P a g e |1Created by: Dr. Michael Verbora, Edited by: Dr. Danial Schecter Last updated: February 16, 2017

CMCPhysicianEducationMedications,CannabinoidEducation,PrescribingProtocolsThefollowingdocumentisdesignedtoprovideeducationandrecommendationsoncannabinoidprescribing.Despiteanincreaseinpopularity,theuseofcannabinoidsasatherapeuticoptionremaininit’sinfancy.Thefollowingsuggestionsarebasedonareviewofavailableliteratureandclinicalexperiencefromnumerouspatientencounters.ThesePrescribingProtocolsaremerelysuggestionsandphysiciansareencouragedtoreflectanddrawupontheirownexperiencewhenprescribing.CannabinoidOptionsNabilone(Cesamet):SyntheticTHCanalogue.Availablein0.25mg,0.5mgand1mgcapsules.Coveredbymostpublicandprivateinsuranceplans(usually0.5and1mgcaps,not0.25mgcaps).Approvedfornauseaandvomitinginchemotherapy.UsedofflabelforavarietyofailmentstreatedatCMCincludingchronicpain(alltypes),nausea/vomiting,insomnia,andPTSD(especiallynightmares).Sideeffects:drymouth,drowsiness,dizziness,psychoactivity.Lacksterpenes,flavonoidsandothercannabinoids(includingCBD)foundinherbalcannabisandassuchdoesnotprovidethe“entourageeffect”.Sideeffectsareoftenmorepoorlytoleratedthanherbalcannabis.Cautionadvisedinelderlytominimizeriskoffalls.Bestreservedforeveningsymptomsgivenpoordaytimetolerabilityalthoughatherapeutictrialduringdaytimeisalsorecommendedgivenfinancialbenefitofcoverage.Canbeusedtohelplowerconsumptionofherbalcannabis(patientsusing>3g/day).Maxdose:2mgTID.Startlow,titrateuptomaxdoseastolerated.CanprovideNabiloneattheinitialvisitandthenreassessin1monthtoevaluateresponsetotreatmentandthenaddorchangetreatmenttoherbalcannabisproductsifnecessary.Sampleinitialtitratingprescription:Nabilone0.5mgqHSx5daysthenNabilone0.5mgqAMand0.5mgqHSx5daysthenNabilone0.5mgqAM,0.5mgqAfternoonand0.5mgqHSx5daysthenNabilone0.5mgqAM,0.5mgqAfternoonand1mgqHSx5daysthenNabilone1mgqAM,0.5mgqAfternoonand1mgqHSx5daysthenNabilone1mgqAM,1mgqAfternoonand1mgqHSx5daysthenreevaluateM:105(onehundredandfive)capsules

P a g e |2Created by: Dr. Michael Verbora, Edited by: Dr. Danial Schecter Last updated: February 16, 2017

Whenprescribingcannabisitisimportanttoinformpatientof“offlabel”useandtoencouragethemtofindtheirbesttolerateddose.Theabovetitrationscheduleshouldbeconsideredaguideforthepatientbuttheyshouldfeelfreetochangeitaccordingtotheirsymptomsandabilitytotoleratesideeffects.Nabiximols(Sativex):“Natural”oral-mucosalspraycontainingcannabinoids,terpenes,andflavonoidsextractedfromthecannabisplant.Comesinonlyonestrength:2.7mgTHC/2.5mgCBDperactuation(1:1THC:CBDratio).Approvedforspasticity,neuropathicpaininMSandchronicpainnotrelievedbyopiates.Notcoveredbymostpublicorprivateinsuranceplans.Comesin10mLvialsandintendedtobeadministeredtooralmucosa.Hasanalcoholbasewithcommonsideeffectsofmucosalirritation.Canbesprayedintoasmallglassofmilkandconsumedorallyifunabletotoleratemucosalabsorption.Similarpharmacokineticsandpharmacodynamicstocannabisoil/edibles/tinctures.Oftenprohibitivegivencostof>$200pervial.Typicalmonthlydosagecancost$700-$1000.CanbereplicatedbycheaperherbalcannabisoilobtainedfromanLP.Recommendedmaximumdosageisupto12spraysdaily.HasaD.I.N.andassuchcanbetransportedacrossinternationalborderswhereasherbalcannabisproductscannot.Samplestartingdose:Sativex1sprayBIDHerbalCannabisDriedFlower/Buds:naturalflowerwithaverywiderangeofcannabinoid,terpeneandflavonoidprofiles.Endlesspossibilitiesofcombinationsofingredientsallowsforverycustomizedmedicineforpatients.Mustbeheatedtoallowdecarboxylationandactivationofmainingredients(THC&CBD).Canbeconsumedviasmoking,vaporizing,orcookedwithfatsforsystemicabsorption.Inhaledformisrapidlyabsorbedandbestutilizedforbreakthroughsymptoms.Homeproductionofcannabisbrowniesandotherediblesgenerallynotrecommendedduetodifficultyindosingandstandardization.CannabisOils:dissolvednaturalflowerwithaverywiderangeofcannabinoid,terpeneandflavonoidprofilesthatisproducedviaCO2extraction.Dilutedwithvariousvegetableoils(grapeseed,olive,sunflower,hemp)toensureHealthCanadaapprovedconcentrations(maxTHC30mg/mL)andtomaximizeabsorptiongivenlipophilicpropertiesofcannabinoids.Longeronsetofaction(1-2hours)butlongeractingeffects(6-10hours).Asorallyconsumedtheyaresusceptibletofirstpassmetabolismandrelyonpatientvariables(GItract,gastriccontacts,medicationinteractions).FineMilledCannabis:naturalflowerwithaverywiderangeofcannabinoid,terpeneandflavonoidprofiles.Heatedpriortodeliverytoallowfordecarboxylation(activationofTHC/CBD)andmilledintofinepowder.Powdertobeusedfororalconsumptiontoproducelongactingeffectssimilartocannabisoils.Shouldbeconsumedwithfats(oil,cream,butter)tomaximizeabsorption.

P a g e |3Created by: Dr. Michael Verbora, Edited by: Dr. Danial Schecter Last updated: February 16, 2017

PharmacokineticsofVaporizedvs.OralCannabinoidConsumption

Best prescribing patterns should incorporate long acting cannabinoids for chronic symptoms to provide baseline symptom management. Short acting cannabinoids are ideal for patients using cannabis as needed, infrequently or for breakthrough symptoms not managed by long acting cannabinoids. Patients using more than 1-1.5g a day should consider using long acting cannabinoid formulations.

Onset of Action Duration of Action Oral/Ingested 1-2 hours 6-10 hours Inhaled 5-15 minutes 2-4 hours

Prescribing Considerations When prescribing cannabinoids the many factors must be considered including (but not limited to) the following: Past cannabinoid exposure (cannabinoid tone/tolerance) Age (elderly/under 25 should use THC cautiously) Medical condition and symptoms being treated Potential drug interactions (warfarin, anti-epileptics, insulin) Patient complexity Patient expectations Previous medications tried Past history of addiction Past history of mental health concerns (schizophrenia/bipolar disorder/anxiety disorder) Other medical conditions that may put them at risk (I.E. unstable heart disease, lung disease) The Cannabis plant has a few different species, two of which are commonly used by patients: Indica and Sativa. Indica and Sativa are identified by their phenotype and not by their chemical composition although patients report different effects to each of these. Anecdotally, Indica strains are sedating, relaxing, calming (often described as a “body stone” or being “couch-locked) while Sativa strains are mentally invigorating, physically stimulating but can cause anxiety, paranoia (in those with baseline anxiety be cautious). Due to the poorly understood difference between Indica and Sativas, we usually recommend to patients to focus on THC:CBD ratios while trying to determine if they are able to respond to the Indica/Sativa division as well. Advising patients it may take 2-3 visits to optimize cannabinoid therapy helps manage expectations and reduce patient frustration while experimenting. Higher THC strains may allow for lower daily total consumption of cannabis.

P a g e |4Created by: Dr. Michael Verbora, Edited by: Dr. Danial Schecter Last updated: February 16, 2017

Patients need to take some ownership on documenting strains, method of consumption, dosage and benefit/adverse events to help guide physician treatment in future encounters. The Entourage Effect When prescribing herbal cannabis one needs to consider the vast complexity of hundreds of different ingredients and their interactions with one another. This is known as the entourage effect. This effect is a theory that tries to explain why patients experience different benefits when using different cannabis strains. The combination of various cannabinoids, terpenes and flavonoids in different proportions allows for different physiologic effects. There is experimentation that is required to best understand how each individual patient responds to different strains of cannabis. Below is a summary of anecdotal data/experiences with various strain ingredients.

P a g e |5Created by: Dr. Michael Verbora, Edited by: Dr. Danial Schecter Last updated: February 16, 2017

Understanding Cannabinoids THC and CBD are the most active cannabinoids in herbal cannabis, most studied and considered to be responsible for the majority of cannabis’ physiologic effects. Each of these ingredients can produce its own effects and the ratio of these two ingredients is important for optimizing symptom management. Patients will often require a number of different strains, with different ratios of THC:CBD at different times of the day or for different symptoms. THC is responsible for the majority of side effects (dizziness, dry mouth, amnesia, sedation, psychoactivity). Increasing the ratio of CBD to THC can minimize side effects and allows patients to tolerate a higher dose of THC. THC and CBD have been show to help with the following (in basic science studies, very limited human trials): THC and CBD exhibit an effect on Cannabinoid Receptors (CB). Two main receptors have been identified: CB1 and CB2. CB1 receptors are found within the CNS/PNS/GI system and thought to be responsible for the vast majority of physiologic effects of cannabis. CB2 receptors are mostly found within the immune system and their function remains poorly understood. There is still an incredible amount of research to understand the role of cannabinoid receptors and the endocannabinoid system.

P a g e |6Created by: Dr. Michael Verbora, Edited by: Dr. Danial Schecter Last updated: February 16, 2017

CASE 1 – Cannabinoid naïve patient

Continue to increase THC to effect, with lowest daily amount for benefit. If not effective without any

THC limit consider cessation of therapy and alternative therapies.

Ispatientacandidateforcannabinoidtherapy?

Advisepatienttoseereferringdoctorforalternativetherapies. StartpatientonCBD

strains(THC<2%)and/orlowCBD/THCstrains(THC<10%)

No

Yes

SampleRx:HerbalCannabis1g/dayTHC<10%

ConsideruptitrationofTHCanddifferentstrain

trials.

FU1-2monthslater.Effectiveforrelief?

SampleRx:HerbalCannabis1g/dayTHC<15%

NoYes

Continuescript,titratedailyamountto

maximizefunction.

ConsideruptitrationofTHCanddifferentstrain

trials.

FU1-2monthslater.Effectiveforrelief?

Yes

Continuescript,titratedailyamountto

maximizefunction.

No

SampleRx:HerbalCannabis1g/dayTHC<20%

P a g e |7Created by: Dr. Michael Verbora, Edited by: Dr. Danial Schecter Last updated: February 16, 2017

CASE 2 – Cannabinoid experienced patient (good candidate for cannabinoid therapy)

Continue to increase THC to effect, with lowest daily amount for benefit. If not effective without any THC limit consider cessation of therapy and alternative therapies.

Ispatientawareofstrainingredients(THCvs.CBD)?

NoConsiderstartingpatientonTHClevelsreported Considerlowto

mediumrangeTHCandCBD.

SampleRx:HerbalCannabis1g/dayTHC<12%

FU1-2monthslaterEffectiveforrelief?

ConsideruptitrationofTHCanddifferentstrainsselection.

Yes

Yes

Continuescript,titratedailyamountto

maximizefunction.

No

SampleRx:HerbalCannabis1g/dayTHC<20%

P a g e |8Created by: Dr. Michael Verbora, Edited by: Dr. Danial Schecter Last updated: February 16, 2017

CASE 3 – Nabilone/Herbal Cannabis Approach (good candidate for cannabinoid therapy)

* good candidates for Nabilone are patients with evening symptoms, low income (Ontario coverage), insomnia related conditions, THC responsive conditions or to help lower herbal cannabis dose in high users

IspatientgoodcandidateforNabilone?

No

Yes

TrialofNabilone

FU1-2monthslaterEffectiveforrelief?Yes

NoContinueNabilone.Addonvaporizedcannabisforbreakthroughif

needed.

ConsiderswitchingtoHerbalCannabis

StartpatientonCBDstrains(THC<2%)and/orlowCBD/THCstrains(THC<10%)

ConsideruptitrationofTHCanddifferentstrain

trials.

FU1-2monthslater.Effectiveforrelief?

NoYes

Continuescript,titratedailyamountto

maximizefunction.

SampleRx:HerbalCannabis1g/dayTHC<10%

SampleRx:HerbalCannabis1g/dayTHC<20%

P a g e |9Created by: Dr. Michael Verbora, Edited by: Dr. Danial Schecter Last updated: February 16, 2017

Harm Reduction Strategies One of the principles at CMC is to ensure there is a minimization of harm caused to patients from the use of cannabinoid therapy. Also to help patients self-medicating reduce the risk of tainted street cannabis, inappropriate strain selection and harmful consumption methods. The following is some counselling advice to minimize harm to patients.

Ø Advise all patients that smoking (bong, pipe, one hitter, joint) is not recommended. All patients wishing to inhale cannabis should do so through a vaporizer. Vaporizing allows for patient to reduce their daily amount given improved efficiency of vaporization over smoking. Smoking cannabis may contribute to COPD, chest infections and potentially lung cancer due to the by-products of combustion being toxic. Patients who do not respond to potential health benefits of vaporizations may respond to the economic benefits as consumption can often be decreased by 50%.

Ø Some patients who are already using cannabis may be combining cannabis with tobacco products. This is considered polydrug abuse and patients tend to become “addicted” to the effects of tobacco and will consume larger quantities of cannabis. Please counsel all patients not to combine cannabis with tobacco. In some areas “poppers” are popular which is a mixture of cannabis and tobacco used in a water pipe. These are extremely addictive due to the “head rush” that they cause and patients can have significant difficulty in stopping their use.

Ø Cannabis should always be purchased from Licensed Producers given the testing for: pesticides, heavy metals, fungus, bacteria and measurement of cannabinoid strength (in % of dry weight of THC and CBD). Purchasing cannabis from the street or illegal “dispensaries” and “compassion clubs” complicates the physician’s role, their ability to aid patients and exposes patients to potentially harmful ingredients given the lack of regulation and oversight. Purchasing cannabis from street sources also has a legal risk, which their prescription does not protect against. Consistency of product and strain availability is important for patients and cannot be guaranteed by street sources but is possible from Licensed Producers.

Ø Patients who exhibit signs and symptoms of cannabis use disorder may benefit from long acting cannabinoid therapy for the goal of harm reduction. This is a similar strategy used for opiate dependence (transitioning to longer acting opiates and then reducing consumption over time). Appropriate long acting cannabinoids include Nabilone and herbal cannabis oils.

Ø Patients who are using large amounts of cannabis (>3g/day), especially if short acting (i.e. Inhaled), should consider a cannabinoid drug holiday for 2 weeks as they may have become tolerant to the effects. By taking a holiday there is a possibility of an “Endocannabinoid reset” and thus patients can restart at a lower dose.

Ø In some scenarios patients report a cluster of symptoms for which they report cannabis helps with. These symptoms are: insomnia, nausea, poor appetite, anger, depression, physical discomfort, anxiety, restlessness, diaphoresis, and headache. If there is not a medical explanation for these symptoms this is possibly due to cannabis withdrawal syndrome. Patients should cease cannabis for a minimum of one month and be reevaluated in clinic when their urine drug screen is negative for THC. Symptom improvement also confirms a cannabis withdraw. Unwillingness to stop cannabis is concerning behavior for cannabis use disorder and does not allow for a proper evaluation of the patient off cannabis.

P a g e |10Created by: Dr. Michael Verbora, Edited by: Dr. Danial Schecter Last updated: February 16, 2017

Ø Patients using opiates or benzodiazepines should be educated on reducing these drugs, which may have more severe side effects, and CMC physicians should be encouraging patients at every visit to reduce these drugs. Communication with their prescribing doctor using follow-up visit notes is encouraged if there are any significant changes in symptoms or medication use. Patients who add cannabinoids to their medication regime but unable to decrease opiate or benzodiazepine use while failing to show any improvement in function should be closely monitored. Physicians should be vigilant for substance use disorder and/or addiction. In those with poly substance use with poor baseline functioning one needs to consider titrating off medications (including cannabinoids).

Ø For patients using cannabis from street sources for inappropriate medical conditions (or poor candidate for cannabinoid therapy) one can consider harm reduction as a reason for prescribing cannabinoids. These patients should have specific goals that include the reduction of cannabis use over time, save consumption (vaporizer/oils), and consider integrating long acting cannabinoids. Harm reduction should not be used for those under 25 years of age.

Ø Recent literature has begun to hypothesize that there may be Endocannabinoid deficiencies in some patients. Patients with a cluster of symptoms that improve with cannabinoid therapy may have this condition. Symptoms are required to be present prior to initial cannabis use and cannabis withdrawal syndrome needs to be ruled out in this scenario. Abstaining from cannabis three-four weeks may be required to determine if cannabis withdrawal is the diagnosis.