CANNABIS - Ministry of Public Health Documents... · Cannabinoids •Cannabis contain ~500 chemicals •Compounds with a skeleton made of a resorcinol type ring with a terpene moiety

CANNABISสมนไพรแหงความเมตตา

Cannabinoidsbull Cannabis contain ~500 chemicalsbull Compounds with a skeleton made of a

resorcinol type ring with a terpenemoiety derivative attached to it (around 70 identified)

bull 80+ (gt113 2018) cannabinoids(21-carbon molecule)

bull Among cannabinoids THC and Cannabidiol (CBD) are the most abundant

Some of the more prominent cannabinoids include

bull Delta-9-tetrahydrocannabinol (THC)

bull Cannabidiol (CBD)

bull Cannabinol (CBN)

bull Tetrahydrocannabivarin (THCV)

bull Cannabichromene (CBC)

bull Cannabicyclol (CBL)

bull Cannabidivarin (CBDV)

bull Yet still another est 80-100 other cannabinoids

CLINICAL PHARMACOLOGY OF CANNABIS

bull 95-99 plasma protein bound

bull Hydroxylation oxidation and conjugation for rapidly clearance from plasma

bull 1st-pass metabolism with oral admin (11-OH-THC)

bull Elimination over several days (adipose)

bull Breast milk distribution

bull Pregnancy Category C

bull Excretion days to wks 20-35 found in urine

bull 65-80 found in feces

bull 5 as unchanged drug (when given PO)

bull Synthetic THC called dronabinol does not contain CBD CBN or other cannabinoids which is one reason why its pharmacological effects may differ significantly from those of natural Cannabis preparations(Entourage effect)

Pharmacological actions of THC

bull Psychotropicbull Initial euphoria and relaxationbull Followed by a depressant periodbull Alterations memory and cognitive perceptual

abilities

bull Immuno-suppressive immuno-modulationbull Cardiovascular (tachycardia orthostatic hypotension

peripheral vasodilation)

bull Analgesic

bull Anti-emetic

bull Appetite stimulant

Pharmacological Effects of CBD

bull Anticonvulsant

bull Analgesic

bull Anti-anxiety

bull Anti-psychotic

bull Anti-inflammatory

bull Anti-arthritic

bull Immunosuppressive

BRAINCB1RIntracellularVesicleMitochondriaLysosomeNeuronInterneuronAstrocyteOliogodendrocyteInfiltrating leukocyteCB2RMicrogliaBrainstem neuronAstrocyteIn response to insultProg neurogbiol2018

I

Implications of CB1 receptor activation

Central nervous system Peripheral tissue

Appetite Motivation

to eatsmoke

Gelfand EV Cannon CP J Am Coll Cardiol 2006471919-26Pagotto U et al Ann Med 200537270-5

Lipogenesis

Altered glucose metabolism

Adipose tissue

Liver GI tract

Skeletal muscle

Hypothalamus Limbic

system

UPREGULATION AT PERIPHERY IN METABOLIC DISEASES-POTENTIAL STRATEGY

Endocannabinoid

bull rdquo28yrs after discovering THC in 1992 Dr Mechoulam Dr William Devane and Dr LumirHanus identified the brains first endogenous cannabinoid (or endocannabinoid) - the brains natural version of THC -which they called

lsquoAnandamide from the Sanskrit word ananda (means eternal bliss or supreme joy)

bull ECS is a group of neuromodulatory lipids and their receptors in the brain that are involved in a variety of physiological processes including appetite pain-sensation mood and memory

bull It mediates the psychoactive effects of cannabis

bull Vigorous exercise stimulates the release of anandamide and the sense of euphoric well-being that comes with a healthy workout

Signal transduction at the CB receptor

(Ameri 1999)

Gio

bull CB receptors are linked to inhibitory G

protein

bull Inhibit adenylyl cyclasecAMP

bull Opening potassium channels cell

firing

bull Closing voltage dependent calcium

channels release neurotransmitters

bull Overall effect is that of cellular inhibition

bull Similar to opioids

CB1 knock-out miceถงแมผอม แตโง และเกดโรคมากมายbull CB1 cannabinoid receptor knockout in mice leads to leanness

resistance to diet-induced obesity and enhanced leptin sensitivity CB1

knock-out mice are healthy and live into adulthood [Int J Obes Relat Metab Disord 28 (4) 640ndash8]

bull Compared to wildtype CB1 knock-out mice exhibit severe deficits in motor learning memory retrieval and increased difficulty in completing the Morris water maze[5][53][54]

bull There is also evidence indicating that these knockout animals have an increased incidence and severity of strokeand seizure

FAAH degradesanandamide

ตกใจๆๆ anandamide มากกลบชก

The CB1 receptor paradox

bull The reasons for these apparent discrepancies are not clear Different processing of endocannabinoids in different species and at different developmental stagesdifferent experimental conditions (such as the method of inducing neurotoxicity and the parameters monitored) or differences in neuronal circuitries at different may be responsible for some of these divergent findings

Science 3 October 2003

Vol 302 no 5642 pp 65-67

ผลตเมอมการรองขอปรบสมดลย

Endocannabinoids amp neuroprotection

bull Anandamide (arachidonoyl-ethanolamide) and 2-arachidonoyl glycerol (2-AG)

bull Both anandamide and 2-AG bind to the cannabinoid receptors CB1 (present principally in the central nervous system and to a lesser extent in the peripheral nervous system) and CB2(present almost exclusively in the peripheral nervous system)

bull These receptors are activated by THC accounting for the effects of cannabis on the nervous system

bull A nonpsychotropic constituent of cannabis cannabidiol effectively treats major seizures in animals and HU-211 (Dexanabinolreg) is neuroprotective during brain trauma

bull Paradoxically neither cannabidiol nor HU-211 (and THC) binds to CB1 or CB2 receptors

AED properties 1977-2012

bull Several cannabinoids (Δ9-tetrahydrocannabinol Δ9-THC cannabidiol CBD Δ9-tetrahydrocannabivarin Δ9-THCV and cannabidivarin CBDV) are anticonvulsant in a variety of animal models of seizure and epilepsy (Consroe amp Wolkin 1977 Hill et al 2012a Hill et al 2010 Jones et al 2010)

bull CB1 cannabinoid receptor (CB1R) agonism is anti-epileptiform and anticonvulsant (Chesher amp Jackson 1974 Deshpande et al

2007b Wallace et al 2003 Wallace et al 2001)

bull The notable psychoactivity associated with CB1R activation hinders the prospective clinical utility of this target

bull CBD which exerts effects via as yet unknown non- CB1R mechanisms in vitro in vivo and in humans (Consroe et al 1982 Cunha et al 1980 Jones et al 2010 Wallace et al 2001)

bull CBD has low affinity for CB1 and CB2 receptors (Pertwee 2008)

PARADIGM SHIFT

bull 2014 AND AFTER

bull BUT HERE IN THAILAND

PAIN CONTROL

Dorsal raphe nuclei - medulla

CBD has been used therapeutically

in doses ranging from 285 to 50

mgkgday meaning that its

therapeutic dose is still unclear

cannabis

bull AddictionPsychotic like reaction

Attempt for ldquohighrdquo purpose

THC

At high dosage (not practical dosing as for medical use)

Genetic predisposition

bull Intellectual decline

gene not associated with cannabis durationdose

Whether regional differences in brain volume measured by MRI can provide clinically useful biomarkers of substance dependence Absence of substance-specific linear effects on brain volume related to nicotine methamphetamine or cannabis dependence despite the collection of large pooled samplesajppsychiatryonlineorg

NATURE NEUROSCIENCE | VOL 21 | SEPTEMBER 2018 | 1161ndash1170 | wwwnaturecomnatureneuroscience

2387 cases and almost 50000 controls plus a replication sample of 5501 cases and ~300000 controls

2016 International Cannabis Consortium (ICC) and is based on a sample size of 32330 individuals in the discovery sample along with 5627 individuals in the replication sample

four genes significantly associated with lifetime cannabis use NCAM1 CADM2 SCOC and KCNT2

Psychotic-like

Human Connectome Project (1188) and the Australian Twin Registry Cohort 3(ATR3 )(3486)

bull frequent use(iegt100times) a DSM-IV lifetime cannabis use disorder diagnosis and current cannabis use

bull Genetic and environmental correlation s between cannabis involvement and PLEs were estimated Generalized linear mixed models examined PLE differences in twin and nontwin sibling pairs discordant for cannabis use

bull RESULTS

bull Psychotic-like experiences were associated with frequent cannabis use(β=01195CI008-014)cannabis use disorder(β=01395CI 009-016)and current cannabis use(β=00795CI004-010) even after adjustment for covariates

bull Correlated genetic factors explained between 692 and 841 of this observed association Within discordant pairs of twinssiblings(Npairs308-324)Psychotic-like experiences were more common in cannabis-exposed individuals compared with their relative who used cannabis to a lesser degree

ความเชอทวา กญชาท าใหเกดโรคจต จรงหรอ1- การตาน CB1 receptor ในผ ปวยจตเภท ไมไดผล2- ระดบกญชาธรรมชาตในน าไขสนหลง anandamide (AEA) ต ากวาปกต ชวาแทจรงอาการทางจตเกดจากการพรองกญชาในตวการรกษาโดยเพมพลงกญชาธรรมชาตในรางกาย ไดผลเทากบใชยาโรคจต แตไมมผลขางเคยง

the presence of baseline differences before marijuana involvement the lack of a dosendashresponse relationship and an absence of meaningful differences between discordant siblings lead us to conclude that the deficits observed in marijuana users are attributable to confounding factors that influence both substance initiation and IQ rather than a neurotoxic effect of marijuana

wwwpnasorgcgidoi101073pnas1516648113

เจง clinical and

scientific evidence 2017

TOTALITY OF EVIDENCE

WHO THC Sept 2018clinical trials

ลกษณะการด าเนนโรคสะทอนถงกลไกของระบบภมคมกนทผดปกต เกดการอกเสบจากกระบวนการแบบตนและปลาย และมผลกระทบตอโครงสรางของสมองในทเปลอกหรอแกนประสาท รวมทงเหนยวน าใหเซลลในสมองท าตวเปนศตร

สตวทดลองคนแบบและระยะตางๆของโรค

กลไลทเกดขนในระยะตางๆ

เชลลในสมองเซลลในระบบภมคมกน

ระบบ eCannabinoid

ระบบ e cannabinoidตอตานการอกเสบทเกดจากสาร IL 1beta TNFซงจะเหนยวน า สารสอประสาทในทางเลว และตานตวด

THC

8112561MOPH

Painspasticity

คณภาพชวต-ปองกน-รกษา-ชะลอ only for medical use

bull 1-อาการแขงเกรง ทอาจรวมกบการบดของกลามเนอทเกดจากความผดปกตของสมอง ยกตวอยางเชนทเกดจากเสนเลอดตนหรอแตก ความผดปกตทระดบของไขสนหลง และรวมถงความผดปกตทเกดขนกบเดกหลงคลอดทมสมองพการหรอเจรญเตบโตผดปกต และโรคmultiple sclerosis

bull 2-อาการปวดทรมาน ทนอกเหนอจากมะเรงหรอปวดจากความผดปกตของเสนประสาทหรอระบบประสาท ยกตวอยางเชนอาการปวดทเกยวเนองจากการอกเสบของขอ เสนเอนและกลามเนอซงโดยปรกตจะตองใชยาแกปวดอยางรนแรงและรวมกบยาแกปวดทเปนอนพนธของมอรฟน

bull 3-ภาวะของการปฏเสธอาหารทงทเกดขนจากโรคทางจตประสาท anorexia nervosa และโรคทางกายทเกดขนทมผลกระทบกบจตใจ และอาการอาเจยนจากเคมบ าบด

bull 4-โรคทางสมองไดแกโรคพารกนสนสและโรคสมองเสอมเชนอลไซเมอร ในทางปองกน การชะลอโรค และการบรรเทาอาการ agitationrestlessnessทมอย

bull 5-โรคลมชกทงในเดกและผใหญทไมสามารถคมดวยยากนชกหนงชนด bull 6-โรคจตschizophrenia หรอโรคจตเภทbull 7-มะเรง เปนยาประกบ เพอคณภาพชวต และแกไขการเจบปวดทรมาน

Superiority

bull no reported deaths due to overdose due to a lack of CB1 receptors in brainstem cardiorespiratory centres

bull Tolerance does not develop to the benefits bull Over time dose escalation is not generally observedbull Existing studies have not demonstrated toxicity loss of effect of

concomitant medications exception is high dose CBD with clobazam metabolite N-desmethylclobazam require a dose reduction

bull M A Ware T Wang S Shapiro et al (2015) Cannabis for the management of pain assessment of safety study (COMPASS)) J Pain 2015 16 1233ndash1242

bull C Stott L White S Wright et al (2013) A Phase I open-label randomized crossover study in three parallel groups to evaluate the effect of Rifampicin Ketoconazole and Omeprazole on the pharmacokinetics of THCCBD oromucosal spray in healthy volunteers (2013) SpringerPlus 2236

Route of administration and absorption

bull Cannabis routes of administration and delivery

bull Smokingvaporization (10-60 absorption)

- Onset (min) 5ndash10 Duration (h) 2ndash4

- Start with 1 inhalation and wait 15 min Then increase by 1 inhalation every

15ndash30 min until desired symptom control has been achieved

bull Smoking produce toxic biproducts tar PAH (polycyclic aromatic hydrocarbons) carbon monoxide (CO) ammonia (NH3) Chronic use associated with respiratory symptoms (bronchitis cough phlegm) but not lung cancer nor COPD (if cannabis only) 0ndash50 of cannabis is lost to lsquoside-streamrsquo smoke

bull Vaporisation produce less CO not complete elimination of PAH Decreased pulmonary symptoms reported compared to smoking

C A MacCallum and E B Russo (2018) Practical considerations in medical cannabis administration and dosing (2018) Eur J Intern Med 4912-19

Route of administration and absorption

bull Oral (20-30 absorption)

- Oils capsules and other po routes increasingly popular due to convenience and accuracy of dosing

- Onset (min) 60ndash180 Duration (h) 6ndash8 (recommend 2-3 timesd)

- Ideally at bedtime to limit adverse events and titrate up from days 1ndash2 25 mg THC-equivalent once a day days 3ndash4 25 mg THC twice a day max according to indication

- Doses exceeding 20ndash30 mgday may increase adverse events or induce tolerance without improving efficacy

bull Oromucosal (Nabiximol)

-Onset (min) 15ndash45 Duration (h) 6ndash8

bull Oral (Chemovar)

-CBD-predominant chemovars

-psychosis (800 mg) and seizure disorders (2500 mg or 25ndash50 mgkg)

As of clinical trial results with approved product

THC-CBD

CBD

As of clinical trial results with approved product

WHY WE LOVE Unapproved product

bull Does not mean that it is not effective

bull Does not mean that it is not safe

bull Adaptmodify from long time experienceuse based on ancient recipe

bull Witnessed by sufferers from various conditions and diseases

bull QUALITY OF LIFE (COMORBIDANXIETY ndash DEPRESSION ndashAPPETITE-SENSE OF WELL BEING)

bull SYMPTOMATIC ARREST OR RETARD DISEASE PROGRESSION

bull CURATIVE TREATMENT

bull Knowing starting dose-step to increase-safety issueprecaution-maximum dosage

bull Benefit from ENTOURAGE EFFECT

Neuropathic pain cancer pain and spasticity- Yellow (Start at 5mg 05mg recommend 6-8

times per day max 24 times per day)- Suggest monitoring with detailed

documentation subjective as symptoms fluctuate according to several factors However scoring such as Unified Parkinsonrsquos Disease Rating Scale (UPDRS) can be used Important side effect profiles

Suggest monitoring with Neuropathic Pain Scale (NPS) and important side effect profiles

Epilepsy - In adult epilepsy use

Green (start from 20mg bedtime max 800mg)

Suggest monitoring with number and duration of seizure and important side effect profiles

Parkinsonrsquos disease - Both motor and non-motor (pain and mood)

use yellow (Start at 10mg 1mg at bedtime and titrate up to 30mg 3mg every 2 days

Suggest monitoring with detailed documentation subjective as symptoms fluctuate according to several factors However scoring such as Unified Parkinsonrsquos Disease Rating Scale (UPDRS) can be used Important side effect profiles

Alzheimerrsquos disease - Agitation and restlessness use red (Start

1mg at bedtime and titrate up to max 3mg twice daily)

- Reduced appetite and depressed mood use yellow (Start at 10mg 1mg at bedtime and titrate up to 30mg 3mg every 2 days)

Suggest monitoring with Mini-mental state examination (MMSE) Neuropsychiatric Inventory (NPI) score and important side effect profiles

cannabidiol (CBD)bull anxiolytic anti-psychotic antidepressant and

neuroprotective properties

bull CBD acts on the ECBS as a weak inverse agonist on CB1 receptors stimulates the TRVP1 and alters the hydrolysis of AEA by inhibiting fatty acid amine hydrolase

bull CBD an agonist of 5-HT1a serotoninergic receptors and to regulate stress response and compulsive behaviors

bull CBD modulates allosterically micro and δ opioid receptors

bull The direct impact of CBD on glutamatergic neurotransmission is not known but its protective effects on glutamate toxicity have been studied

bull Altogether CBD has been associated with many neural circuits involved in the acquisition of addiction and subsequent drug seeking behaviors pharmacological candidate to treat substance-use disorders

bull

SubStance abuSe ReSeaRch and tReatment 20159

กลมกญชา เพอผปวย