Lecture 14: Cannabis & Cannabinoids

Question 1

What is the definition of cannabis?

Answer 1

genus of flowering plant

contains many bioactive compounds, but most studied are tetrahydrocannabinol (THC) and cannabidiol (CBD)

THC is the primary psychoactive compound in cannabis

Question 2

What is the definition of cannabinoids?

Answer 2

class of chemical compounds that act at the cannabinoid receptors

Question 3

What are terpenoid non-cannabinoid constituents in cannabis?

Answer 3

cannabis also contains hundreds of non-cannabinoid constituents, including terpenoids which give plant characteristic smell

in vitro and in vivo studies found some terpenoids to have anti-inflammatory, anti-bacterial and anti anxiety effects, but no clinical trials to support this

possibility of synergy between compounds may explain differences in experience based on strains, makes harnessing clinical utility very difficult

Question 4

What is the absorption of THC?

Answer 4

absorption, aka bioavailability = fraction of an administered drug that reaches effectors (plasma, central nervous system)

most pharmacokinetic information relates to THC, only

smoking provides rapid and efficient delivery from lungs to the brain; bioavailability of smoked THC is 25%, reaching peak plasma concentration in 6-10 minutes

when ingested, bioavailability around 6%, time to peak plasma concentration is 2-6 hours

Question 5

What is the distribution of THC?

Answer 5

THC is highly lipophilic so rapidly taken up by tissues with high blood flow, including heart, lungs, brain, and liver

tissues with less blood flow accumulate THC more slowly and release it over a longer period of time (i.e. adipose tissue)

THC stored in fat in chronic; frequent cannabis smokers can be released into the blood for days

Question 6

What is the metabolism and elimination of THC?

Answer 6

THC metabolism occurs mostly in the liver by cytochrome P450 2C9 enzyme producing the metabolites 11-OH-THC and THC-COOH

within 5 days, 80-90% of a THC dose is excreted, primarily as metabolites, 65% in feces and 25% in urine

can detect THC in urine 2-5 days for low dose THC, but can extend to weeks in chronic daily cannabis smokers (because THC is lipophilic can accumulate in adipose tissue)

Question 7

What are the characteristics of cannabinoid receptors?

Answer 7

cannabinoid receptors are inhibitory G-protein coupled receptors (Gi coupled)

cannabinoid receptors come in two flavors: CB1 and CB2

CB receptors leads to decrease in cyclic adenosine monophosphate (cAMP) accumulation which inhibits the influx of calcium in the firing neuron and inhibits neurotransmitter release

decrease synaptic transmission, inhibit neurotransmitter release

Question 8

What are the pharmacodynamics of THC?

Answer 8

THC is a partial agonist at CB1

cannabidiol (CBD) mechanism of action is poorly understood; binds a lot different targets poorly (low affinity)

some evidence it can act as negative allosteric modulator at CB1 (binds outside the binding pocket to block receptor activation)

CBD can blunt psychotropic effects of THC (maybe?)

Question 9

What are CB1 receptors?

Answer 9

CB1 receptors are among the most abundant GPCRs

CB1 receptors found in brain, peripheral organs (heart, liver, fat, stomach, testes) and peripheral nerves

Question 10

What are CB2 receptors?

Answer 10

receptor distribution mostly on immune cells

Question 11

What are the general effects of THC?

Answer 11

euphoria
relaxation
disinhibition
changes in perception
vasodilation
increase pulse rate

Question 12

What are the potential therapeutic effects of THC?

Answer 12

attenuation of nausea
increased appetite
decreased intraocular pressure
chronic pain relief

Question 13

What are unwanted effects of THC?

Answer 13

memory impairment
dysphoric state
visual hallucinations
depersonalization
psychotic episodes

Question 14

What are CBD effects?

Answer 14

some preclinical research suggests CBD has therapeutic potential for management of inflammation, anxiety, emesis, nausea, inflammatory pain and epilepsy (but usually doses many fold higher than what is biologically possible in vivo, off target effects?)

strong clinical data lacking for these claims

pediatric epilepsy is the only condition in which high quality clinical data (randomized, placebo controlled, control clinical trials)

Question 15

What was the effect of CBD on Dravet Syndrome?

Answer 15

patients (2-18 years old) with confirmed diagnosis of Dravet Syndrome (genetic disorder associated with severe seizures from birth)

oral CBD significantly reduced frequency of seizures more than placebo

Question 16

What are the adverse acute effects of THC?

Answer 16

panic attacks, severe anxiety, psychosis, paranoia, convulsion, hyperemesis

these are rare and usually associated with high doses of THC

Question 17

What are the adverse prenatal effects of THC?

Answer 17

cannabis use may lead to neuroanatomical and behavioral changes in offspring

fetal growth affected (particularly neurodevelopment), but dose-response relationship not identified

Question 18

How is lung cancer an effect of THC?

Answer 18

particularly through smoked cannabis

Question 19

What are the effects of THC on driving?

Answer 19

driving while intoxicated seems to increase the risk of being in a motor vehicle accident

THC impairs perception, psychomotor performance, cognitive functions and affective functions

decreased reaction time

Question 20

Does THC overdose cause death?

Answer 20

no documented evidence of a death that can be exclusively attributed to overdosing with cannabis, probably because sparsity of CB1 receptors in the brain stem region that controls respiratory and cardiovascular systems

Question 21

Does cannabis use (particularly in adolescence) increase the risk of later developing psychotic disorders, such as schizophrenia?

Answer 21

a lot of correlative data suggesting schizophrenics are more likely to use cannabis, and early cannabis use dose-dependently predicts the development of schizophrenia later on

however, these studies do not indicate causation; does not take into account reverse causality bias, and confounding variables

majority of people who use cannabis do not develop schizophrenia; however, cannabis can elicit acute psychosis, can worsen course of pre-existing schizophrenia, and may be a trigger in the development of schizophrenia in at-risk populations (i.e. those with genetic predisposition)

Question 22

What is psychological dependence on cannabis?

Answer 22

compulsive drug-seeking behavior in which the individual uses the drug receptively for personal satisfaction, often in the face of known risks to health

Question 23

What is physiological dependence on cannabis?

Answer 23

revealed when withdrawal of the drug produces symptoms and signs that are frequently opposite of those sought by the user

Question 24

What are the symptoms of cannabis withdrawal?

Answer 24

relatively mild and short-lived

symptoms of restlessness, irritability, mild agitation, insomnia, nausea, and cramping

may be worse in chronic, long-term users, and may contribute to continued drug use

Question 25

What is addiction (or substance use disorder)?

Answer 25

addiction (or substance use disorder) is defined as the inability to control the use of legal or illegal substances despite negative consequences

diagnosed by 11 diagnostic criteria

severity of the substance use disorder is determined by the number of criteria the person meets (2/11 = mild; 4/11 = moderate, 6+/11 = severe)

approximately 9% of those who use cannabis develop a substance use disorder

rates similar to other recreational drugs of abuse, such as alcohol

Question 26

What are synthetic cannabinoids?

Answer 26

a manufactured compound whose properties imitate those of the active constituents of cannabis

Question 27

What create synthetic cannabinoids?

Answer 27

increased specificity

decreased off target effects

easier dosing

better controlled studies

Question 28

What are the medical uses of synthetic cannabinoids?

Answer 28

well confirmed clinical effects for refractory nausea and vomiting, appetite loss, HIV/AIDS/cancer cachexia

Question 29

What is the synthetic cannabinoid nabilone?

Answer 29

synthetic analog of THC

Question 30

What is the synthetic cannabinoid dronabinol?

Answer 30

(-) trans isomer of delta 9-THC, approved for nausea and vomiting in patients who undergo chemotherapy and anorexia in AIDS wasting syndrome

Question 31

What are the similarities between synthetic cannabinoids nabilone and dronabinol?

Answer 31

both are partial agonists at the CB1 receptor

both nabilone and dronabinol are taken orally

oral THC analogs have less psychotropic effects than cannabis

Question 32

What is the synthetic cannabinoid rimonabant?

Answer 32

rimonabant is an inverse agonist at the CB1 receptor

leads to the reduction in appetite

originally approved for the treatment of obesity, but later withdrawn due to serious adverse effects (depression and suicide ideation)

Question 33

What are endocannabinoids?

Answer 33

cannabinoid receptors didn’t evolve to respond to cannabis; they exist because we have endogenous cannabinoids (“endocannabinoids”) that mediate mood, feeding, motor function

come in two flavors: anandamide (AEA) and 2-arachinoyl glycerol (2-AG)

Question 34

What is the synthesis of endocannabinoids?

Answer 34

AEA and 2-AG are made from the phospholipid bilayer of the cell membrane

Question 35

What is the signaling of endocannabinoids?

Answer 35

AEA and 2-AG are retrograde neurotransmitters

in contrast to most neurotransmitters (i.e., glutamate, GABA), AEA and 2AG are not stored in vesicles, but rather synthesized on demand when and where they are needed

like THC, endocannabinoids decrease neuronal release of other transmitters

synthesis of 2AG or AEA is stimulated by increase in concentration of intracellular calcium when the postsynaptic neuron becomes depolarized by the action of a neurotransmitter

thus, produced only in regions of brain that are activated

Question 36

What is the metabolism of endocannabinoids?

Answer 36

AEA and 2AG are rapidly cleared from the synapse and inactivated by fatty-acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL)

suppression of these enzymes prolongs the activity of endocannabinoids

Question 37

What are the medical uses of FAAH/MAGL inhibitors?

Answer 37

because AEA and 2AG are synthesized and released on demand at the site of action, inhibition of AEA or 2AG metabolism would enhance CB1 activation where AEA and 2AG levels are highest, not globally throughout the brain

FAAH/MAGL inhibitors do not produce typical psychoactive effects of THC, sedation, catalepsy, or hypothermia, but do not have analgesic effects

several compounds under development for the treatment of chronic pain

BUT, recent clinical trial of FAAH inhibitor halted, because of several severe adverse events