolds, D.J. Moore, R.A., & Quay H.J. (2001). Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ, Jul 323(7303), 1-8. Truini A, Galeotti F, Cruccu G. (2011). Treating pain in multiple sclerosis. Expert Opin Pharmacother. 2011 Oct;12(15):2355-68. Tucci, S. (2010). Addiction and pain: cannabinoid and opioid interactions. Curr Drug Targets, Apr;11(4):392. Ulugöl A. (2014). The endocannabinoid system as a potential therapeutic target for pain modulation. Balkan Med J, Jun;31(2):115-20. Vermersch P. (2011). Sativex(®) (tetrahydrocannabinol + cannabidiol), an endocannabinoid system modulator: basic features and main clinical data. Expert Rev Neurother. 2011 Apr;11(4 Suppl):15-9.

Vidinský B, Gál P, Mojzis J. (2006). Different views on the association between cannabinoids and cancer. Cas Lek Cesk. 145(6):453-7; discussion 458-9. Review. Slovak. Wade, D.T., Makela, P., Robson, P., House, H., & Bateman, C. (2004). Do cannabis-cased medicinal extracts have general or specific effects on symptoms in multiple sclerosis? Double-blinded, randomized, placebo-controlled study on 160 patients. Mult Scler, 10(4), 434-41. Ware, M.A., Fitzcharles, M.A., Joseph, L., Shir, Y. (2010). The effects of nabilone on sleep in fibromyalgia: results of a randomized controlled trial. Anesth Analg. 110:604-610. Weil, A., Zinberg, N., & Nelson, J. (1968). Clinical and physiological effects of marijuana in man. Science, Dec 3859(162), 1234-1242. DOI: 10.1126/science.162.3859.1234 Wesley, T. et al. (2012). Drug Interactions between Common Illicit Drugs and Prescription Therapies. The American Journal of Drug and Alcohol Abuse, 38(4), 334-343. Yadav, V., Bever, C., Bowen, J. et al. (2014) Summary of evidence-based guideline: Complementary and alternative medicine in multiple sclerosis Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology, March;(82):12 1083-1092.

Zajicek, JP., Hobart JC., Slade, A. et al. (2012). Multiple sclerosis and extract of cannabis: results of the MUSEC trial. J Neurol Neurosurg Psychiatry. 2012 Nov;83(11):1125-32. Zajicek, JP., Apostu, VI. (2011). Role of cannabinoids in multiple sclerosis. CNS Drugs, Mar;25(3):187-201. Zajicek, J., Fox, P., Sanders, H., et al. (2003). Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomized placebo-controlled trial. Lancet, 362(9395), 1517–26. doi: 10.1016/s0140-6736(03)14738-1

• California Department of Public Health. (2010). California’s Medical Marijuana Program. Retrieved from www.cdph.ca.gov/programs/mmp

• Concept 420. (2010). Marijuana History & Timeline. Retrieved from http://www.concept420.com/marijuana_cannabis_history_timeline.htm

• Drug Policy Alliance. (2010). Marijuana. Retrieved from http://www.drugpolicy.org/marijuana/medical/

• Drug Policy Alliance. Marijuana Policy Project. (2010). Marijuana health effects. Retrieved from http://www.mpp.org/library/marijuana-health-effects.html

• Medical Marijuana. (2010). Medical Literature. Retrieved from http://www.medicalmarihuana.ca/for-doctors/marijuana-literature

• Medline Plus: Health Information from The National Library of Medicine. (2010). Marijuana. Retrieved from http://www.nlm.nih.gov/medlineplus/marijuana.html

• National Institute on Drug Abuse. www.drugabuse.gov/

• National Institutes of Health. (2010). Workshop on the Medical Utility of Marijuana.

Retrieved from http://www.nih.gov/news/medmarijuana/MedicalMarijuana

• Recent Research on Medical Marijuana. (2010). Emerging Clinical Applications for Cannabis and Cannabinoids: A Review of the Recent Scientific Literature, 2000-2010, Retrieved from http://norml.org/index.cfm?Group_ID=7002

• Recommendations of The National Institute on Drug Abuse National Advisory Council. (2010). Provision of Marijuana and Other Components From Scientific Research, Retrieved from http://www.drugabuse.gov/about/organization/nacda/MarijuanaStatement.html

• Schaffer Library of Drug Policy. (2010). Marijuana/Hemp Historical Information, Retrieved from http://www.druglibrary.org/schaffer/hemp/history/history.htm

• http://www.scribd.com/doc/68908151/Kofalvi-Cannabinoids-and-the-Brain

Canadian Consortium for the Investigation of Cannabinoids (CCIC) Accredited cannabinoid education (ACE) programs Interactive Informed by needs assessments, expert faculty www.ccic.net

International Cannabinoid Research Society (ICRS) 25th Annual Symposium July 2015, Halifax, Nova Scotia www.icrs2014.org

International Association for Cannabinoid Medicine (IACM) www.cannabis-med.org

Patients out of Time Conferences and resources www.medicalcannabis.com

The Answer Page: www.theanswerpage.com - online CME, accredited by Massachusetts Medical Society