Cannabis. Medical Marijuana: The Science, not the Politic. Alan P. Agins, Ph.D

Transcription

1 Objectives: Medical Marijuana: Examining the Science, Not the Politics Alan P. Agins, Ph.D. President: PRN Associates, Ltd Continuing Medical Education Tucson, AZ Upon completion of this learning activity, the participant will be able to: Review the basic and clinical pharmacology of botanical and synthetic marijuana and their active constituents. List various types and dosage formulations of medical marijuana available to patients. Discuss a number of possible uses for, and clinical study data regarding, the effectiveness of medical marijuana. Recognize potential physical and psychiatric side effects and drug interactions that may occur with the use of marijuana. Disclosure: The speaker has no financial or other conflicts of interest to disclose Any mention of unlabeled uses for specific medications will be prefaced verbally to that regard Cannabis Species Cannabis sativa grows worldwide Tall plant with long, thin light green leaves used for fibers to make cloth and rope, but also used for psychoactive properties. Cannabis indica Plentiful in Mideast, India, and Central Asia Short plant with broad dark leaves Mainly used for psychoactive resins. Indica plants have high THC:CBD ratios Sativa plants have high CBD:THC ratios Cannabinoids Plant Leaves, flowers, stems, seeds collected from Cannabis sativa plant (aka phytocannabinoids) Purified Purified from plant sources: Cannabidiol (CBD), 9 tetrahydrocannabinol (THC), and Sativex (mixture of THC and CBD) Synthetic Synthesized in laboratory: Nabilone, Dronabinol, others in development as potential cannabinoid agonists and antagonists for therapeutic use Endogenous (2-AG, AEA) Cannabis Complex alkaloid mixture of more than 400 compounds derived from the cannabis sativa plant 60 different compounds described with activity on the cannabinergic system 9 -tetrahydrocannabinol - THC Tetrahydrocannabinolic acid (THC-A ) Cannabidiol - CBD Cannabinol - CBN Cannabigerol Cannabichromene Cannabicyclol Cannabielsoin Cannbitriol Δ 8 -tetrahydrocannabinol 9 tetrahydrocannabivarin Miscellaneous Alan P. Agins, Ph.D

2 Synthetic THC nabilone dronabinol Synthetic Agents Generic medication Nabilone C-II Dronabinol C-III Nabiximols THC/CBD mouth spray Trade name(s) Country Licensed indications Cesamet Marinol Marinol Sativex U.S., Canada U.S., Canada U.S. Antiemetic (treatment of nausea or vomiting) associated with chemotherapy that has failed to respond adequately to conventional therapy Antiemetic (treatment of nausea or vomiting) associated with chemotherapy that has failed to respond adequately to conventional therapy Anorexia associated with AIDS related weight loss Canada, New Limited treatment for spasticity Zealand, and neuropathic pain associated eight European with multiple sclerosis and countries intractable cancer pain. as of 2013 Cannabinoids Endogenous - Endocannadinoids Discovered in 1992 Anandamide (AEA) 2-arachidonoylglycerol ( 2-AG) Activity is limited by metabolism or reuptake 2-AG MAGL Arachidonic Acid AEA FAAH Endocannabinoids Different cells produce different compounds Different stimuli: 2 AG synthesized & released via voltage-sensitive calcium channels involves PLC Anandamide after activation of metabotropic glutamate receptors involves PLD Different actions: 2-AG full agonist, attains higher levels in CNS, has highest CB 1 and CB 2 relative intrinsic activities. Anandamide partial agonist, Affinity for CB1>CB2. Also binds to TRPV1 receptors (stimulate/inhibit) and others Cannabinoid Receptors CB 1 (metabotropic G-protein coupled) Higher in CNS than PNS On neuronal axon terminals (presynaptic) High concentration in mesolimbic system, cerebellum, cerebral cortex, spinal dorsal horn and periaqueductal gray and peripheral nerves Hippocampal Pyramidyl Neuron Up to 30,000 excitatory connections - Glutamate - Up to 2,000 inhibitory connections - GABA - Alan P. Agins, Ph.D

3 Cannabinoid Receptors CB 1 (metabotropic G-protein coupled) Highest on GABA neurons in forebrain Highest on Glutamate releasing neurons in hippocampas and cerebellum Highly expressed in axon terminals within medullary nuclei which control emesis (ie., postrema) Relatively low levels within medullary respiratory control centers High in Periaqueductial Grey area Differences in distribution within CNS structures allows for specialized control Endocannabinoids Example: Spinal cord Descending NA input (antinociceptive) from the brainstem usually under inhibitory control by GABA. Cannabinoids modulate activity by reducing GABA release freeing NA neurons to more freely release NE in Dorsal horn and ganglia net result attenuation of incoming pain signals Endocannabinoids Retrograde neural transmission Released from depolarized postsynaptic neurons in a calciumdependent manner Act on presynaptic cannabinoid receptors (retrograde) to suppress neurotransmitter release. Activation of the CB1 causes suppression of synaptic transmission in various regions of the CNS. Can affect both excitiatory (Glutamate) and inhibitory (GABA) pathways involved in neuroplasticity. Acetaminophen - FYI Blocks AE AM-404 Also a TRPV1 agonist and inhibitor of cyclooxygenase [COX-1 and COX-2] But flooding the brain with exogenous CB1 agonists/partial agonists None selective stimulation of CB receptors in all regions affecting memory, emotion, cognition, appetite, decision-making, movement, etc Cannabinoid Receptors CB 1 in the Periphery Found in majority (89%) of DRG sensory neurons - similar degree of localization in nociceptor & non-nociceptor excitatory (glutamatergic) terminals of Aδ- and C-fiber primary afferents in the spinal cord Also found in pituitary, thyroid, and adrenal glands; male & female reproductive system; liver, adipocytes, lungs, kidney In macrophages, mast cells, sebaceous cells, keratinocytes Number of human tumor cells Alan P. Agins, Ph.D

4 CB 2 Cannabinoid Receptors Located peripherally, with high density on immunemodulating cells, including monocytes, macrophages, B and T-cells highest expression on B-lymphocytes, NK cells, brain microglial cells and astrocytes Modulates cytokine release and immune response May have a protective effect on autoimmunity and inflammation Pharmacodynamics of various cannabinoids THC Anandamide THC Targets receptors in a manner far less selective than endocannabinoid molecules Mental effects Euphoria, relaxation and wellbeing Increased appetite ( munchies ) Talkativeness, disinhibition Physical effects Vasodilator (systemic and portal) Bronchodilation (short-term effect only) THC Adverse effects include decreased episodic memory; decreased attention, concentration, and working memory; decreased decisionmaking capabilities; increased risktaking; decreased inhibitory control; and decreased psychomotor control. Highly variable Many people dislike it and discontinue use Influenced by surroundings Cannabidiol (CBD) Very low affinity for CB 1 and CB 2 receptors Acts as indirect antagonist of THC Powerfully opposes the action of THC at the CB1 receptor, muting psychoactive effects of THC Mechanism unknown possibly effects other neurotransmitters (ie., adenosine, serotonin) Stimulates release of endogenous 2-AG that activates both CB1 and CB2 receptors Suppresses the enzyme fatty acid amide hydroxylase ( FAAH ) the enzyme that breaks down anandamide. Cannabidiol (CBD) Additionally, CBD... Stimulates TRPV-1 receptor, which is known to mediate pain perception, inflammation and body temperature (useful for Neuropathic pain). May exert an anti-anxiety effect by activating adenosine receptors / also neuroprotection At high concentrations, directly activates 5-HT 1A serotonin receptor (possible antidepressant effect) Alan P. Agins, Ph.D

5 Cannabidiol (CBD) Additionally, Stimulates PPAR gamma (and indirectly alpha) receptors Believed to decrease angiogenesis May decrease tumor growth / metastisis?? May decrease abberant angiogenesis in nephropathy, neuropathy and retinopathy???? PPARγ activation degrades amyloid-beta plaque Polymorphisms in gene encoding for PPARα are associated with schizophrenia PPAR-alpha activation can decrease dopamine release And wait... There s more CBD... May ihhibit COX-2 (CBD-Acid) anti-inflammatory, anti-proliferative Potent inhibitor of oxidative and nitrosative stress related to its neuroprotective effects with implications for the treatment of Alzheimer's, Huntington's and Parkinson's diseases. Attenuates high-glucose-induced mitochondrial superoxide generation and NF-κB activation, along with the expression of adhesion molecules = neuroprotective / antioxidant/ anti-inflammatory effects CBD Tolerability Chronic high doses of up to 1500 mg per day are well tolerated and produce no noticeable physiological effects. Optimal dosage levels of CBD are uncertain due to a lack of human studies. Evidence suggests medical benefits of CBD disappear when dosages become excessive Bell shape dose-response Fewer than 5% of recent cannabis samples tested show appreciable amounts of CBD Differing Actions of: THC + Appetite stimulant, antiemetic, antispasmodic, analgesic, anti-tremor actions CBD Anti-inflammatory, antianxiety, anticonvulsant, antipsychotic, antioxidant, neuroprotective, immunomodulator The THC CBD paradox THC is not necessarily the most relevant cannabinoid with medical applications Research indicates that CBD mitigates euphoria associated with THC - resulting in efforts to remove CBD from marijuana (genetically manipulate) Composition of marijuana has changed significantly over past two decades due to hybridization. Some strains may have 30% THC w very low CBD Others have higher CBD concentrations (since it was found to be a potential money-maker) Cannabis pharmacokinetics Cannabinoids are highly lipophilic and lipoprotein bound Vd = 10 L/Kg Blood concentrations are therefore not directly related to drug effect A real issue in determing a legal limit for DUI, etc Release from lipid stores and enterohepatic recirculation account for retention of THC and terminal half life > 4 days in frequent users. Alan P. Agins, Ph.D

6 Pharmacokinetics of Marijuana Oral Dronabinol, Nabilone Edible marijuana products (cookies, brownies, cakes, beverages, popcorn, etc) Extensive first pass metabolism CYP450: CYP2C9 and 3A4 Only 10-20% reaches systemic circulation unchanged High intra-patient variability! Takes minutes to achieve an effect Hard to titrate Peak level varies from 1 5 hours Generally longer duration of acivity Pharmacokinetics of Marijuana Oral Blood levels of marijuana decline quickly Distribution / redistribution Elimination from the body is slow Cannabinoids persists in fatty tissue t½ absorption 0.8 hr t½ distribution 3.8 hr t½ for elimination hr Sensitive urine screening tests can detect THC-COOH more than 2 weeks following last use Pharmacokinetics of Marijuana Smoke or Vaporization Onset of action within seconds Bioavailability of THC varies according to the depth of inhalation, puff duration and breath-hold Bioavailability: 10-25% ~ 50% of THC content delivered into smoke ~ 60% of smoke may be metabolized in lung Peak concentrations are high & occur within minutes t½ distribution 0.5 hr t½ for elimination 30 hr. Pharmacokinetics of Marijuana Vaporization Similar pharmacokinetics as smoking Vaporizer heats cannabis to F Causes THC / CBD to evaporate into a gas without combustion of plant material Therefore - lower proportion of carbon monoxide and other toxic chemicals than smoking Percentage of vaporization appears to be dose dependent Lower doses vaporize to greater extent THC metabolized by CYP2C9 and CYP3A4 CYP2C9 inhibitors (might reduce THC elimination) amiodarone, cimetidine, cotrimoxazole, metronidazole, fluoxetine, fluconazole, voriconazole Pharmacogenetics: Poor metabolizers shown to have THC concentrations ~ 3x higher than those of normal metabolizers White >> Black > Asian CYP3A4 inhibitors (might reduce THC elimination) clarithromycin, e-mycin, cyclosporine, verapamil, itraconazole, voriconazole, ritonivir, colbistat, others Potential Drug Interactions - CBD Limited data may not be of clinical significance with low to moderate doses Reported to be strong inhibitor of CYP2C19 and CYP3A4 (both inhibition and inactivation) Because drugs metabolized by CYP2C19 often have other pathways, if the patient is deficient in CYP2C19, the other pathways may become more important CYP2C19-3% to 5% of Caucasians PMs 12 25% of Asians PMs Some drugs cleared primarily via CYP2C19: Citalopram, escitalopram, sertraline, PPIs Clopidogrel relies on this isoform for activation Alan P. Agins, Ph.D

7 Potential Drug Interactions In vitro studies indicate that THC & CBD unlikely to inhibit CYP450 enzymes. Induction of P450 Smoked marijuana (but not PO administration) can lead to induction of CYP1A2 May increase clearance of: Olanzepine, cloazpine, tizanidine, duloxetine, mirtazapine, zolmitriptan, triamterene May occur with as little as smoking 2 joints or more of marijuana per week. Unlikely an issue with vaporization Potential Drug Interactions Pharmacodynamic interactions should be expected between marijuana and drugs with: Sympathomimetic activity tachycardia, hypertension Central nervous system depressants drowsiness, ataxia Drugs with anticholinergic effects tachycardia, drowsiness, dry mouth, blurred vision, diminished Short-term memory Medical Marijuana (cannabis) vs. approved oral THC Medications: Which is better? THC medications still have psychoactive effects Mix of chemicals in medical marijuana that moderate THC s psychoactive effects Not present in synthetics Medical marijuana may be cheaper Not made/patented by pharmaceutical industry Medical Marijuana vs. THC Medications Which is better? FDA approval assures that medications are effective, safe, and properly labeled FDA cannot evaluate medical marijuana as a drug since it is a plant, not a standardized formulation Medical marijuana is different everywhere, depending on how it is bred, under what conditions it is grown, etc. No way to know if medical marijuana is pure. Can be contaminated by pesticides, mold, fungus. Medical Marijuana (cannabis) vs. approved oral THC Medications: Which is better? Smoked medical marijuana takes effect in minutes; THC medications take over an hour Instant feedback allows users to titrate accordingly Due to rapid relief, may consume less if smoked When swallowed, THC absorption is more erratic, and less concentrated THC effects more unpredictable and variable, possibly less effective Medical Marijuana vs. THC Medications Are THC Medications Better? Difficult to approve something that is smoked as medicine Negative effects of smoking Depending on type of marijuana, can undergo different types of chemical changes when burned No standard measurement of dosage (inhalations vary by the individual, unlike pills) Alan P. Agins, Ph.D

8 Medical Marijuana Key questions include: Is it safe? Is there adequate evidence for its efficacy? If so, for what conditions is it effective? If it is sold in dispensaries rather than on street corners, should it be considered "medical"? If it is "medical," can it still be abused? Is marijuana medical, or do certain components of marijuana have medical benefit and are safe? Why do people use medical marijuana REASON FOR USE % REPORTING REASON Pain Relief 82.6% To Sleep 70.6% To Relax 55.6% Muscle Spasms 41.3% Anxiety 38.1% To Stimulate Appetite 38.0% Nausea 27.7% Depression 26.1% Medical Marijuana approved indications Wasting Syndrome One of the strongest effects of the marijuana high is appetite stimulation 53%-70% of HIV+ individuals who use marijuana report using it to stimulate their appetite Marijuana also dulls the vomiting reflex 33%-66% of HIV+ individuals who use marijuana report using it to control nausea Antiemetic effects Animal Studies have shown that this effect appears to be CB1 dependent. 60 Peer-Reviewed Studies on Medical Marijuana Medical Studies Involving Cannabis and Cannabis Extracts ( ) w.resource.php?resourceid= Pain and Cannabinoids CB1 stimulation Decrease peripheral & spinal transmission of ascending pain signals (antinociceptive) Activate descending inhibitory pathways from PAG area Alter perception of pain? CB2 stimulation Decrease peripheral and/or central inflammatory pain (hyperalgesic) signalling May have most robust effects on neuropathic pain remember, there s an element of neuropathy in all forms of chronic pain. Pain 2015 study found 80% of M.M. users reported substituting cannabis for prescribed medications, particularly among patients with pain-related conditions. A literature review of 38 studies evaluating medical marijuana s efficacy for treating pain found that 71 percent (27) concluded that cannabinoids had empirically demonstrable and statistically significant pain relieving effects, whereas 29 percent (11) did not meta-analysis of 79 studies found a 30 percent or greater reduction of pain with the use of cannabinoids compared to placebos. Alan P. Agins, Ph.D

9 Pain Retrospective survey of 244 medical cannabis patients in Michigan found that cannabis use was associated with a 64% lower opioid use in patients with chronic pain 2014 JAMA - report that states with M.M. laws are associated with a significant reduction in mortality from opioid abuse; these states saw a 25 percent reduction in opioid overdose deaths, compared to states without such laws, resulting in 1,700 fewer deaths in 2010 alone Used in combination with opioid analgesics, cannabis may lower opioid dose requirements, side effects, cravings and withdrawal severity Pain Many pain clinicians and researchers agree that cannabinoids are clinically promising chemical compounds, and there is a critical need for robust research on herbal cannabis to identify targets for medical development American Pain Society June 23, 2016 Multiple Sclerosis Sativex reduced spasticity in MS patients (2014) MS patients using cannabis reported more fatigue, numbness, tingling or pain, and heat sensitivity, and said they were "more disabled (2014) Conflicting findings on use of Sativex for MS central neuropathic pain (2013) Cannabis extract relieved muscle stiffness in patients with MS (2012) Smoked cannabis helped with symptom and pain reduction in MS patients (2012) MS patients using cannabis had significantly poorer cognitive skills and were twice as likely to be globally cognitively impaired (2011) Epilepsy CBD is anticonvulsant in many acute animal models, but there are limited data in chronic models. Currently no Class I, II, or III studies All anecdotal reports to date Survey of 19 parents: CBD-enriched formulations 84% improved: 11% seizure-free, 42% with more than 80% decrease GW Pharmaceuticals is developing a pure CBD extract known as Epidiolex, which is undergoing FDA orphan drug studies for treatment of pediatric epilepsy. Is Marijuana an Effective Treatment for Epilepsy (Seizures)? CU School of Medicine - Current Clinical Study recruiting Dravet syndrome, also known as Severe Myoclonic Epilepsy of Infancy (SMEI) Charlotte's Web strain of medical marijuana processed into a marijuana extract that is high in cannabidiol (CBD) content, called Realm Oil and Alepsia. Does not induce the psychoactive "high" typically associated with recreational marijuana strains (high THC) In September 2014, the content was measured at 0.3% THC and it was classified "as a hemp-derived food product". Epilepsy - Interesting study design issue: Because the trial was open-label and without a control group, a main concern is the placebo effect, which previous studies have shown might be especially strong with marijuana-based products. A 2015 study carried out at the University of Colorado revealed that 47 percent of patients whose families had moved to Colorado for cannabis-based epilepsy treatment reported improvement, compared with 22 percent in people who already lived there. Alan P. Agins, Ph.D

10 Anxiety / PTSD Marijuana use is significantly higher in those with anxiety Limited use - may cause relaxation but also panic, paranoia, and psychosis Regular use: Short-term: may decrease anxiety Long-term: may increase anxiety and decrease effectiveness of anxiety meds Variable effects may be due to different components Marijuana and THC Modest doses: decreased anxiety High doses: panic, psychosis, phobia CBD - More consistent anti-anxiety effect Alzheimers Disease In vitro (cell culture) and animal studies indicate extremely low doses of THC reduce the production of amyloid beta and prevent abnormal accumulation Other studies show that the combination of THC and CBD exhibits a better profile than each cannabis component alone Low concentrations of THC also selectively enhance mitochondrial function CBD has been linked to neuroprotection THC may reduce B-amyloid accumulation No large, placebo-controlled, randomized, doubleblinded clinical trials have been conducted on the effect of whole-plant cannabis in humans Cancer Cannabinoids reported to have antitumor effects by various mechanisms: induction of apoptosis, inhibition of cell growth, and inhibition of tumor angiogenesis, invasion and metastasis. Research has shown positive effects on prostate, breast, colon, liver, pancreatic, glial and hematological malignancies (in vitro and in animals studies) Cannabinoids appear to kill tumor cells but do not affect their nontransformed counterparts and may even protect them from cell death. Some effects mediated by THC, some by CBD May also potentiate actions of some chemotherpeutic drugs Research Issues Marijuana is a Schedule I drug a barrier to conducting prospective RCTs, DB w/ placebo Studies are short - two weeks average, ranging from a few hours to one year Difficult to generalize between oral TCH preps and smoked cannabis Impossible to Blind a study with a psychoactive, particularly with cross-over designs. Cannabis - Toxicology THE DOWN SIDE (there s always a downside) Very wide therapeutic index No known direct deaths Fatal dose is unknown, but implied from animal studies may be 4000 to times the highest recreational dose. Implied association with deaths due to underlying heart conditions especially arrythmias/ heart attacks; not confirmed Alan P. Agins, Ph.D

11 Regional Brain Abnormalities Effects on cognition Associated with Long-term heavy Cannabis Use 15 long term (>10 years) and heavy (>5 joints daily) cannabis using men compared with 16 age matched non using controls by MRIs of brains Cannabis users had bilaterally reduced hippocampal and amygdala volumes p=.001 Increase in positive symptoms (psychotic) p<.001 Significantly worse performance on measures of verbal learning p<.001 All worse if started in early life (adolescence) Cannabis and Psychosis Risk Can adolescent marijuana use contribute to developing psychosis later in adulthood? Appears to depend on genetic vulnerability AKT1 gene governs an enzyme that affects dopamine signaling. Risk depends on variants Source: Di Forti et al. Biol Psychiatry Marijuana and Psychosis Risk COMT also genetically variable. Governs catabolism of dopamine Met and Val variants (SNP) Source: Caspi et al. Biol Psychiatry Marijuana and Driving Acute cannabinoid intoxication adversely impacts processing speed, attention, learning and recall, perception of time and velocity, reaction time and psychomotor abilities in a dose-dependent fashion Studies of acute THC use have found a 50% increase in risk of MVAs Individual variability greater than for alcohol due to tolerance, differences in smoking technique and difference in THC content Marijuana and Driving Cannabis use associated with increased awareness of impairment (e.g., altered perception of time and speed), which results in compensatory behavioral strategies. Over-diligence, compensation Pronounced with highly automatic driving functions but less pronounced with complex tasks that require conscious control opposite from that seen with alcohol Li MC, Brady JE, DiMaggio CJ, et al. Marijuana use and motor vehicle crashes. Epidemiol Rev. 2012;34:65-72 Hartman RL, Huestis MA. Cannabis effects on driving skills. Clin Chem. 2013;59(3): Potential for Abuse/Dependence Regular and prolonged use can result in activation of reward pathways in Nucleus Accumbens Regular use associated with down-regulation of CB1 receptors Marijuana abuse/dependence most common among individuals with pre-existing mental health disorders In 2011, 22.9% of people in US who received addiction treatment received treatment for marijuana use disorders Average adult entering treatment for marijuana abuse/dependence has used daily for ten years, tried to quit six times Newer strains with higher THC may increase the numbers Alan P. Agins, Ph.D

12 Other areas of concern Respiratory Cannabis-smoking causes chronic bronchitis in 20-30% (cough, sputum) Histopathological changes in bronchi: acute and chronic bronchitis and dysplasia cancer? Cardiovascular complications Raises blood pressure & heart rate % 4.8 times risk of heart attack in hour after use GOING FORWARD Where Are We Today? Unresolved Issues DC Many studies are with standardized preparations some not available in the US Products that are available Many are non-standardized, non-regulated, and high in THC How to translate research studies with oral preparations to smoked products and visa versa? Are some hybrids more effective or safer? What dose, frequency, and preparation is best? Can it be combined with meds for synergy? Relative safety and effectiveness of marijuana vs conventional meds or procedures? What we need Movement of Cannabis to Schedule II so medical research can be conducted more readily Studies of specific strains / extract combinations, routes of administration, long-term safety, etc Low, medium, and high THC CBD alone or in combination with THC Best routes of administration Standardization of products Oversight on dispensaries (quality and safety testing) Thoughtful, evidence-based risk:benefit analysis Clinical practice recommendations: Monitor patients the same as for treatment with opioids or other controlled substances. Consider a Medical Marijuana Agreement Patient follow up should assess progress toward achieving treatment goals, incidence of side effects, and evidence of psychobehavioral changes. Alan P. Agins, Ph.D

13 Remember... All but the most biased reviews articles on this topic conclude with generic statements, such as.. "Medical cannabis appears to have some benefit in patients with certain conditions. Fitzcharles MA, Clauw DJ, Ste-Marie PA, Shir Y. The dilemma of medical marijuana use by rheumatology patients. Arthritis Care Res. 2014;66: Clinical practice recommendations: Know federal and state laws governing use of medical cannabis Be clear with pts re: goals for therapeutic cannabis Counsel patients about routes of administration and potential benefits and risks, based on scientific evidence and individual symptoms, conditions and comorbidities Advise patients of limitations due to lack of herbal/substance uniformity and regulatory oversight "Simply acceding to patient demands for a treatment on the basis of popular advocacy, without comprehensive knowledge of an agent, does not adhere to the ethical standards of medical practice...any recommended therapy requires proof of concept by sound scientific study that attests to both efficacy and safety." Clinical practice recommendations: Monitor patients the same as for treatment with opioids or other controlled substances. Consider a Medical Marijuana Agreement Patient follow up should assess progress toward achieving treatment goals, incidence of side effects, and evidence of psychobehavioral changes. Fitzcharles MA, Clauw DJ, Ste-Marie PA, Shir Y. The dilemma of medical marijuana use by rheumatology patients. Arthritis Care Res. 2014;66: Clinical practice recommendations: Know federal and state laws governing use of medical cannabis Be clear with pts re: goals for therapeutic cannabis Counsel patients about routes of administration and potential benefits and risks, based on scientific evidence and individual symptoms, conditions and comorbidities Advise patients of limitations due to lack of herbal/substance uniformity and regulatory oversight Thanks for attending Alan Alan P. Agins, Ph.D