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Cannabis Provider Education PacketFebruary 2020

ContentsContents & terminology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Dosing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Routes of administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Cannabis & chronic pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Harms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Cannabis use disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Harm reduction strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Policy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Note: This packet was produced for the Veterans Health Administration by the Evidence Synthesis Program to help familiarize VHA clinicians with basic information about cannabis so that they might feel more comfortable engaging in discussions with their patients and answering questions. Current VHA policy stresses that clinicians should be prepared to engage in these discussions because cannabis is relevant to clinical practice, but the policy also stipulates that VHA providers cannot certify patients for, or recommend them to, state-approved medical cannabis pro-grams. We interviewed and surveyed VHA clinicians and prioritized issues for inclusion here that they had voiced as important. This is meant to be a very broad, high level evidence-based overview of a very complex topic. There are undoubtedly subtleties and nuances to the information presented that are not adequately captured in this overview. The information presented in this packet is based on our current understanding of a rapidly evolving body of evidence; readers are referred to the bibliography at the end for more details.

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The cannabis plant contains over 140 compoundsCannabinoidsThe two best-studied cannabinoids are:Delta-9-tetrahydrocannabinol (THC)

• Produces much of the intoxicating effect or “the high” associated with cannabis• Popularlythoughttocontributetovariouspotentialtherapeuticbenefits

Cannabidiol (CBD) • Nosignificantintoxicatingeffect• Potentialanxiolyticandtherapeuticbenefits,butnotwell-studied• May decrease the intoxicating effects of THC

TerpenesAlargelyunstudiedgroupofcompoundsthatproducetheuniquearomaandflavorofcannabis,andmayinflu-ence the intoxicating effects of cannabinoids in whole-plant products. These may be part of the reason that different cannabis products with the same THC and CBD content might have differing effects.

Sativa or Indica?These terms are used colloquially to characterize the expected effects of a given product: Sativa products are purportedtohaveenergizing,uplifting,andcreativeeffects(a“mindhigh”),whileIndicaproductstendtobesedating,andrelaxingphysicallyandmentally(a“bodyhigh”).Whilethesetermsarecommonlyused,theyarenotscientificallygrounded.The degree to which a product will have energizing, intoxicating, or relaxing effects is most likely determined by the relative amounts of THC and CBD in the product.

Cannabis plant

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ThepotencyofacannabisproductistypicallydefinedbytheamountofTHCintheproduct.Thereisnocleardefinitionofasingle“dose”ofTHC.Afewstateshavedefinedasingledoseas5-10mgofTHC.However, cannabisdosingiscomplicatedbythevariationinbioavailabilityacrossformulationsandacrossindividuals,andby the complex interaction among the different compounds present in whole plant and plant extract products.

In studies• Nabiximols is an oromucosal spray which has been effective in improving neuropathic pain in some

studies.Asingledoseofnabiximolscontains2.5mgTHCand2.5mgCBD.Participantsinthesestudiesused, onaverage,25mgorlessofTHCover24hours.

• DronabinolisasyntheticformofTHCthathasbeenFDAapprovedfortreatmentofAIDS-relatedcachexia,andrefractorychemotherapy-inducednauseaandvomiting.Therecommendedstartingdoseis2.5-5mgdaily,withamaximumdivideddailydoseof20mg.

In dispensaries• The concentration of THC in cannabis has been increasing over time and the amount of THC in dispensary

products is much higher than the amount of THC in products studied in clinical trials.• Inonestudy,themedianamountofTHCina1.5gramedibleproductindispensarieswas54mg

- ThemedianTHC:CBDratiowas36:1- Only17%ofproductlabelswereaccurate

Calculating the dose of THC• Multiply the weight of the product by the percentage of THC in the product• Accordingtoestimates,theaveragejointweighsabout0.32to0.66grams.Ahigh-potencycannabisproduct mightcontain20%THCJoint is 320 mg x 0.20 = 64 mg THC/high-potency jointJoint is 660 mg x 0.20 = 132 mg THC/high-potency joint

Dosing

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Form Other Development Terms

Route of Administration

Plant Flower,bud Thehighestconcentrationof Smokingcannabinoidsarefoundintheflower, Vaporizationnottheleaf,ofthefemaleplant; Topicaltopical preparations and rectal Rectal

suppositories can be made with dried flowerorplantextract

Edibles Brownies, Typicallybutteroroilusedtoextract Oralcookies,candy cannabinoidsandputintoavariety

of edible products

Tincture Goldendragon, Alcoholorglycerinusedtoextract Oralgreen dragon active ingredients Sublingual

Oromucosal

Oil RickSimpson Alcoholusedtomakehighlyviscous Oraloil concentrated extract Topical

Resin Hash,drysift, Concentratemadebymechanically Smokingkief separatingtrichromes(hairlike Vaporization

protrusionsonflowerwithhighconcentrationofcannabinoids)from

the plant

Nabiximols Sativex™ Pharmaceutically prepared whole Oromucosalplantextractinsprayform;1:1

THC:CBDconcentration;approvedfor prescription use in many

countries outside the US

Dab Wax,shatter Dabbing(concentrateplacedonveryhot

Ultraconcentratedextractmadewithsolventssuchasbutane;veryhighlevelsofTHC; risk of overdose and

acute psychosismetalrodandinhaled)

Dronabinol™, DronabinolandnabiloneareFDA OralPharmaceutical cannabinoids Nabilone™, approvedsyntheticTHC

Epidiolex™ (chemotherapyinducednausea/vomiting;AIDSrelatedcachexia);EpidiolexisahighlypurifiedCBDplant extract and is FDA approved

for the treatment of two rare epilepsy syndromes

Cannabis formulations

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Route Smoking Oral/Edibles TopicalVaporization (“Vaping”*)

Notes Combustionof Vaporizerisused Manyformsdriedcannabis toheatdried available:flowerusing floweror creams,

severalmethods: concentrated ointments,cigarettes extract(oil,resin) patches,

(joints,spliffs), andtheresultant poultices,oilspipes,water vaporisinhaled

Varietyofediblesavailable;often

dose/singleservingisafractionoftheproduct(ie,onepartofacookieor

brownie)pipes(bongs)

Pharmacology Rapidonsetand Noinhalation;broad Noneofthepeaksimilarto rangeofproducts; pulmonary

smoking sloweronsetand effects

Rapidonsetandpeak

longer duration of associated withaction inhalation;

probably much less intoxicating

Cautions Bronchialirritation;

cough;sputum;production contains

carcinogens;potentialforadverseeffectsonlungfunctionwith heavy use overmanyyears

Verylittleis knownabout

topical preparations; unknown systemic absorption

Onsetandpeakaredelayedandeffectscanlastmany

hourswhichmakes it moredifficulttotitratedose;oralmetaboliteofTHC(11-OH-THC)mayhavefour-foldmore powerful

psychoactiveeffect;riskofoverdose;cautionespecially

in novice users

SubstantiallyhigherbloodTHCconcentrations

achieved at a given dose than withsmoking;higherriskofadverseeffectsinnoviceusers;longterm

lung safety is unknown;needforpotentiallycostly

equipment;potentially fatal vaping-related

pulmonary illness

Routes of administration: compare & contrast

*Atthistime,providersshouldcautionpatientsagainstvapinggiventhelackofcertaintyregardingthecauseandscopeofthe recently described series of severe vaping-related pulmonary illness cases.

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Note:Thegraphismeanttoillustraterelativedifferencesintimetopeakconcentration.TheactualconcentrationofTHCatdifferenttimepointsvariesmarkedlyacrossindividualsandisinfluencedbypatientcharacteristics,dose,andfrequencyofuse.Lowlevelscanpersistfordaystoweeksinfrequentusers.

The pharmacology of cannabis

Pharmacokinetics

Cannabis-drug interactionsCannabis has the potential to compound the sedative effectsofdifferentdrugclasses,including anticholinergics and CNS depressants. The sedative effect of cannabis combined with antidepressants or lithium is unpredictable.CannabinoidscaninduceorinhibitCYPenzymesandcan,therefore,decreaseorincreasethelevelsofpharmacologic drugs. For example:

• THC may reduce levels of the following drugs: aminophylline/theophylline, clozapine, ropinirole• CBD may increase levels of the following drugs: clobazepam, diazepam, proton pump inhibitors,

phenytoin/fosphenytoin

SinceTHCandCBDaresubstratesofdifferentCYPenzymes,theirlevelscanalsobeincreasedbycertaindrugs. For example:• Boceprevir,Ritonavir,Clarithromycin,Conivaptan,Ketoconazole,Posaconazole,andVoriconazolecan

increase levels of CBD• Carbamazapine,Phenobarbitol,Phenytoin,Rifampin,andSt.JohnsWortcanincrease levels of THC

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Chronic musculoskeletal pain• Insufficientinformationbecause

these populations have largely notbeen included in well-done studies

Spasticity in multiple sclerosis• Productswithpreciselydefinedamounts(ina2:1or1:1ratio)ofTHC and CBD were associated withimproved spasticity and pain in MSpatientsatupto15weeks

• Longer-termeffectshavenotbeenstudied

• The formulations that have beeneffective are different from what isoften available in dispensaries

Neuropathic pain• Productswithpreciselydefined

amounts of THC and CBD wereassociated with clinically importanteffects on neuropathic pain in a smallsubset of patients over hours to a fewweeks

• Longer-termeffectsareunknown• The formulations that have been

effective are different from what isoften available in dispensaries

Chronic pain

Spasticity

Neuropathy

Arthritis

Cannabis & chronic pain

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Cannabis hyperemesis syndrome• Increasinglyrecognizedformofcyclicvomiting

syndrome seen in those using cannabis on a regularbasis

• Hallmarkisimprovedsymptomswithhotshowers,though this symptom is not present in all individuals

• Treatmentisdiscontinuationofcannabis(maytakeweeks)

Cardiovascular• ImpactonriskofMIandstrokeareunknown

• Associated withtachycardia,hypertension,and hypotension

Cannabis withdrawal syndrome• Canpresentuptoaweek

after discontinuation andpersistforseveralweeks

• Symptoms includedysphoriaordepression,anxiety,insomnia,chills,and restlessness

Mental health• Increasedriskofacutepsychosis,especiallywith

high-THC products• Long-termcannabisusehasbeenlinkedtoanincreasedriskandearlieronsetofchronicpsychoticsymptoms,especiallyinat-riskindividuals(eg, thosewithafamilyhistoryofpsychoticillness)

• Mayincreasetheriskofmania

Lung function• Lightsmoking(weeklyorless)hasnotbeenassociat-

ed with a decline in lung functionover20yearsinyounger individuals

• Daily use over many yearsmay reduce lung function

• Theimpactofsmokinginolderpatientsorthose withmultiple medicalcomorbiditiesisunknown

• Smokingisalsoassociatedwith bronchitis symptoms

Cannabis Use Disorder (CUD)/Substance Use Disorder (SUD)One in three cannabis users meets criteria for a CUD. Seepage10fordetails.

Motor vehicle accidents• Acute intoxication has beenassociatedwitha35%increasedrisk

Cognition• Active,regularcannabisuseisassociated

with negative effects on cognition• Particular concern in the developing brain(adolescentsandyoungadults),andpossibleriskofneuropsychiatricsymptomslater in adulthood

• Effects of past use are unclear

Harms

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Cannabis & overdose• Whilecannabishasnotbeenassociatedwithdeathfromoverdose,intakeofahighamountofTHCcan

cause symptomatic overdose often manifesting as acute psychosis. There have also been recentlydescribed fatalities associated with vaping cannabis.

• Acute psychosis from THC overdose has been reported, particularly with edible cannabis- Patientscaninadvertentlytaketoohighadosebecausethepeakeffectofediblecannabisisdelayed(usuallyabout1-3hours),andtheymaytakemorethantherecommendeddoseafterfeelingnothinginitially

- Oral ingestion produces a particularly potent metabolite of THC• Inacaseseriesofpatientshospitalizedforcannabis-inducedpsychosis,patientshadingested100mgor

more of THC

Non-prescription synthetic cannabinoids: BEWARETherehavebeenseverallargeoverdoseoutbreaksassociatedwithnon-prescriptionsyntheticcannabinoids.• Productsgobythenameof“K2”or“Spice”andcanbepurchasedonthestreet,oratconveniencestores

and gas stations• Inonelargeoutbreak,cannabinoidswereadulteratedwithbrodifacoum,whichpotentiatescannabiseffects and is a coumarin derivative

- Numerous hospitalizations and several deaths related to bleeding complications• Two“zombie”outbreaksassociatedwithultrapotentstreetcannabinoidAMB-FUBINACA• These compounds are not detectable on urine drug screen

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NoStep 1. Do you currently use cannabis? Yes

Step 2. If yes:1. Howoftenduringthepast6monthsdidyoufindthatyouwerenotabletostopusingcannabisonceyouhad

started?(1) Never(2) Lessthanmonthly(3) Monthly(4) Weekly(5) Dailyoralmostdaily

2. Howofteninthepast6monthshaveyoudevotedagreatdealofyourtimetogetting,using,orrecoveringfrom cannabis?(1) Never(2) Lessthanmonthly(3) Monthly(4) Weekly(5) Dailyoralmostdaily

3. How often in the past 6 months have you had a problem with your memory or concentration after usingcannabis?(1) Never(2) Lessthanmonthly(3) Monthly(4) Weekly(5) Dailyoralmostdaily

Total score _______Positive screen = 2 or higher

• TheprevalenceofCUDamongthosereportingcannabisuseinthepastyearisabout1in3• Cannabisuseisassociatedwithatwo-foldincreasedriskoffuturealcoholusedisorderoranySUD

Assessing for Cannabis Use DisorderThereareavarietyofCUDassessmenttools,althoughtheyhavenotbeenasbroadlytestedinclinicalpracticeastools for other substance use disorders. The following short screener is one option.

Stepwise assessment of cannabis use disorder

Cannabis Use Disorder (CUD)/Substance Use Disorder (SUD)

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Treatment of Cannabis Use DisorderAnumberofmedicationshavebeentested,buttherearenonewithadequateevidencetosupportroutineuseintreating CUD yet.Themainstayoftreatmentispsychological:cognitivebehavorialtherapy,motivationalenhancementtherapy,and contingency management. These are accessed through specialty substance use disorder treatment programs.

%withanypastyearcannabisusewhometcriteriaforCUD 36

%ofthosewithpriorcannabisusewhodevelopCUD(incidence) 25

Oddsofdevelopinganyothersubstanceusedisorder 2.1

Oddsofdevelopingalcoholusedisorder 2.0

Cannabisusedisorderisanincreasinglyrecognizedharm.Dailyusers,youngadults,andmenareathigherrisk. The risk of frequent non-medical cannabis use and the risk of cannabis use disorder is also higher among patients with chronic pain.

Step 3. Confirm with DSM5 criteria for cannabis use disorder• Using a larger quantity or over a longer duration than intended• Unsuccessfulattemptstolimit/quit• Significantamountoftimespentobtainingcannabis• Cravings• School/occupationalimpairment• Social/interpersonalimpairment• Reductionofsocial/occupational/recreationalactivities• Recurrent use in physically harmful situations• Continued use despite recurrent physical or psychological harms• Tolerance• Withdrawal

Mild 2-3 criteriaModerate 4-5 criteriaSevere 6 or more criteria

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Harm reduction strategies

WhileVAprovidersmaynot provide medical recommendations for cannabis use,inmanystatespatientshavereadyaccesstocannabisthroughmedicaland/orrecreationaldispensaries.Forpatientswhoareusingcannabis,thereareseveralstrategies that may help mitigate potential harms:

• Askpatientsaboutcannabisuse:formulation,dose,frequency,route

• Considerassessingforcannabisusedisorder(seeprevioussection)

• Keep cannabis out of reach of children and adolescents

• Educate patients about:

o Cannabis withdrawal syndrome and that the symptoms of withdrawal are similar to some of thesymptoms patients may be using cannabis to help treat

o Avoidingprolonged,dailyuse

o Avoiding products with high levels of THC

o Cannabis-naïveindividuals shouldbeespeciallycautiousstartinguseofedibleproducts,uselowdoses,andavoidrapid dose escalation

o Dabbing is best avoided by everyone

o Advisepatientsatriskforpsychoticspectrumdisordersandsevereanxietytoavoidcannabis,especially high-THC products

o Vapinghasbeenassociatedwithsevere, life-threateningpulmonaryillness,andshouldbeavoided

o Avoid products sold outside of state-licensed dispensaries given the greater potential for unknowncontent including synthetic cannabinoids

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Cannabis policy

Veterans Health AdministrationVHA policy is that:• Providersdiscusscannabis use withVeteransduetoitsclinicalrelevance• Providersmakeindividualizeddecisionsaboutmodifyingtreatmentplansbasedoncannabisuse• Thereisnopolicymandatingspecificactionforthosebeingprescribedopioidswhoarealsousing cannabis.

• Providers document discussions regarding cannabis in the medical record• Providerscannotrecommend,referto,orcompleteformsrelatedtostate-approvedmedical

cannabis programs.• VeteransmustnotbedeniedVHAservicessolelybecausetheyareparticipatinginstate-approvedcannabis

programs. However, an individual's treatment plan may be modified as clinically indicated due to cannabis use.

Federal law• CannabisremainsaSchedule1substanceundertheControlledSubstanceAct,whichmeansthatthefederalgovernmentclassifiesitasasubstancewithhighpotentialfordependenceoraddictionandnoacceptedmedical use.

• Research on cannabis in the US is very challenging because of the scheduling of cannabis.

State policy• In2019,cannabisislegalformedicalpurposesin33statesandtheDistrictofColumbia(seehttps://medicalmarijuana.procon.org/view.resource.php?resourceID=000881).

• Itislegalforrecreationalpurposesaswellin10ofthosestatesandDC.• Monitoring,labeling,andqualitycontrolrequirementsvarysubstantiallyacrossstates.• Chronic pain is the most commonly approved medical indication for cannabis.

Cannabis policy & opioids• Widely publicized ecological studies in the US initially suggested that states with medical cannabis

legalization saw an accompanying decrease in opioid prescription and overdose deaths. However, the same analyses extended through 2017 actually found a reversal of that trend, and suggest caution in applying the results of these ecological studies.

• Data from individual patient-level studies are mixed, but have not shown a consistent decrease in opioid use among chronic pain patients using cannabis. Some studies show that cannabis has no impact on opioid use, while others show higher opioid use in those using cannabis.

• The use of cannabis as an opioid substitute has garnered interest, but there has been little evidence examining this practice.

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AcknowledgementsDevelopedbythePortlandEvidenceSynthesisProgram,andsupportedbyVAHSRDESP#05-225

Wewelcomequestions,suggestions,andcorrections:Devan.Kansagara@va.govDevanKansagara,MD,MCRDirectorPortlandEvidenceSynthesisProgram,VAPortlandHealthCareSystemAssociateProfessorofMedicine,OregonHealthandScienceUniversity

We thank the following content experts for their extensive input and editorial suggestions:KendallBrowne,PhDCoreInvestigator,CenterofExcellenceinSubstanceAbuseTreatmentandEducation(CESATE),VAPugetSoundAssistantProfessorofPsychiatryandBehavorialSciences,UniversityofWashington

JosephBubalo,PharmD,BCPS,BCOPAssistantProfessorofMedicine,OregonHealthandScienceUniversity

MichelleCameron,MD,PT,MCRAssociateProfessor,DepartmentofNeurology,OregonHealthandScienceUniversityCo-Director,MSCenterofExcellence-West,VAPortlandHealthCareSystem

KimDJones,RNC,PhD,FNPProfessorofNursing,OregonHealthandScienceUniversityDean,Linfield-GoodSamaritanSchoolofNursing

SalomehKeyhani,MD,MPHCoreInvestigator,CenterforHealthcareImprovementandMedicalEffectiveness(CHIME),SanFranciscoVAHealthCareSystemProfessorofMedicine,UniversityofCalifornia,SanFrancisco

AndrewSaxon,MDDirector,CenterofExcellenceinSubstanceAbuseTreatmentandEducation(CESATE),VAPugetSound ProfessorofPsychiatryandBehavorialSciences,UniversityofWashington

SpecialthankstoLynnKitagawa,MFA,attheVAPortlandHealthCareSystem,fortheillustrationsandgraphicdesign, and to Julia Haskin, MA, at the VA Portland Health Care System, for editorial support.