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) A 20.8 21.3 20 B CBDA 20 18.7 • 41 families across NSW and 15 15 CBD 10 10 8 8 7 CBD and CBDA concentration (mg/kg/day) Queensland using (illicit) cannabis 6 6 CBD tot (mg/kg/day) 5 4.7 4.4 4 4 extracts to treat their children’s 3.3 2.9 2.8 3 2.7 2.4 2 2 1.6 1.5 epilepsy 1 1 .7 .5 .6 .5 .3 .18 .1 .1 .09 .1 .1 .02 0 <.01 <.01 .04 .03 <.01 0 .06 <.01 0 .02 .04 <.01<.01 . 0 2 <.01 .01 <.01 .04 0 .02 .04 .03 .03 .02 .03 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 1 2 3 4 5 6 7 8 9 10 11 12 13 C 20 D THCA 20 15 THC 15 • Decision to use cannabis extracts 10 10 8 8 7.1 THC and THCA concentration (mg/kg/day) 6.2 6 6 linked to failure to get response from 5.7 THC tot (mg/kg/day) 4.5 4.1 4 4 3.7 conventional treatment 3.1 2 2 1.7 1.3 1.3 1.2 1.3 1.2 .9 .5 .5 .5 • Contrary to family’s expectations, .4 .3 .3 .3 .24 .2 .2 .24 .2 .2 .2 .2 .1 .15 .16 .11 .13 .13 .1 .06 <.01 .1 .02 .03 .02 .07 .01 .05 .07 .05 .03 .01 .03 .06 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 1 2 3 4 5 6 7 8 9 10 11 12 13 E 8 5.7 F THCVA 6 8 3.4 4 6 THCV 2 4 2 CBDV 1.5 most samples did not contain CBD, 1.5 1.5 CBDVA 1.4 Trace cannabinoid concentration (mg/kg/day) CBGA CBG Trace cannabinoids (mg/kg/day) 1.2 CBN CBC 1.03 while THC was present in most 1.0 1.0 .69 .6 .6 .6 samples 0.5 0.5 .4 .32 .3 .2 .2 .16 .1 .12 .1 .1 .05 .06 .06 .06 .1 .05 .03 .07 .08 .06 .04 .02 .03 .04 .01 .03 .03 .05 .02 .01 .01 .05 .03 <.01<.01 <.01 <.01 0 0 .01 0.0 <.01 0.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 1 2 3 4 5 6 7 8 9 10 11 12 13
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 / Oral routes Stats inhaled routes (mean ± SD) (mean ± SD) (n=194) (n=1120) 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 1 st 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)
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