Medical Cannabis Clinical Pharmacology Professor Nicholas Lintzeris - - PowerPoint PPT Presentation

Medical Cannabis Clinical Pharmacology

Professor Nicholas Lintzeris MBBS, PhD, FAChAM

Director D&A Services, SESLHD University of Sydney, Division Addiction Medicine NHMRC Australian Centre Cannabinoid Research Excellence

COI statement

• NL has received funding for medical cannabis related research

with NSW government (OMC), NSW Health, NHMRC, and University Sydney Lambert Initiative

• NL has provided paid consultancies to Mundipharma and Indivior,

and received research funding from Braeburn/Camurus.

Overview

• Pharmacology of THC and CBD
• Patterns of use & experiences of Australian medical cannabis users
• Understanding different routes of administration
• Adverse events
• Relevant drug-drug interactions

Endocannabinoid system

• CB1 receptors:
• Brain: memory, mood, executive function,

cognition, analgesia, movement

• GI: appetite, lipolysis
• Respiratory
• CB2 receptors
• Immune system: reduce inflammation,

neuropathic pain

• Endogenous cannabinoids
• Anandamide, 2 AG
• Metabolic enzymes (FAAH, DAG, MAGL)
• Impacted upon by exogenous cannabinoids
• Plant or synthetic

(I (Ill llicit) Cannabis use for medical reasons is is not uncommon

• Cross sectional studies suggest 10-15% of patients with certain chronic conditions

have used cannabis to assist with symptoms ―Chronic non-cancer pain (POINT Cohort, Degenhardt, Lintzeris et al 2014)

―43% had ever used cannabis for any reason; 16% for pain; ―13% used cannabis past yr; 8% past month; 6% weekly ―24% indicated would use cannabis for pain if they could access

―Palliative care (Luckitt et al 2016)

―N=204 respondents, 13% reported prior medical cannabis use.

―Epilepsy (n=976 online survey) (Suarev et al 2017)

―15% adults reported current / past use cannabis products to treat epilepsy with 90% reporting reduced seizure frequency ―13% of children, reported current / past use cannabis products to treat epilepsy with 71% reporting reduced seizure

• Surveys indicate strong community support for medical cannabis (>80%)

Cannabis extract use in Australia PELICAN study (Suraev, Lintzeris in press)

C A E D B F

• 41 families across NSW and

Queensland using (illicit) cannabis extracts to treat their children’s epilepsy

• Decision to use cannabis extracts

linked to failure to get response from conventional treatment

• Contrary to family’s expectations,

most samples did not contain CBD, while THC was present in most samples

Pharmacology of THC

• Partial agonist at CB1 receptor system
• Derived from plants or made

synthetically

• Produces range of psychoactive and

physiological effects

• Psychoactive effects: sedation, euphoria,

cognitive performance effects such as memory and delayed reaction time

• Physiological: increased BP, PR, analgesia,

antispasmodic, antiemetic

Reference: World Health Organisation. CANNABIDIOL (CBD) Pre-Review Report. Expert Committee on Drug Dependence. Thirty-ninth Meeting. Geneva, 6-10 November 2017

Pharmacology THC

• Higher bioavailability inhaled
• 10-35% inhaled
• 5-15% oral (first pass metabolism)
• 10-20% oromucosal / suppository
• poor absorption topically
• Peak effects:
• Inhaled:10-90 minutes after use
• Oral: 60- 240 minutes after use
• Hepatic metabolism (CYP 2C8/9/19) to 11-

OH THC (active) then THC-COOH (inactive)

• Reference Fig 5. and 6 : Didier M.Lambert 2009, Cannabinoids in Nature and Medicine. Wiley-VCH Switzerland.

Smoking cannabis …

Vaporising

• Vaporising: similar to ‘e-cigarettes’
• heats cannabis at lower temperature
• fewer ‘toxins’, higher bioavailability than smoking
• no side stream smoke (fewer concerns re: passive smoking)
• TGA-compliant devices: Volcano, Mighty Medic

Table Ref: Didier M.Lambert 2009, Cannabinoids in Nature and Medicine. Wiley-VCH Switzerland.

Namisol

• Oral THC tablet with rapid onset

and reliable absorption than other marketed oral THC formulations

Klumpers et al 2012 BJCP

Current & preferred routes of administration in Australia

CAMS16: Lintzeris et al MJA 2018

Client reported time effects (CAMS16 in press)

Smoked / inhaled routes (mean ± SD) (n=1120) Oral routes (mean ± SD) (n=194) Stats Time to onset of effects 5.5 ± 8.1 32.4 ± 27.3 P<0.001 Time of maximum effects 17 ± 19 59 ± 69 P<0.001 Time duration of effects 135 ± 219 295 ± 477 P<0.001 Number of times used per day 5.4 ± 5.1 2.8 ± 2.5 P<0.001

Selecting route of administration

(MacCullum & Russo 2018)

THC excretion in chronic cannabis users

Reference Figure 2: Didier M.Lambert 2009, Cannabinoids in Nature and Medicine. Wiley-VCH Switzerland.

Cannabidiol (CBD)

• A non-psychoactive cannabinoid
• Anticonvulsant effects
• Anxiolytic, antipsychotic
• Neuroprotective: ?dementia
• Analgesia: THC+CBD > THC or CBD only
• Doses:
• ?200-1200mg oral / day prescribed
• 10-50mg oral / day OTC for ‘wellness’
• Schedule 4 drug in Australia
• Main areas of interest: epilepsy, mental health,

neurodegenerative conditions, addictions, auto-immune

CBD: Pharmacokinetics

• Poor (& highly variable) oral bioavailability; estimated at 6-10%, due to first

pass metabolism

• Usually dissolved in oral olive / sesame oil capsules or drops
• Topical, inhaled and sublingual routes also available and avoid 1st pass metabolism
• Half life 20-36 hrs
• Extensively metabolised in the liver by CYP enzymes
• Primary route is hydroxylation to 7-OH-CBD, which is then further metabolised into a

number of (inactive) metabolites (e.g. CBD-COOH), excreted in faeces and urine

• CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5
• Inhibits CYP activity upon other drugs, resulting in potential accumulation of other

drugs (e.g. phenytoin, carbamazepine, clobazam)

• Lipid soluble and accumulates in adipose tissue
• Excreted in urine and can be assayed

CBD: Pharmacodynamics

• Anxiolytic, antipsychotic, anticonvulsant, anti-inflammatory, analgesic, neuro-

protective effects

• No effects on physiological parameters (BP, PR, RR)
• No psychoactive properties, no abuse potential, no withdrawal
• CBD in addition to THC does not reduce the reinforcing, physiological, or positive

subjective effects of THC. May reduce AEs when added to THC

• Mechanism of action of CBD unclear
• Acts to reduce or antagonize some of the effects of THC and other CB1 agonists (?negative

allosteric modulator of the CB1 receptor)

• Interacts with endocannabinoid system (increases anandamide activity)
• Modulates several non-endocannabinoid signaling systems
• Inhibition of adenosine uptake
• Enhanced activity at the 5-HT1a receptor.
• Enhanced activity at glycine receptor subtypes
• Blockade of the orphan G-protein-coupled receptor GPR55

Adverse events

Potential harms of illicit cannabis use (high % THC, smoked)

• Cognition & performance

– Sedation and mild cognitive impairments: attention, memory, learning, psychomotor function – Most effects reversible with abstinence, but may persist in heavy adolescent users – Intoxication related injuries (e.g. driving, falls)

• Mental health

– Anxiety symptoms, panic attacks with acute intoxication – Acute psychosis can be associated with acute intoxication or may persist for days (weeks) beyond intoxication – Persistent psychosis: linked to early onset & heavy adolescent use. Cannabinoids are a 'component cause' interacting with other known (genetic predisposition) and unknown factors to result in psychosis outcomes

• Dependence: estimated at 1 in 10 users
• Physical effects

– Hypotension, tachycardia, dizziness, dry mouth, respiratory problems (smoking)

Side effect reported (N=1302) n (%) Severe and/or intolerable side effect reported (N=1302) n (%)

Increased appetite 963 (74.0%) 79 (6.1%) Drowsiness 873 (67.1%) 23 (1.8%) Ocular irritation (red, sore, itchy eyes) 530 (40.7%) 13 (1.0%) Lack of energy 488 (37.5%) 16 (1.2%) Memory impairment 412 (31.6%) 7 (0.5%) Racing heart (palpitations) 201 (15.4%) 2 (0.2%) Paranoia 198 (15.2%) 14 (1.1%) Decreased appetite 171 (13.1%) 5 (0.4%) Confusion 162 (12.4%) 3 (0.2%) Dizziness 124 (9.5%) 5 (0.4%) Anxiety 119 (9.1%) 9 (0.7%) Sweating 95 (7.3%) 3 (0.2%) Difficulty controlling movements 78 (6.0%) 2 (0.1%) Gastro-intestinal irritation 62 (4.8%) 4 (0.3%) Headache 57 (4.4%) 4 (0.3%) Indigestion 55 (4.2%) 1 (0.3%) Depressed mood 52 (4.0%) 5 (0.4%) Diarrhoea 52 (4.0%) 4 (0.3%) Hallucinations 38 (2.9%)

‘Side effects’

CAMS16

(Lintzeris MJA in press)

Common but generally well tolerated

Adverse events with prescribed medical cannabis

Most side effects are dose related (increase as dose increases) About 10-30% patients enrolling in medical cannabis trials withdraw from treatment (usually side effects)

Reference table 4 and graph: Didier M.Lambert 2009, Cannabinoids in Nature and Medicine. Wiley-VCH Switzerland.

Responding to psychiatric complications

• THC based medicines contraindicated in patients with history of psychosis,
• r severe anxiety, cognitive impairment related to cannabis use
• AEs can be minimised by:
• Slow dose titration (2.5-5 mg / day, increasing to 10-20mg over 1-2 weeks)
• Low doses and avoid high peak concentrations (e.g. inhaled routes)
• Counter THC effects with CBD (avoid THC only products if concerns)
• First principles of managing AE: discontinue cannabis, consider

symptomatic treatment

• Psychiatric AEs may be reason to discontinue THC treatment

Cannabis withdrawal syndrome DSM-5 (CAMS:16)

≥ 3 of the 7 symptoms within several days of ceasing heavy and prolonged cannabis use

0% 10% 20% 30% 40% 50% 60% 70% Irritability, anger or aggression Nervousness or anxiety Sleep difficulty (insomnia) Decreased appetite or weight loss Restlessness Depressed mood Physical symptoms

Withdrawal symptoms endorsed (n=1074) Proportion endorsing ≥3 symptoms 47.0%

Development of cannabis use disorder in patients using long term medical cannabis (THC) use

• Diagnosis of dependence / addiction to a medication used therapeutically

is often difficult

• Tolerance and withdrawal insufficient for diagnosis
• Focus more on ‘loss of control’
• Based on current estimates, predict 10-20% patients with chronic medical

cannabis use will develop dependence criteria (mod-severe CUD, DSM5)

• Consider ‘universal precaution’ approach to prescribing medical cannabis

(screening for risk of CUD, modify treatment conditions according to risk, treatment agreement)

Safety issues CBD use in children

• Adverse events of CBD oral doses 5-30mg/kg/day (TGA

review)

• Diarrhoea (20%), somnolence (18%), increased appetite (17%),

decreased appetite (17%), worsening seizures (15%), pyrexia (13%), fatigue (11%), status epilepticus (10%)

• Elevated ALT, ADT (>3 x normal range) in 22% patients
• SAEs estimated at 1-3% patients (status, LFTs)
• Long term effects (e.g. >5 years) high dose CBD unknown
• Drug-drug interactions
• Reference data: Didier M.Lambert 2009, Cannabinoids in Nature and Medicine. Wiley-VCH Switzerland.
• Reference data: Australian Government Dept of Health, Guidance in the use of medicinal cannabis in the

treatment of epilepsy in paediatric and young adult patients in Australia. Version 1, December 2017.

Driving and medical cannabis

• Cannabinoids can impair driving
• Epidemiological studies (major confounds): comparable to Blood alcohol 0.02-0.04%
• Drug driving simulation studies (major confounds)
• Probably no greater impact upon driving than range of commonly used medicines (BZDs,
• pioids, TCAs, neuroleptics)
• The law states a patient should not drive if a medication impairs their ability to

drive (no specific legislation for any drug classes)

• Mobile Drug Testing test for and penalises presence of THC – not impairment
• Vaped & buccal (e.g. nabiximols) CBs positive for several hours after use
• Uncertain re: oral tablets / liquids
• Talking to patients: like other medications - should not drive if impaired; but

beware uncertain status re: MDT

Drug-drug interactions

• CBD
• Key interactions relate to hepatic CYP interactions (3A4, 2C19)
• CBD inhibits activity of these enzymes, such that get reduced metabolism of
• ther drugs - and can result in ‘toxicity’
• Particularly relevant with anticonvuslants (carbamazepine, clobazam,

phenytoin), some antidepressants (fluvoxamine)

• Note: these other drugs can inhibit metabolism of CBD: 2 way interaction
• THC
• Hepatic CYP interactions possible, but probably less clinically relevant
• Key interactions: cumulative sedation / cognitive impairment with alcohol and
• ther sedating medications (falls, driving)
• Some evidence for potentiation effects of opioids (THC + opioids > analgesia

than THC or opioids alone)

Conclusions

• Great uncertainty in composition of illicit cannabis products in Australia
• Legal approaches provide greater certainty re: composition
• Dose and route matter re: safety and effectiveness
• THC relatively safe medication – side effects are common but generally

well tolerated in most (but not all) patients

• CBD – generally safe medication, but beware drug-drug interactions with

high doses