The Endocannabinoid System and Harm Reducon with Cannabis

Gregory Gerdeman, PhD Mary Lynn Mathre, RN, MSN, CARN Cannabis is real medicine

• Cannabis is safe medicine

• Studying cannabis led to discovery of the Ethan Russo, MD ENDOCANNABINOID SYSTEM (ECS) • Cannabinoid receptors (acvated by THC) • Endogenous THC-like cannabinoid signaling molecules (endocannabinoids) • Endocannabinoid metabolic enzymes

• ECS is a “master regulator” of human physiology Effects of cannabis in the brain are undeniably the root of human aracon and aversion – both – to this plant that has been culvated and ulized as medicine for longer than any historical record. A meline of major discoveries in the research of cannabis and the cannabinoids

1964 – Gaoni and Mechoulam isolate Δ9-THC from hashish

1980’s – “Tetrad” test of cannabinoid effects is developed, and used to test synthec analogs.

1988 – CB1 cannabinoid receptor is idenfied.

1992 – Anandamide is discovered as first endocannabinoid

The focus of cannabis research in the 2nd half of the 20th century was not so even-handed.

• How does marijuana make someone…

• Stoned

Led to … The • Lazy endocannabinoid • Addicted (including to other drugs) system

• Violent!!!

• Mentally impaired for life… brain damage model (THC as neurotoxin)

• Insane (paranoid schizophrenia)

Mainstream scienfic concepons of the endocannabinoid system are now well beyond the exclusive domain of drug abuse research …

Endocannabinoid signaling as a synapc circuit breaker in neurological disease István Katona & Tamás F Freund Nature Medicine, Sept 2008, pp923 - 930 Endocannabinoids as guardians of the nervous system

Physical trauma or seizure acvity rapidly and significantly elevates endocannabinoids in the brain.

Administering endocannabinoids to animals:

• aenuates many kinds of chemically or electrically induced seizure acvity

• reduces the extent and severity of brain injury following experimentally inflicted head wounds

• reduces the severity of inflammaon that naturally follows brain injury, and which has enormous clinical consequence for recovery What about drug abuse and addicon?

Prevailing NIDA-funded paradigm is exclusively one of risk, abuse and addicon.

Yet, clinical use of cannabis to successfully treat drug abuse has a long history that includes esteemed doctors.

Results of preclinical animal research in the modern NIDA era are also uerly inconsistent with labeling cannabis simpliscally as a “dangerous and addicve drug” and having “no accepted medical use.” 1988 – 1990 A cannabinoid receptor in the brain!

Uptake of [18F]MK-9470 in human brain Prominence in reward centers and circuits relevant to addicon

Burns H. D. et.al. PNAS 2007;104:9800-05 Herkenham, M. et.al. PNAS 1990; 87: 1932-36 Neurocircuitry of addicon It’s all much more complicated than dopamine Principal neurotransmiers: Glutamate – excitatory (+) GABA – inhibitory (-)

Dopamine – can enhance or decrease excitability

Dopamine is much more than a “pleasure signal”

Research into dopamine as a trigger to reward and addicon has helped drive neuroscience outside the addicon paradigm.

• Acon selecon • Movated behavior • Motor programs / sensorimotor integraon • Implicit memory (procedural, non-declarave) Koob, G. and Volkow, N. (2010) AND Neuropsychopharm Reviews 35: 217-238 • Addicon as a pathology of habit formaon

Neurocircuitry of addicon It’s all much more complicated than dopamine Principal neurotransmiers: Glutamate – excitatory (+) GABA – inhibitory (-)

Dopamine – acetylcholine – pepdes

Endocannabinoids regulate ALL of the above

As dopamine drug-abuse model expanded foundaonal understanding of how the brain works, research into cannabis as a drug of abuse is leading to similar revoluons in understanding nervous system funcon, and homeostac wellbeing.

Major findings • Endocannabinoids and retrograde synapc signaling • ECS migates neuroinflammaon Koob, G. and Volkow, N. (2010) Neuropsychopharm Reviews 35: 217-238 • THC is anomalous as a drug of abuse

Retrograde synapc signaling by endocannabinoids

eCB signaling provides negave feedback to excitatory synapses. Glutamate (+) Neuron 1 -blocks excitotoxicity and seizures -regulates informaon processing -mechanisms of learning & memory

- including the circuitry of pleasure/ eCBs reward and decision-making

Neuron 2 eCB signaling also acts to DISINHIBIT certain neurons by tuning down inhibitory synapses

-regulates informaon processing - mechanisms of learning & memory - filtering and gain at synapses Gerdeman & Schechter (2010) in The Pot Book Excitotoxicity

An EXCITATORY synapse is formed when an axon terminal EXCITES its target cell to elicit a response.

Presynapc axon release site

An excitatory glutamatergic synapse Postsynapc target dendrite (or cell body)

Animaon from: Katona, I and Freund, T (2008) Nature Medicine 14: 923-930

hp://www.nature.com/nm/journal/v14/n9/extref/nm.f.1869-S1.swf Mulple cannabinoid pathways to brain resilience and repair

Excitotoxicity (cell damage due to excessive excitaon and calcium signaling)

Reacve oxygen species (ROS) and nitrosylaon - cannabinoids as anoxidants

Microglial acvaon Innate Immune Response

Pro-inflammatory cytokines Neuroinflammaon

Vasodilaon and cerebral perfusion

Neurogenesis – growth of new neurons from neuronal stem cells

Synapc modulaon by endocannabinoids Intrinsic defense against excitotoxicity

A mechanism intrinsic to numerous circuit-level processes of learning & memory

Encoding of explicit, declarave memory. • Episodic memory, spaal orientaon • involving hippocampus

Consolidaon and exncon of behavioral habits, procedural memory • smulus-response behavior in rodent models • automac rounes, resistant to devaluaon. • These kinds of S-R habits are facilitated by amphetamines • Impaired by blocking CB1 cannabinoid receptors, BUT • NOT facilitated by exogenous cannabinoids and … • Exncon or unlearning of S-R habits is also hampered by blocking CB1 receptors. • Involving OFC, striatum and mesolimbic dopamine systems (basal ganglia)

Neurobiological axis of stress • Fear percepon and its translaon into acute HPA stress responses • Terminang the HPA stress response (long loop corsol feedback) • Exnguishing fearful/traumac memories • Involving PFC, amygdala, hypothalamus So, is cannabis an addicve drug … how does ECS fit the drug abuse paradigm? Condioned Place Preference (CPP)

THC and synthec cannabinoids are found to be anomalous Drug-paired compared to typical drugs of context abuse.

Many studies fail to find place preference or instead find place aversion to CBs.

Posive CPP results, when found, are narrowly dose dependent.

(Panagis, et al., 2007)

Parker et al. (2004) : CPP to smulants reversed by THC or CBD or rimonabant!

eCBs are important for the neural encoding and/or recall of behavioral context! Drug abuse paradigms… how does ECS fit? Self-administraon

Cue!

Drug of interest (i.e., THC or synthec CB1 agonist)

Again, CB agonists are highly atypical… most methods requiring drasc restraint (esp. in mice), food or water deprivaon, prior cocaine self-admin, or a combinaon of these. (Panagis, et al., 2007) But see studies by S. Goldberg, Z. Jusnova and colleagues. But, why? Cannabis is oen a rewarding experience in humans!

Studying the ECS in detail is revealing:

• insight into how cannabis is rewarding (how it’s different from the dopamine model)

• neurobiology of why dependence/addicon CAN occur

• how frequent is a “cannabis dependence disorder” (DSM V)

• Genec variaon in ECS genes ( FAAH, CNR1) may contribute suscepbility to addicon •and anxiety

•and depression (drug-resistant)

By far the most compelling theme that has emerged from cannabis addicon research – and most consistent across groups – is the evidence that endocannabinoid signaling modulates cue-induced relapse to the seeking of OTHER drugs. Reinstatement of drug seeking

Protocol:

Subjects learn to self-administer drug whenever a CUE indicates drug availability. Cue!

Drugs!!! Reinstatement of drug seeking

Protocol:

Subjects learn to self-administer drug whenever a CUE indicates drug availability.

Followed by…

Prolonged absnence No cue. Lever pressing yields no drug. Drug seeking behavior is exnguished. Reinstatement of drug seeking

Protocol:

Subjects learn to self-administer drug whenever a CUE indicates drug availability. Cue!

To seek or not

Prolonged absnence to seek? No cue. Lever pressing yields no drug. Drug seeking behavior is exnguished.

Followed by…

Reinstatement Pretreang animals with CB1-acng compounds BLOCK reinstatement of drug seeking in many studies. Drug abuse paradigms Reinstatement of drug self-administraon CB1 receptors are found to be necessary for condioned (cue- directed) reinstatement of drug seeking behaviors. • A model of relapse in drug addicts

Consistent for numerous psychosmulant drugs of abuse: • Cocaine (De Vries, Nat Med, 2001) • Nicone (Cohen, Neuropsychopharm, 2005;) • Sucrose and nicone (De Vries, Behav Brain Res, 2005) • Methamphetamine (Anggadiredja, Neuropsychopharm, 2004) * also blocked relapse with THC*

CBD found to block heroin reinstatement (Ren, J. Neurosci. 2009)

CB1 blockade also reduced breakpoint for cocaine self-admin (Soria, Neuropsychopharm, 2005; Orio et al. J Neurosci, 2009)

Take home: In translang to clinical reality, do not oversimplify...

The human reward circuitry is not a simple on/off switch, even in the addicted brain.

Nonetheless the circuits of stress, reward, habit learning and relapse to compulsive drug seeking are finely modulated by eCB signaling... targeng this system makes at least as much sense as other pharmacotherapeucs developed by targeted medicinal chemistry.

Need to study human populaons and real world controlled use of cannabis as a treatment modality

What about the risks?

All pharmacotherapies have risks and must be compared to the danger of the paent's condion.

Numerous recent studies seem to find that the presence of CBD can migate or eliminate some risks of THC idenfied in lab models of chronic use.

According to preclinical research, CBD as a regulator might: • elevate eCB levels in extracellular fluid • block or inhibit THC acons at CB1 as an allosteric antagonist

Other preclinical findings relevant to ECS and addicon from human genomics.

Polymorphisms in CNR1 or FAAH might predict: • substance use disorders • anxiety disorders, or forms of stress • depression or other affecve disorders

This field is young, but serious… the pracce of nursing should be at the forefront of acquiring and implemenng new knowledge.

Cannabis as an “exit drug” for the treatment of addicons

Observaonal human research supports it - Jamaican “roots daughters” study (Dreher)

- Therapeuc use of cannabis by crack addicts in Brazil (Labigalini)

- Cannabis as a substute for alcohol and other drugs (Reiman, Mikurya, Lucas)

- Preclinical animal models create a powerful proof of concept for the use of CBD- containing cannabis for the prevenon of relapse in treatment seeking addicts.

- This must be talked about more seriously… as seriously as any risk of cannabis addicon per se

The Endocannabinoid System and Harm Reducon with Cannabis

Gregory Gerdeman, PhD Mary Lynn Mathre, RN, MSN, CARN Opioid Use

• Americans, constung only 5% of the world’s populaon, • have been consuming 84% of the global oxycodone (Oxyconn) consumpon, • and 99% of the global hydrocodone (Vicodin, Lortab) consumpon. CDC, 2016 Opioid Overdoses

• Opioid overdose epidemic – 16,651 prescripon opioid overdoses and 3036 heroin overdoses in 2010 (WHO) • Immunosuppressive effects of opioids may increase morbidity from infecous diseases, autoimmune diseases, and cancer • Newly approved Zohydro ER (pure hydrocodone) – 5-10 X stronger than Vicodin Made by Alkermes: Maker of Vivitrol (naltrexone extended release) – used to treat addicons OPIOID STATISTICS AND ITS IMPACT

◆ Almost 2 million Americans are opiate dependent ◆ 259 million opiate prescripons wrien in 2012 ◆ 4 in 5 heroin users started with opiate prescripons ◆ 40 Americans die each day from prescripon opioids ◆ For 2013 economic burden of opioid epidemic is esmated to be $78.5 billion

3 0 Long term use of Opioids

• 2015 review showed no evidence to support long term use of opioids for pain management • Increased risk of harm from long term use of opioids: overdose, opioid abuse, fractures, heart aacks, and sexual dysfuncon – Chou et al. The Effecveness and Risks of Long-term Opioid Therapy for Chronic Pain: A Systemic Review for a Naonal Instutes of Health Pathways to Prevenon. Long–term Use of Cannabis

• 2016 study of 176 pain paents using cannabis at 6 months follow-up • Improved pain management and funconal outcomes • Reduced use of opioids by 44% – Haroutounian, S et al. Cannabinoids 101

• Phytocannabinoids (e.g. THC, CBD,CBN) are produced by cannabis

• Endogenous cannabinoids (e.g. anandamide) are termed endocannabinoids, made within the body

• Synthec cannabinoids (e.g. dronabinol, HU-210) have been developed Non-THC Components of Cannabis

• Δ9-tetrahydrocannabinol (THC) is the primary psycho-acve ingredient of cannabis • Secondary compounds may enhance the beneficial effects of THC • Other cannabinoid and non-cannabinoid compounds may reduce THC-induced anxiety, ancholinergic effects and immunosuppression • Terpenoids and flavonoids may increase cerebral blood flow, enhance corcal acvity, kill respiratory pathogens and provide an-inflammatory acvity Non-psychotropic Cannabinoids Cannabis Synergism: The Entourage Effect

• “This type of synergism may play a role in the widely held (but not experimentally based) view that in some cases plants are beer drugs than the natural products isolated from them.” (Mechoulam & Ben- Shabat 1999) • “The whole is greater than the sum of its parts.” (McPartland) Cannabinoids and Pain

• Connuous descripons of cannabis as an analgesic throughout history • Brain regulates pain and processes the pain experience occurring elsewhere in the body • Endocannabinoids centrally regulate our interpretaon of the pain phenomenon • Endocannabinoids also work directly in the periphery to curb the pain sensaon Cannabinoids and Pain

• Elevated levels of the CB1 receptor - like the opioid - are found in areas of the brain that modulate nociocepve processing • CB1 and CB2 agonists have peripheral analgesic acons • CBs may also exert an-inflammatory effects • Analgesic effects not blocked by opioid antagonists THC and Analgesia • In cancer trial, oral THC 20 mg was comparable to codeine 120 mg (5mg THC = 30mg codeine) • Cannabinoid-induced analgesia appears linked to opioid system • Cannabinoids act on the kappa and delta receptors, while opioids act on the mu receptors and the mu receptors can be enhanced by cannabinoids • Cannabinoid analgesic effects not blocked by opioid antagonists THC and Opioid Interacons

• Animal studies show: – THC + opioids are synergisc in analgesic effects – When combined can decrease tolerance to opioids – When combined can decrease physical dependence of opioids – When THC is introduced to a mouse that developed tolerance to opioids, the effecveness of the opioids is restored

• Cichewicz DL et al, 1999; Cichewicz & Welch, 2013 Cannabis and Opioid Interacons

• Study of 21 pain paents on sustained release oxycodone or morphine adding vaporized cannabis: • Lowers plasma level of the opioids but yields a stascally significant reducon in pain – Abrams, DI et al (2011). Cannabis Can Reduce Opioid Use

• 2014 study looked at death cerficate data from 1999-2010 • showed a 24.8% decreased mortality rate from opioids in the 23 states with medical cannabis laws compared to the other states • It was a progressive decrease over me • Conclusion: Medical cannabis laws are associated with significantly lower state-level opioid OD mortality rates. – Bachhuber et al. Cannabis Can Reduce Opioid Use

• Michigan study: retrospecve survey of 244 chronic pain paents at a dispensary from 11/2013 to 2/2015 • 64% lower opioid use • Increased quality of life • Fewer medicaon side effects and medicaons used • Boehnke et al., 2016 Cannabis May Decrease Opioid Use

• 2016 published study of 68,394 drivers from 18 states who died within one hour aer a traffic accident from 1999-2013. • Reducon of opioid use in the medical cannabis states • Opioid presence was reduced by 50% in drivers aged 21-40 years. – Kim et al, 2016, AJPH Decrease in Medicare Part D

• 2016 study from U of GA • Review of all prescripons filled by Medicare Part D from 2010 – 2013 • Results: Decreased use of prescripon drugs for which cannabis could serve as a clinical alternave in states with medical marijuana laws – Bradford & Bradford Cannabis – Harm Reducon

• A 2013 study of cannabis use during inducon of methadone treatment • Associated with decreased symptoms of opiate withdrawal. • Potenal role for cannabis during methadone inducon.

– Scavone JL, Sterling RC, Wienstein, SP & Bockstaele EJ (Farber Instute for Neurosciences at Thomas Jefferson University, Philadelphia) Cannabis – Harm Reducon

• 2009 study at NY State Psychiatric Instute • Higher retenon in naltrexone treatment for heroin addicon seen with cannabis users • (Naltrexone is an opioid receptor antagonist used in heroin addicon and alcoholism treatment) – Raby WN et al. Medical Research Cannabis & Opiates • “When used in conjuncon with opiates, cannabinoids lead to a greater cumulave relief of pain, resulng in a reducon in the use of opiates (and associated side-effects) by paents in a clinical seng. Addionally, cannabinoids can prevent the development of tolerance to and withdrawal from opiates, and can even rekindle opiate analgesia aer a prior dosage has become ineffecve.” – Lucas, P. 2012 • hp://www.tandfonline.com/doi/full/ 10.1080/02791072.2012.684624#abstract

Cannabis + Opioids for Pain Management

• Using cannabis with opioids is safer • Cannabis + opioids work synergiscally • Cannabis slows the tolerance to opioids • Cannabis can treat opioid withdrawal symptoms • Cannabis can serve as a harm reducon medicaon for persons with an opioid use disorder Silver Bullet vs. Natural Medicine

• Single drugs – more potent effect, usually more side effects • Poly pharmacy – medicaons added to deal with side effects of medicaons • Natural plant medicine – synergy among the constuents Use of Cannabis with Opioids

• Opiate sparing effect • Helps prevent nausea that somemes accompanies opioids • No conspaon with cannabis • Acts as an an-depressant • Acts as an an-inflammatory agent • No significant withdrawal symptoms • Helps with sleep CDC Guideline for Prescribing Opioids

• “Clinicians should not test for substances for which results would not affect paent management or for which implicaons for paent management are unclear. For example, experts noted that there might be uncertainty about the clinical implicaons of a posive urine drug test for tetrahyrdocannabinol (THC).” (#10 of the recommendaons) CDC Guideline for Prescribing Opioids

• “Clinicians should not dismiss paents from care based on a urine drug test result because this could constute paent abandonment and could have adverse consequences for paent safety, potenally including the paent obtaining opioids from alternave sources and the clinician missing opportunies to facilitate treatment for substance use disorder.” (#10 of the recommendaons) Key Points

• We have an epidemic of overdose deaths caused by opioids • Cannabis works synergiscally with opioids • Most paents with chronic pain will decrease their use of opioids when they have access to cannabis • Cannabis is a harm reducon medicaon for pain management and opioid use disorder How to reduce harm from Cannabis

• Organically grown • Start low and go slow with dosing • Vaporize rather than smoke • If smoke – limit breath holding, clean pipe daily • Cauon with edibles – SLOW onset • If not home grown – Need a known source with tesng • De-schedule the plant; Regulate cannabis products References

• Abrams D, et al, “Cannabinoid-opioid interaction in chronic pain,” Clin Pharmacol Ther, 90(6):844-51 • Bachhuber M.A., Saloner B., Cunningham C.O. & Barry C. L. (August 25, 2014). Medical Cannabis laws and opioid analgesic overdose mortality in the United States, 1999-2010. JAMA Internal Medicine. 174(10):1668-1673. doi:10:1001/jamainternmed.2014.4005 • Boehnke, KF, Latinas, E & Clauw, DJ. (2016). Medical cannabis use is associated with decreased opiate medication use in a retrospective cross-sectional survey of patients with chronic pain. The Journal of Pain. 17(6):739-44. • Bradford AC & Bradford WD. (2016) Medical marijuana laws reduce prescription medication use in Medicare part D. Health Affairs. 35(7):1230-6. doi: 10.1377/hlthaff. 2015.1661 • Chou R et al (2015) The effectiveness and risks of long-term opioid therapy for chronic pain: a systemic review for a National Institutes of Health Pathways to Prevention workshop. Annals of Internal Medicine. 162(4):276-86. References cont.

• Cichewicz, D.L.; Martin, Z.L.; Smith, F.L. & Welch, S.P. 1999. Enhancement of mu opioid antinociception by oral delta9- tetrahydrocannabinol:Dose-response analysis and receptor identification. Journal of Pharmacology and Experimental Therapeutics 289 (2):859–67. • Cichewicz, D.L. & Welch, S.P. 2003. Modulation of oral morphine antinociceptive tolerance and naloxone-precipitated withdrawal signs by oral Delta 9-tetrahydrocannabinol. Journal of Pharmacology and Experimental Therapeutics 305 (3): 812–17. • Di Marzo, V, Melck, D, Bisogno, T & De Petrocellis, L. (1998). Endocannabinoids: endogenous cannabinoid receptor ligands with neruomodulatory action. Trends in Neuroscience. 21: 521-528. • Dreher M. (2002). Crack heads and roots daughters: The therapeutic use of cannabis in Jamaica. Journal of Cannabis Therapeutics, 2(3/4):121-33. • Florence, CS, Zhou, C, Luo, F & Xu, L. (2016). The economic burden of prescription opioid overdose, abuse, and dependence in the United States, 2013. Medical Care. 54(10):901-6. References cont.

• Grant I, Atkinson JH, Gouaux B & Wilsey B. (2012). Medical marijuana: clearing away the smoke. The Open Neurology Journal. 6:18-25 • Harouounian S, Ratz Y, Ginosar Y, Furmanov K, Saifi F, Meidan R & Davidson E. (2016) The effect of medicinal cannabis on pain and quality of life outcomes in chronic pain: a prospective open-label study. Clin J Pain. DOI: 10.1097/AJP.0000000000000364 • Injury Prevention & Control: Prescription Drug Overdose. Centers For Disease Control and Prevention. 01/2016 - http://www.cdc.gov/drugoverdose/ • Izzo AA, Borrelli F, Capasso R, Di Marzo V & Mechoulam R. (2009). Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends in Pharmacological Sciences. 30(10):515-27. • Joy, J.E., Watson, S.J. & Benson, J.A. (1999). Marijuana and Medicine: Assessing the Science Base. Washington, DC: National Academy Press (Institute of Medicine). ISBN 0-309-07155-0 • Kim JH et al. (2016). State medical marijuana laws and the prevalence of opioids detected among fatally injured drivers. American Journal of Public Health. doi: 10.2105/AJPH.2016.303426 References cont.

• Lucas, P. “Cannabis as an adjunct to or substitute for opiates in the treatment of chronic pain.” J Psychoactive Drugs. 2012 Apr-Jun;44(2):125-33. • Mikuriya TH. (2004). Cannabis as a substitute for alcohol: a harm-reduction approach. Journal of Cannabis Therapeutics. 4(1):79-93. • Pacher P, Bátkai S & Kunos G (2006). The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacological Reviews. 58(3):389-462. • Powell D, Pacula RL & Jacobson M. (July, 2015). Do medical marijuana laws reduce addictions and death related to pain killers? NBER Working Paper # 21345 • Raby WN, Carpenter KM, Rothenberg J, Brooks AC, Jiang H, Sullivan M, Bisaga A, Comer S & Nunes EV. (2009). Intermittent marijuana use is associated with improved retention in naltexone treatment for opiate-dependence. American Journal of Addictions, 18(4): 301-8. • Reiman A. (2009). Cannabis as a substitute for alcohol and other drugs. Harm Reduction Journal. 6:35. DOI: 10.1186/1477-7517-6-35. References cont.

• Russo, E. B. (2004). Clinical endocannabinoid deficiency (CECD): Can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuroendocrinol Lett, 25(1-2), 31-39. • Russo, E.B. (2008). Review - Cannabinoids in the management of difficult to treat pain. Therapeutics and Clinical Risk Management. 4(1): 245-59. • Russo, E. B., Mathre, M. L., Byrne, A., Velin, R., Bach, P. J., Sanchez-Ramos, J., et al. (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. • Scavone JL, SterlingRC, Weinstein SP & Van Bockstaele EJ. (2013). Impact of cannabis use during stabilizaon on methadone maintenance treatment. The American Journal on Addicons. 22(4):344-31. • Welch, SP. (2009). Interacon of the cannabinoid and opioid systems in the modulaon of nocicepon. Internaonal Review of Psychiatry 21(2): 143-151. • Werner, Clint (2011) Marijuana Gateway to Health: How Cannabis Protects Us From Cancer and Alzheimer's Disease. San Francisco:Dachstar Press Websites

• www.patientsoutoftime.org • www.medicalcannabis.com • www.themedicalcannabisinstitute.org • www.americancannabisnursesassociation.org • http://medicalmarijuana.procon.org/view.resource.php? resourceID=000881 • hp://www.cdc.gov/mmwr/volumes/65/rr/rr6501e1.htm CDC Guideline for Prescribing Opioids for Chronic Pain – United States, 2016 • hp://www.cdc.gov/drugoverdose/pdf/guidelines_factsheet-a.pdf Fact sheet of CDC recommendaons