W7 - Cannabis Flashcards
What is cannabis?
- Cannabis sativa
- Plants vary in size; male and female plants
- Female plant must be fertilized by pollen from male plant to generate seeds
- Female plant produces sticky resin at top to attract pollen and protect seeds
What are the active ingredients of cannabis?
Over 60 cannabinoids
active ingredient Delta-9-tetrahydrocannabinol (delta-9-THC),
What does the amount of active ingredient (THC) depend on?
o Preparation
o Route of administration
o Inactive ingredients altering potency or metabolism
What can create new cannabinoids?
• Burning cannabis, GI digestion & metabolism
What are the forms of cannabis?
• 3 forms of cannabis:
o Marijuana: dried leaves and flowers; usually smoked/baked
o Hashish: dried resin from female plant; usually smoked or baked
o Hash oil*: hashish boiled in alcohol, then residue is filtered & alcohol evaporated
What is the THC content of plants?
- Changes over time:
o 1960’s – 1.5%
o 1990s – 3.5 - 4.5%
o 2008 – 10%
o Can be as high as 30% but typically contain 3-15% THC (see NSW study stats next slides; Swift et al., 2013).
o Industrial hemp contains < 0.5 - 1% THC by Aus. & NZ laws & regulations.
What are the uses of Cannabis?
• Historically, hemp has been used for:
o Fibre (e.g. clothes/textiles, paper and rope)
o Oil (lamp oil & food) & as an ingredient in the manufacture of soap, paint and varnish (seeds)
o Medicinal purposes
o Psychoactive properties
What are the synthetic cannabinoids?What are they used for?
o Marinol (dronabinol –THC extracted from cannabis) & Nabilone (Cesamet – entirely synthetic THC): to alleviate nausea & vomiting in people w. cancer undergoing chemo & radiation therapy; anorexia & weight loss assoc. AIDS o Sativex (THC + CBD (+other cannabinoids + non-cannabinoids) extracted from cannabis): neuropathic pain assoc. multiple sclerosis o Epidiolex (CBD extracted from cannabis): “Investigational New Drug” for severe forms of epilepsy in children (incl. QLD govt study at Lady Cilento + NSW clinical trials)
What is the pKa of cannabis?
10.6
What is the absorption of cannabis orally?
Readily absorbed
o Not ionized: THC (weak acid) with a pKa = 10.6
o Lipid soluble: cannabinoids are extremely lipid soluble
o Peak effects: 1-3 hrs>ingestion; effects may last>5hrs
What is oral absorption effected by? What is the difference compared in inhalation?
o Absorption is slow and affected by considerable 1st pass metabolism
o Oral vs. inhalation: 1/3 potency; more likely assoc. vomiting & nausea
What is the absorption of cannabis when inhaled?
- 10-25% of cannabinoids enter lungs
- Peak blood levels < 15 mins; peak effects: 30-60 mins> ingestion
- Holding smoke does not increase absorption
- Depth (not duration) of inhalation may alter THC absorption
- Vaporizers now popular method (< boiling point of THC decrease tars + other carcinogens entering lungs)
Where is cannabis distributed in the body?
- Distributed to all areas of body (capable of altering all biological systems)
- Concentrated in lungs, kidneys, liver
- ~1% enters the brain but levels continue to increase after ingestion and peak blood levels
How is cannabis excreted ?
- Initial metabolism in lungs or G.I. tract, dep. on admin
* Most metabolism in liver
What is the transformation of Delta-9-THC in liver?
• Delta-9-THC → 11-hydroxy-delta-9-THC → other metabolites (> 100)
o Other metabolites also have effects but most are less lipid solube and more easily excreted
What is the active metabolite of cannabis?
• 11-hydroxy-delta-9-THC (active metabolite)
o More active than delta-9-THC
o Penetrated BBB easier
What is the metabolism of other cannabinoids?
Cannabidiol (CBD) – (20 metabolites)
• Blocks enzyme that metabolizes THC (increased duration of action)
Cannabinol (CBN) – (20 metabolites)
• Increased metabolism of THC
What are the interactions between metabolites in the body?
Possible interaction effects btwn THC, CBN, & CBD to displace THC from blood binding sites (increased amount available for distribution)
How is THC excreted?
THC Phase 1 excretion:
- ½ life ~ 30 min; redistribution effect
Phase 2 excretions
- ½ life ~20-30 hrs; metabolism effect
- Slow metabolism due to lipid solubility and speed that THC is released from fatty tissues
- > Traces of THC can be detected 2-4 weeks> ingestion
- Excreted in faeces (55%) & urine (20%)
- Effects of frequent use on metabolism: unclear
What are the effects of cannabis on receptors?
- 2 types of cannabinoid receptors
- Work on second messengers and neuromodulators
What is CB1 and what does cannabis do to effect it?
- Located in CNS: cortex, hippocampus, cerebellum, basal ganglia, hypothalamus, & nucleus accumbens, brain stem, spinal cord
- Uneven distribution of receptors in the CNS
- Most in higher centres, therefore affect memory, emotional expression, mental process, but also movement
What is CB2 and what does it effect?
- Located outside in the CNS in spleen and immune system; could account for effects on immune functioning
- Affected by CBN
- Recently found in brain too
What are endogenous ligands (endocannabinoids)?
- Anandamide
- Fat soluble, but simpler molecular structure
- Exact function unknown
- Discovery has lead to abundance of research
What is the function of endocannabinoids?
“relax, eat, sleep, forget & protect”
What are the neuromodulating effects of endocannabinoids?
- Alters functioning of: NE, DA, 5-HT, Ach, GABA, Histamines & Opoid peptides
- Retrograde action – allow the postsynaptic neuron to shut down presynaptic neuron
- Depolarization-induced suppression of inhibition
- Depolarization-induced suppression of excitation
What are the effects of cannabis on the body?
Low-Moderate Dose: • Dilation of small blood vessels in eyes • Dry mouth, thirst • Hunger • Increase BP at low does/ Decreased BP at high doses or repeated use • Increased HR • Headaches • Neusea/vomiting • Talkativeness
What are the effects of cannabis on sleep?
- Increased drowsiness
- Increased sleeping time
- High doses cause insomnia
- No withdrawal effects
What are the effects of cannabis on perception?
- Blurred vision
- Usually no change in sensory thresholds (vs. subjective report)
- Decreased pain sensitivity
- Increase in time rate (time distortion effect)
What are the effects of cannabis on attention?
- Decreased performance on vigilance tasks/sustained attention
- Decreased concentration
What are the effects of cannabis on creativity?
- No evidence
What are the effects of cannabis on mood?
- Gaiety – dreaminess
- Anxiety/panic
- Variability in subjective mood and arousal ratings
- Depends on environment and mood of others
What are the effects of cannabis on performance
- Variable
* Depends on experience, instructions, motivation, setting, dose, performance task
What are the effects of cannabis on driving?
- Decreased performance for most people; potentiated by alcohol
- Decreased ability to attend to peripheral stimuli
What are the medically beneficial effects of cannabis?
• Decreased BP in eye – glaucoma
• Decreased nausea/vomiting – cancer treatments
o Nabilone and Marinol (synthetic cannabinoids)
• Anticonvulsant (epilepsy, CBD, e.g. Epidiolex) & spasticity (MS, e.g. Sativex/nabiximols)
What are the acute effects of cannabis at high doses?
‘drug-induced psychosis’
- Distorted perception, anxiety, panic, paranoia, psychotic-like experience
- CBD may counteract such THC effects (Morrison et al., 2009)
What are the longer-term effects of cannabis
: árisk of psychosis & schizophrenia (trigger 1st episode of psychotic illness; make pre-existing psychotic illness worse)
What is a lethal dose of THC?
• Phylogenetically higher animals are less susceptible to acute toxicity of THC
➢ LD50 of THC administered intravenously is 40mg/kg in rats vs. 130mg/kg in dogs & monkeys (Rosencrantz, 1983; min. lethal dose in dogs is 3mg/kg – Fitzgerald et al., 2013).
—> No experimental evidence to determine lethal dose in humans
What is unconditioned behaviour in animals?
- Biphasic effect on SMA: ↑activity followed by ↓
- High doses – ataxia
- ↓ appetite & subsequent weight loss, but ↑ sweet preference
- ↓ aggression
- ↓ response to painful stimuli
What is conditioned behaviour in animals?
- Interferes with STM tasks (↓ neuronal firing in hippocampus)
- Interferes with timing tasks
- Performance on other tasks normal (except at high doses)
- ↓ avoidance responding but not escape responding
- Does not affect punished responding
What is the discrimination in animals?
- Reliable discrimination of THC from placebo
- Delta-9-THC generalizes to:
- Delta-8-THC
- 11-hydroxy metabolite
- CBN
What is the generalisation in animals?
- Partial generalization to sedatives
- Does not generalize to:
- CBD
- Anandamide (unless at high doses of anandamide)
- Or drugs from other classes
What is the discrimination in humans?
• Humans can discriminate marijuana cigarettes which don’t contain THC <90 sec. inhalation; if THC content is > 0.09 %
Dissociation in animals & humans (state dependent learning)
What is the self-administration tendencies?
- Not typically self-administered by animals
- In lab studies humans have fairly stable intake
- Titration
- Some studies show titration of dose
- Others show inability to account for different potencies
- May be more reinforcing if higher THC content (e.g., 1.95% vs. 0.63%)
What happens to tolerance in animals?
Develops rapidly - 5-6 days
What does tolerance develop to in animals?
- Tolerance develops to:
- ↑ SMA
- ↓ SMA (slower to develop)
What doesn’t tolerance develop to in animals?
- Tolerance does not develop to:
- Anorexic effects
- Discrimination
How long does tolerance last and what is the cross tolerance and assocations with this?
- Tolerance lasts for > 1 month & there is cross-tolerance btwn delta-9 THC & its 11-hydroxy metabolite
- Assoc. with ↓ cannabinoid receptors in some brain regions & down-regulation/desensitization of receptors
What is the tolerance in humans?
- Tolerance seen with high doses but not low doses
- Tolerance develops to most psychological effects
- No tolerance to increased food consumption
- Most tolerance due to learning
- (subjective) reverse tolerance?
- Dose
- Experience/situations/company etc.
What is the withdrawal in animals?
- In continuous admin. of high doses
- Typically mild symptoms (e.g., ↑ SMA in rats)
- Withdrawal symptoms may be masked by long ½ life
- Injection that blocks cann. receptors →withdrawal: stress hormones
What is the withdrawal in humans?
- Onset 1-3 days post abstinence, peaks 2-6 days, lasts for 2 wks; typically mild:
- Hot flashes, sweating, runny nose, diarrhea, hiccups, ↓ appetite
- Irritability, restlessness, insomnia, anxiety
- Cravings for cannabis
What are the harmful effects on reproduction?
- Males: ↓ testosterone, sex drive (dose-dependent), ↓ sperm motility
- Interferes with fertility in females (anandamide & fertility)
- Abnormal sleep patterns of newborns
- Chromosomal damage
What are the harmful effects on the immune system?
Complex but includes decreased immune functioning
What are the effects on respiration?
- Bronchodilation – helpful in asthma
- ↓ size of lung passage – causes asthma
- ↓ activity of macrophages
- Increased risk of respiratory disease associated with smoking, including cancer
What are the effects on cancer?
- 50-70% more carcinogens than tobacco
- Inhale more tar than tobacco
- May accelerate carcinogenic effects of tobacco smoke
- Antioxidant effects of THC & CBD?
What are the effects on violence?
- No empirical evidence; though widely held belief
* Usually show ↓ hostility
What are the effects on mental disturbance?
- Paranoia & anxiety
- Acute psychotic episode
- Can precipitate psychosis in people with psychotic tendencies
What happens to the brain after LT use?
- loss of mental functioning (mild), dose/recency effects
- Animal research has found:
- Altered brain structure (hippocampus)
- ↓ neuronal plasticity & learning
What happens to the reward response in nucleus accumbens?
- ↓ Nacc response to monetary reward anticipation (Martz et al., August 2016)
- ↑ mesolimbic response to cannabis cues vs. fruit rewards (Filbey et al., May 2016)
What is the evidence of marijuana as a gateway drug?
- High correlation but no causal evidence
- Social not physical
- Or personality variables (common factor model)
