Week 8 - Cannabis Flashcards
Cannabis plant
- Cannabis sativa
- plants vary in size; male and female plants
- female plant must fertilized by pollen from male plant to generate seeds
- female plant produces sticky resin at top to attract pollen and protect seeds
Active ingredient in cannabis
- over 60 cannabinoids (all found only in cannabis)
- amount of delta-9-THC depends on preparation, route of admin and inactive ingredients altering potency or metabolism
- all parts of plant contain THC
- burning cannabis, GI digestion & metabolism can create new cannabinoids
Forms of cannabis
marijuana: dried leaves & flowers; usually smoked (joint or bong)
hashish: dried resin from female plant; usually smoked, eaten (foods)
hash oil: hashish boiled in alcohol, then residue is filteres & alcohol evaporated; can be smoked
concentrates: extracts (dabs, wax, shatter) use butane hash oil as solvent & vaporised in small quantities (high THC)
edibles: foods containing cannabis
medicinal cannabis - TGA approved, capsules/oral solutions
THC content of plants
changes over time
60s - 1.5%
90s - 3.5 - 4.5%
2008 - 10%
can be as high as 30% but typically contain 3-15% THC
industrial hemp contains < 0.5-1%
uses of cannabis
- fibre (clothes, textiles, paper, rope)
- oil (lamp oil & food) and as an active ingredient in the manufacturing of soap, paint & varnish
- medicinal purposes
- psychoactive properties
Pharmaceutical canabinoids
- Marinol & nabilone: to alleviate nausea and vomiting in people w/ cancer; anorexia & weightloss assoc AIDS
- sativex: neuropathic pain assoc multiple sclerosis
- epidyolex: seizures assoc rare epileptic disorders
historical medical uses
- rheumatism
- mania
- whooping cough
- asthma
- bronchitis
- spasms
- epilepsy
- convulsions
- palsy
- uterine haemorrhage
- dysmenorrhea
- hysteria
- alcohol withdrawal
- loss of appetite
Oral administration
slow absorption by this route, but long duration of effect - affected by first pass metbolism by liver
- not ionized pKa = 10.6
- extremely lipid soluble
- onset of action: 30-90mins >ingestion
- peak: 1-4hrs after ingestions; psychoactive effects may last 4-12hrs, appetite >24hrs
inhalation
readily and rapidly absorbed
- 10-25% of cannabinoids reach general blood circulation from lungs
- peak blood levels <10 mins; peak effects: lags about 30 mins
- holding smoke does not increase absorption
- depth and frequency of inhalation may alter THC absorption
- vaporizers now popular method
distribution
- 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 & peak blood levels
- crosses placenta and is present in breat milk
excretion
- initial metabolism in lungs or gastrointestinal tract depending on admin
- most metabolism in liver; CYP450 enxymes
- delta-9-thc and 11-hydroxy-delta-9-THC are more lipid soluble and harder to excrete than other metabolites (> 100)
- 11-hyroxy-delta-9-THC is more active than delta-9-THC and penetrates BBB easier
metabolism of other cannbinoids
cannabidiol (CBD) - 20 metabolites
- blocks enzyme that metabolizes THC
cannabinol (CBN) - 20 metabolites
- increases metabolism of THC
- possible interaction effects between THC, CBN & CBD to displce THC from blood binding sites (increases amount available for distribution
excretion: THC
Phase 1:
- 1/2 life ~ 30-80 minutes; redistribution effect
Phase 2:
- 1/2 life ~ 20-30 hours; metabolism effect
- slow metabolism due to lipid solubility & speed that THC is released from fatty tissues - traces of THC can be detected 1-4 weeks after ingestion
- excreted in feces (65%) and urine (20&
- effects of frequent use on metabolism unclear
CBD half life 9-32 hrs
Receptor sites
- 2 known types of cannabinoid receptors (CB1 & CB2)
- work on second messengers & neuromodulators
CB1
- Located in CNS
- uneven distribution of receptors in the CNS
- most in higher centres therefore affect memory, emotional expression, mental processes; but also affect movement, appetite & analgesia
CB2
- mostly outside the CNS in spleen & immune system; could account for effects on immune functioning
- in CNS ; glial cells, stem-like cells and other brain areas
Endogenous Ligands (endocannabinoids)
- anandamide
- fat soluble, but simpler molecular structure
- exact function unkown
- discovery has lead to abundance of research
function of endocannabinoids: relax, eat, sleep, forget & protect
THC & endocannabinoids alter the functioning of
GABA, NE, DA, seratonin (5-HT), ACh, histamines, glutamate & opiod peptides
how are endocannabinoids synthesized?
on-demand in dendrites & cell body then released, cross synapse & bind to presynaptic CB1 receptors - due to binding they have a retrograde action
what is retrograde action?
allows the postsynaptic neuron to shut down presynaptic neuron which causes a depolarization induced suppression of inhibition and excitation (DSI & DSE)
3 types of neuromodulation
Increased synthesis of:
- NE
- DA
- 5-HT
- GABA
alter receptors for:
- NE
- ACh
- DA
- potentiate action of:
- NE
- ACh
- DA
Reinforcing effects of cannabinoids
- CB1 receptors located with dopamine receptors in mesolimbic dopamine pathway regions (midbrain, pfc, basal ganglia)
- CB1 receptor stimulation decreases inhibitory actions of GABA neurons projecting on to dopamine neurons in the nacc
- positive dopamine neurons in the ventral tegmental area synthesise & release endocannabinoid when stimulated
Reinforcement via opioid receptors
- CB1 overlap & interact with mew opiod receptors in nacc
- mew opioid receptor abolishes preference to THC
- naloxone (opioid antagonist) blocks THC self-administration & THC induced dopamine release in nacc
- naltrexone decreases cannabis use and positive subjective effects in daily marijuana smokers
- CB1 reinforce effects and devt of phys dependence of some opioids (morphine & heroin)
Low-moderate dose effects on body
- dilation of small blood vessels in eyes
- dry mouth, thirst
- hunger (max 3hrs after smoking; tolerance after few weeks)
- decreased blood pressure @ low doses/repeated use - increases @ high dose
- body temp changes
- increased heart rate
- increased cortisol
- headache, dizziness, nausea/vomiting
effects on sleep
- increased dwosiness, decreased time to fall asleep, increased sleeping time, decreased REM
- high dose = insmonia, chronic use = LT decreased slow wave sleep
- habitual use, tolerance to sleep-latency but not to REM
- withdrawal effects: increased time to fall asleep, increased awakenings, decreased total sleep time & quality, vivd dreams, decreased slow-wave sleep, REM rebound
effects on perception
- blurred vision
- usually no change in sensory thresholds (vs subjective report)
- decreased pain sensitivity
- slowing in time rate (time distortion effects)
effects on memory
- disrupts ability to recall verbal material
- STM (dose-dependent impairments)
- temporal disintegration
effects on attention
- decreased performance on vigilance tasks/sustained attention
- decreased concentration
effects on creativity
no evidence
effects on mood
- gaiety (dreaminess)
- anxiety/panic
- variability in subjective mood and arousal ratings
- depends on environment & mood of others
effects on performance
- variable
- depends on experience, instruction, motivation, setting, dose, performance task
- in general, choice reaction time & complex tasks most impaired; chronic users less impaired than occasional users
effects on driving
- decreased performance for most people; potentiated by alcohol
- decrease ability to attend to peripheral stimuli
medically beneficial effects
- decrease nausea/vomiting - cancer treatments
- anticonvulsant & spasticity
- modulating pain
- decreased blood pressure in eye glaucoma
psychosis - acute effects
- drug induced psychosis
- distorted perception, anxiety, panic, paranoia, psychotic-like experience
- CBD may counteract such THC effects
psychosis - long-term effects
increased risk of psychosis & schizophrenia (can trigger 1st episode; make pre-exising illness worse)
flaws in psychosis research
- correlational
- includes large dose/chronic users
- small sample sizes
lethal doses of THC?
- phylogenetically higher animals are less susceptible to acute toxicity of THC
- no experimental evidence to determine a lethal dose in humans - from animal research LD50 = 65kg adult would be 8.45kg of THC
unconditioned physical behaviour in animals
- mice: cannabinoid tetrad dose dependent effect (decreased SMA, muscle rigidity, decreased pain sensitivity & hypothermia)
- biphasic effect of SMA: increased activity followed by decreased SMA
- high doses - ataxia
unconditioned feeding behaviour in animals
dependent on dose, route of admin and timepoint
- inhalation of vapor increases food intake in first hour
- high doses decrease appetite and subsequent weight loss
- increases sweet preference
unconditioned behaviour in animals
- decrease in aggression (taming effect)
- decreased response to painful stimuli (THC as potent as morphine)
conditioned behaviour in animals
- THC interferes with STM tasks (correlates with decreased neuronal firing in hippocampus in rats)
- research mixed on effects on LTM
- chronic use during adolescence leads to adult deficits in spatial memory & STM
- decreased avoidance responding but not excape responding
- does not affect punished responding
discrimination (animals)
- reliable discrimination of THC from placebo
- delta-9-THC gerenralizes to delta-8-THC, nabilone, 11-hydroxy metabolite, CBN
- partial generalisation to sedatives
- does not generalize to CBD, anandamide (unless at high doses of anandamide), or drugs from other classes
discrimination (humans)
humans can discriminate marijuana cigarettes which don’t contain THC after 90 sec inhalation; if THC content is > 0.09%
dissociation in animals & humans
self-administration (animals)
animals self-administer but not reliably intravenously
- rats will lver-press for THC injections to VTA or NAcc
self-administration (humans)
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
tolerance (animals)
- develops rapidly (5-6 days) to many effects
- tolerance develops to the initial SMA but the suppression of SMA is more resistant to tolerance
- tolerance does not develop to anorexic effects and discrimination
- lasts for > 1 month and cross-tolerance btwn delta-9-thc and 11-dyroxy metabolite
- associated with decrease in CB1 receptors
tolerance (humans)
- more consistent with high doses and frequent use
- develops to acute nerucognitive impairment and most subjective psychological effects (downregulation of CB1 receptors)
- no tolerance to increased food consumption
withdrawal (animals)
- in continuous admin of high doses
- typically mild symptoms
- symptoms may be masked by long 1/2 life
withdrawal (humans)
onset 1-3 day pasr abstinence, peaks 2-6 days, lasts for 2 weeks (mild)
- irritability, restlessness, insomnia, anxiety, depressed mood
- hot flashes, swetaing, runny nose, diarrhea, hiccups, decreased appetite
- cravings for cannabis
- oral THC capsules can alleviate symptoms
Cannabis use disorder
- 1 in 5 risk of developing and 13% had cannabis dependence
- risks of developing cannabis dependence increases to 33% if cannibis is intiated early and used frequently
effects on reproduction
- Males: decreased testosterone, sex drive, decreased sperm motility
- females: fertility (anadamide & fertility)
- increase risk of miscarriage, preterm birth & fetal growth restriction; mild cognitive impairments, attentional & mood disorders in children
- abnormal sleep pattern of newborns
- chromosomal damage
effects on immune system
complex but includes decreased immune functioning
effects on respiration
- acute effect: bronchodilation - helpful in asthma
- repeated cannabis smoking increases inflammation of large airways, increase in airway resistance, & lung damage similar to cigarett smoking
- decreased activity of macrophages
- increased risk of respiratory disease associated with smoking, including cancer
cancer
- more carcinogens than tobacco
- inhale more tar than tobacco
- may accelerate carcinogenic effects of tobacco smoke
- antioxidant effect of THC and CBD
violence
- no empirical evidence; though widely held belief
- usually show decrease hostility
mental disturbance
paranoia & anxiety (large doses)
acute psychotic episode
can precipitate psychosis in people with psychotic tendencies
brain damage
- loss of mental functioning (mild), dose/recency effects
- animal research has found altered brai structure and decreased neuronal plasticity & learning
amotivational syndrome
- evidence from clinical observations
- recent studies show acute effects on motivation/choice to engage in less effortful/lower reward tasks over more effortful/higher reward tasks
altered reward response in nucleus accumbens
- decreased nacc response to monetary reward anticipation
- increased mesolimbic response to cannbis cues vs fruit rewards
marijuana as a gateway drug
- high correlation but no causal evidence
- social not physical
- or personality variables
