Cannabinoids Flashcards
Terminology
Some variance in terms used
Cannabis
Cannabinoids
Marijuana (not preferred)
Cannabis vs cannabinoids - Cannabis - the plant based term\
Cannabinoid - anything that targets the cannabinoid receptor
○ Includes synthetics and cannabis
- Marijuana
○ Not the preferred term
○ Tied to xenophobia and has historical origins
Medication Approval Process
Typically, well-designed, adequately powered
RCTs are required for approval of a drug for any
specific indication
Cannabis has largely been approved based on
low-quality evidence, anecdotal reports,
individual testimonials, and public opinion
cannabis Langley low qlty evidence
Langley bypassed scientific standard and entered mainstream science backwards without high qlty evidence, gone backwards
cart before the horse
benefits of cannabis
Only some of the claims from these resources have true evidence beh- Question of if cannabis is the sol’n for the opioid crisis
lots of health benefits claims for cannabis
• pain
• sleep
• anxiety
• anxiolytic
• cancer
• glaucoma
• antisemitic
• appetite
• migraines
• improving lung capturing
• diabetes
• seizures
• mending bones
• ADHD
• some evidence says it does opposite of what it claims it can do
Cannabis
● Plant taxonomy is still under debate
● Cannabis is a genus of flowering plant in the family
Cannabaceae
● The number of species within the genus is disputed
○ The main one studied is Cannabis sativa
● C. sativa is highly variable
Cannabis indica, cannabis ruderalis - Questionable if they are a different or subspecies of cannabis saC.Sativa has lots of variability (there are 100 known cannabinoids and of >400 compounds other than THC)
• lots of variability in products that could be present
• 100 known cannabinoids
• cannabis is a complex of more the 400 molecules other than THC
• CB1 modulated pain perception, mood
• 2 main endocannabinoids act on CB1 AND CB2 in periphery
Pharmacology
Cannabinoid receptors: CB1 and CB2
CB1: most abundant GPCR in CNS
● Inhibits neurotransmitter release via inhibition of
voltage-gated Ca2+ channels and inwardly rectifying
K +
channels
● Regulates neuronal growth and synapse formation
● Modulates pain perception, mood, anxiety, satiety,
hormonal control, and voluntary motor control
CB2: expressed on glia and immunomodulatory cells
throughout the body
● Activation limits cell migration and release of
pro-inflammatory stimuli, thereby limiting
inflammatory response
THC and CBD are the most studied cannabinoids
THC = Δ9-Tetrahydrocannabinol (most studied)
● Most psychologically active
● Partial agonist at CB1 and CB2
CBD = Cannabidiol
● Pharmacology not fully elucidated
● Considered non-psychoactive
● Rat studies suggest weak antagonism at CB1 and CB2
● May bind at orphan GPCR55, 5HT1A
● May inhibit endocannabinoid uptake and metabolism (anandamide)
• THC most psychologically active
• CBD not as fully well understood, non psychoactive, weak antagonist at CB1 AND 2, may inhibit endocannabinoid uptake
• on its own may mitigate psychoactive effects
• works in periphery and spinal cortex
• don’t really see receptors in brainstem. won’t see respiratory depression with cannabinoids
Variability of Compounds
Marketplace study
● From 7 Toronto dispensaries,
collected 12 of the most popular
cannabis strains
○ Mean THC levels ~ 20%
■ Some ~ 30%
■ (1970s → 2-8%)
○ CBD not detected
○ Labelling often inaccurate
■ Only 2 samples fell within
1% of listed amount
■ Some had more and some
19 had less than labelled
• can be variability and what chemicals are there
• don’t know what all the compounds do and are there in variable amounts
• health Canada allows od 15% diff of what was labeled
If PDT is not pharmaceutical grade, variability is higher, likely to not know what pt is getting
CannaSafe, a California
cannabis testing company,
did a blind analysis of 20
popular CBD products
● Only 3 contained what
labels said
● 8 contained < 20% of the
amount of CBD labelled,
including 2 that
contained none
Evidence - General Indications
Based on the available evidence, cannabinoids may be effective
for:
● Prevention of chemotherapy-induced nausea and
vomiting
● Decreasing spasticity of multiple sclerosis or spinal cord
injury
● Preventing seizures in Lennox-Gastaut and Dravet
syndrome (with CBD)
● Decreasing pain in chronic neuropathic pain
For most other indications, there is insufficient evidence,
evidence indicating a lack of benefit, or both
• evidence for pain
• a lot of these studies had sml numbers of patients
• duration tends to be short, 5 days or hours
these are chronic pain pt and hard to know if benefit long term, is it sustained or does it wear off?
Evidence for Pain
Encouraging, but
some obvious
limitations:
Duration =
generally short
N = usually small
• nabixomol has most consistent evidence of effect
• effect size is not huge, nt a large diff for pain sad, going down 2
• heterogeneity no evaluation of qual of life or function
• 30% reduction of chronic pain,NNT 11
• AE: NNH was low, 14
• experienced users, tolerant to side effects, kr are regular users cuz they don’t experience side effects, AE is underestimated
• modest effects size
• placebos, a lot of pts were unblinded, pts preference for cannabinoids exceeds effects, they like it
Analgesic
efficacy of
nabilone or
nabiximols
Note:
- Effect size
- Heterogeneity
- No evaluation
of quality of
life or function
Evidence - Summary
● For chronic pain, NNT ~ 11-24 for a ≥ 30% decrease in
pain scores
● Effect size generally modest, at best
● NNH ~ 6 to experience an adverse effect
○ But no “serious adverse effects”
● Nabiximols has most robust data for pain
● Most studies used a placebo comparator and added
cannabinoids to stable doses of analgesics
● Higher doses may not produce improved analgesia,
but do cause more adverse effects
challenges with the evidence:
● Small sample sizes, short durations, heterogeneity
○ Trials of longer duration tended to show less
benefit
● THC content - generally lower than what is currently
available
● Studies often included primarily experienced users
(may underestimate adverse effect potential)
● Few adequately blinded (unblinding common)
Pregnancy & Lactation
Limited studies suggest that use in pregnancy may be
associated with:
● low birth weight, ?preterm/stillbirth
● ?negative effect on neurodevelopment
Lactation
● limited data indicate that THC does transfer into
breast milk - no evidence for safety or harm
● ?effect on neurodevelopment
Risk for Neurodevelopment
The endocannabinoid system plays a role in
neurodevelopment
The direct and indirect regulation of the
endocannabinoid system by exposure to exogenous
cannabinoids during development may have
important effects on the brain and behaviour later in
life
• limited evidence • age 18 to purchase cannabis brain does not stop growing until 25
Cannabinoid Hyperemesis
Syndrome
Cyclic vomiting secondary to chronic cannabinoid use
Characterized by:
● Regular cannabinoid use for more than a year
● Regular cannabinoid use at least weekly
● Severe nausea and vomiting
● Resolution of symptoms after stopping cannabinoid
● Compulsive hot bathing/showering for symptomatic relief
Treatment
● Stop cannabinoid
● Supportive measures (IV fluids, anti-emetics, etc)
33 ● ? capsaicin cream
• supposed to help with NV
they take more and get more NV, vicious cycle
Approach to
Cannabinoid Usage
In the Context of Pain
Always start with a pain assessment; define goals of
treatment; appropriately set expectations
Screen for risk of misuse (e.g., CAGE-AID, CUDIT-R)
Pharmaceutical grade cannabinoids (i.e., nabilone or
nabiximols) preferred over non-pharmaceutical grade,
particularly over the inhaled route
○ Difficulty dosing, respiratory risk (inhaled), variability of composition
Start low, go slow
Reasonable trial duration may be 12 weeks
36 ○ Consider taper if goals not met (~25% ↓ per week)
• pain assessment
• define goals of TX
• set expectations
• would not just stop opioids
• screen for misuse
• pharmaceutical pptopns preferred
• 12 wks trial reasonable
• dosing unkiwn for while cannabisdont need to jnwo how to dose for exam
• inhaled - go w 1-2 puffs qnd titration up
uncertainty or how they use it and how they are getting it
Drug Interactions
Pharmacodynamic
● Ethanol, opioids, benzodiazepines, anticholinergics, etc
○ Additive CNS effects
Pharmacokinetic
● THC is a CYP2C9 and 3A4 substrate
● CBD is a CYP2C19 inhibitor and substrate and 3A4
substrate
● If smoked, may result in CYP1A2 induction
• nabilone is THC mimick but does not have the same interactions as THC
