Cannabis and Cannabinoids

Cannabis and Cannabinoids

• Cannabis is a genus of flowering plants with many bioactive compounds.
• The most studied bioactive compounds are tetrahydrocannabinol (THC) and cannabidiol (CBD).
• THC is the primary psychoactive compound in cannabis.
• Cannabinoids are a class of chemical compounds that act at the cannabinoid receptors

Cannabis Constituents

• Cannabis contains hundreds of phytocannabinoids.
• Examples of phytocannabinoids include delta-9 tetrahydrocannabinol (△9 THC), delta-8 THC, cannabidiol (CBD), cannabigeral (CBG), and Cannabinol (CBN).
• Cannabis also contains hundreds of non-cannabinoid constituents, including terpenoids, which give the plant its characteristic smell.
• In vitro and in vivo studies have found that some terpenoids have anti-inflammatory, anti-bacterial, and anti-anxiety effects, but these lack clinical trials.

Pharmacokinetics and Dynamics

• Absorption, or bioavailability, is the fraction of an administered drug that reaches effectors, such as plasma or the central nervous system.
• Most pharmacokinetic information focuses on THC.
• Smoking provides rapid and efficient THC delivery from the lungs to the brain.
• When smoked, THC has a bioavailability of 25%, reaching peak plasma concentration in 6-10 minutes.
• When ingested, THC has a bioavailability of around 6% and can take 2-6 hours to reach peak plasma concentration.
• THC is highly lipophilic, so it is rapidly taken up by tissues with high blood flow, including the 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).
• Cytochrome P450 2C9 enzyme metabolizes THC mostly in the liver, 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.
• THC can be detected in urine for 2-5 days after a low dose, but this extends to weeks in chronic daily cannabis smokers because THC can accumulate in adipose tissue due to being lipophilic.
• Cannabinoid receptors are inhibitory G-protein coupled receptors (Gi coupled).
• There are two types of cannabinoid receptors: CB1 and CB2.
• CB receptors reduce cyclic adenosine monophosphate (cAMP) accumulation, which inhibits the influx of calcium in the firing neuron and inhibits neurotransmitter release, decreasing synaptic transmission.
• Some evidence suggests that cannabidiol (CBD) can act as a negative allosteric modulator at CB1, binding outside the binding pocket to block receptor activation.
• Cannabidiol (CBD) can blunt the psychotropic effects of THC.
• CB1 receptors are abundant GPCRs that are found in the brain, peripheral organs like the heart, liver, fat, stomach, testes and peripheral nerves.
• CB2 receptor distribution is mainly on immune cells.

THC Effects

• General effects of THC can include Euphoria, Relaxation, Disinhibition, Changes in perception, Vasodilation and Increased pulse rate.
• Potential therapeutic effects of THC can include Attenuation of nausea, Increased appetite and Chronic pain relief.
• Unwanted effects of THC can include Memory impairment, Dysphoric state, Visual hallucinations, Depersonalization, Psychotic episodes.

CBD Effects

• Preclinical research suggests that CBD has therapeutic potential for managing inflammation, anxiety, emesis, nausea, inflammatory pain, and epilepsy
• It is important to note this research uses high doses that are not biologically accurate for off-target effect.
• Strong clinical data are lacking to support these claims.
• High quality clinical data exists for pediatric epilepsy.

Adverse Effects:

• Acute effects: Panic attacks, severe anxiety, psychosis, paranoia, convulsions, hyperemesis.
  • These are rare and usually associated with high doses of THC
• Prenatal effects: Cannabis use may lead to neuroanatomical and behavioral changes in offspring. Fetal growth, but dose-response relationship not identified.
• A correlation exists between cannabis use and schizophrenia.
• Driving while intoxicated increases the risk of motor vehicle accidents, impairing perception, psychomotor performance, cognitive functions, and affective functions, decreasing reaction time.

Synthetic Cannabinoids

• A manufactured compound whose properties imitate active constituents of cannabis.
• Why make synthetic cannabinoids?
  • Increased specificity
  • Decreased off-target effects
  • Easier dosing
  • More controlled studies

Medical Uses

• Conditions in which multiple randomized clinical trials have confirmed THC can be effective:
  • Refractory nausea/vomiting, anorexia appetite loss, HIV/AIDS/cancer cachexia
• Medical Conditions that have not been confirmed multiple by randomized clinical trials, but in which lesser quality evidence exists include spasticity due to spinal cord injury, and multiple sclerosis
• Other medical uses include neurogenic pain, neuropathy, allodynia
• Conditions that may be treated by THC, but solid human data is lacking
  • Epilepsy, Hiccups, Bipolar disorder and more.
• Nabilone is a synthetic analog of THC
• Dronabinol is a (-) trans isomer of △9-THC, approved for nausea and vomiting in patients undergoing chemotherapy and anorexia in AIDS wasting syndrome.
• Both Nabilone and Dronabinol are taken orally and are partial agonists at the CB1 receptor.
• Oral THC analogs have less psychotropic effects than cannabis.
• Rimonabant is an inverse agonist at the CB1 receptor
• this leads to reduced appetite
• originally for obesity treatment, but later withdrawn due to serious adverse effects, such as depression and suicide ideation

Endocannabinoids

• Cannabinoid receptors exist because we have endogenous cannabinoids ("endocannabinoids") that mediate mood, feeding, and motor function.
• There are two types of endocannabinoids: anandamide (AEA) and 2-arachinoyl glycerol (2-AG).
• AEA and 2-AG are retrograde neurotransmitters.
• AEA and 2-AG are not stored in vesicles but are synthesized on demand.
• THC, endocannabioids decrease neuronal release of other transmitters.
• The synthesis of 2AG or AEA is stimulated by an increase in concentration when the postsynaptic neuron becomes depolarized by the action of a neurotransmitter.
• Thus, it only produces an increase in concentration within regions of the brain that are activated.
• AEA and 2AG are rapidly cleared from the synapse and inactivated by fatty-acid amide hydrolase (FAAH) or monoacylclycerol lipase (MAGL), fatty-acid amide.
• Inhibition would enhance CB1 activation where AEA and 2AG levels are highest, not globally throughout the brain.
• FAAH/MAGL inhibitors do not produce the typical psychoactive effects of THC, sedation, catalepsy, or hypothermia, but they do have analgesic effects.