DBB: 13 Marijuana and cannabinoids

what is hemp

cannabis satvia - non-psychoactive form

earlier cultivated non-food plants 8000BC

• grown for its tough natural fibres (e.g. rope, sails, bags)

what ‘species’ of marijuana is there

• cannabis satvia

• cannabis indica

what part of the plant is smoked - where does most of the THC come from

the flowering hemp (dried flowering tops, leaves, stem)

• cannabinoids highly concentrated in the flowering tops of female plant buds

how many types of cannabinoids are there what’s the most important one

about 70

• Δ9-tetrahydrocannabinol - aka THC

what is the importance of CBD

dampens the THC effects

how can potency be increased

by prevention of pollination and seed production by female plants → energy diverted to production of sticky resin

how do different strains within theses species differ

in terms of smell, taste, type of high

how come THC content has increased over the years - what does this mean

new cultivation methods, growers selectively breed - make it stronger

• high THC = increased risk of dependence, psychosis

what are 2 other cannabis derivatives

• hashish-dired resin - from fine outgrowths from top of female plant (aka trichomes) which are pressed into blocks contains high THC

• hash oil-solvent - extraction from hashish - high in THC 10-30%

what are the typical 3 routes of administration

• smoking - most common, typically in cigarettes (only 20-40% of THC is absorbed)

• vaporising - inhalation of vapour at high temperatures, heat hash oil on tinfoil (less irritating)

• eating - dissolve in oils contained in food (slow but strong effect)

history of cannabis (3 time frames)

• medical/religious use since 1000s of years ago

• mid 1800s: western interest

• early 20th century: marijuana use brought in via Mexican and west Indian immigrants

examples of places which show world wide increase

• decriminalised in Amsterdam

• more USA states legalising/decriminalising (public figures admitting cannabis use)

what does medical marijuana help with (4)

• treatment for glaucoma (increased intraocular pressure)

• antiemetic (reduce nausea/vomiting)

• anticonvulsant

• enhance appetite (e.g. in AIDS patients)s mei

what about the UK

have ‘sativex’ spray containing THC and CBD which can be prescribed for multiple sclerosis

how effective is medical marijuana

debate about it - obviously comes with side effects like psychosis

what are the 2 main cannabinoid receptors and where are they found

• CB1 (main one) - in brain, density high in basal ganglia, hippocampus, cerebellum - areas associated with working memory, spatial memory, motor coordination

• CB2 - primarily found in the immune system, glia - more in the periphery

how quickly does THC reach the brain through inhalation - why

within minutes - since cannabinoids are highly lipid-soluble

• it distributes to body fat stores - hence rapid decrease in peak concentration

how long after use can a drug test still detect cannabis

longer than 2 weeks later

in chronic users it would be longer, maybe months

where does THC metabolise

in the liver, with multiple pathways

• ??

on 3 levels of intoxication, what are the effects

• buzz: slight lightheaded feeling, tingling in extremities

• high: euphoria and exhilaration

• stoned (higher doses): floating sensations, slowing of time, enhanced visual and auditory perception

come-down

what about physiological effects

• increased heart Arte, blood flow to skin (warm sensation)

• appetite stimulation

• red eyes (because blood flow is increasing)

what about undesirable effects

• psychotic symptoms: depersonalisation, agitation, paranoia (replicate schizophrenia symptoms)

• anxiety (dependent on set and settings)

• impaired judgement, reaction time

• motor impairment, impaired memory recall

name one difference and one similarity in THC experimental animals

• cannabinoids are readily discriminated as different to other abused drugs (e.g. rats know it isn’t cocaine

• but THC does enhance accumbens dopamine release

what do animals prefer high or low doses of THC

• low doses of usually produce CPP and are self-administered (← in monkeys)

• high doses produce CPA (conditioned place aversion) and are not self administered (← in monkeys)

what about IV self-adminstration

unreliable in rats

what about vapour self-administration (simulating smoking) STUDY

rats nose poked for THC or CBD enriched plant extracts puffs

findings:

• rats reliably self-administer THC, but not CBD vapour

• THC, but not CBD, is rewarding in animals - but can only be seen when modelled like how humans take it (i.e vapour/smoking)

what’s an example of a synthetic cannabinoids (3)

WIN55212

• full agonist at CB1 and CB2 receptor

• different structure to THC (‘milder’ effects)

• rats self-administer WIN55212, THC is unreliable (maybe because it is milder)

what is rimonabant

referred to as an ‘antagonist’ - more like an inverse agonist at CB1 receptor

• reduced subjective effects of marijuana

3 reasons why the CB1 receptor is important for reward

• rimonabant blocks self-administration of THC, and synthetic CB1 agonists are themselves self-administered (at low doses)

• rimonabant also decreases self-administration of alcohol, opioids, cocaine etc. - so generally CB1 receptors needed for reward

• CB1 knockout mice seem less sensitive to rewards - whether drugs or natural rewards such as food (and show correspondingly less NAc dopamine release)

why do we have these CB1 receptors to begin with

because we have cannabinoid compounds in our brain - endocannabinoids

what do we know about cannabinoids so far (3 things)

• structures unrelated to THC

• most have little selectivity for CB1 Vs CB2

• too lipid-soluble to be stored in vesicles (synthesised as needed)

2 examples of natural cannabinoids

• anandamide (AEA) - partial agonist at CB1 and CB2 (similar affinity as THC for CB1)

• 2-AG present - present in higher brain concentrations than AEA, full CB1 and CB2 agonist

what is the function of endocannabinoids

important regulators of synaptic transmission for both excitatory and inhibitory synapse

what’s the process

typically synthesised in the post-synaptic side of the synapse at the cell membrane

• see as retrograde messengers to alter the physiology of the presynaptic terminal

• released when necessary, uptake mechanism still not clear

give an example (easier explanation)

phospholipid is converted into the endocannabinoid → binds to CB1 (inhibitory) → sends signals that slow down the release of transmitters

• like when you’re stoned you chill, slow down - so does neural transmission

• endocannabinoids slow down transmission - so does THC

what role does endocannabinoid function play (with examples)

hunger, feeding, social play

• rimonabant reduces feeding

• accumbens injections of AEA increase feeding and pleasurable reactions for sucrose (tongue protrusion = pleasurable reaction)

• amygdala injections of AEA hydrolysis inhibitor URB587 increase social play in young rats

effects of repeated cannabis administration

tolerance - but mixed evidence for the ‘high’

• many heavy users do not consume escalating doses

• but lab studies have shown tolerance

examples of tolerance for behavioural effects and pharmacological tolerance

• effects of THC in animals induced in few days (analgesia, motor inhibition)

• reduction of CB1R following repeated THC treatment - less activity, less binding in the striatum, hippocampus, cerebellum

what are the effects of repeated or heavy cannabis use

• acute effects - impaired inhibition, working memory, verbal fluency

• residual and long term effects typically normal/mixed findings for all executive functions

• only one is decision making and risk taking is impaired at residual and long term effects

what are some withdrawal symptoms

• irritability, anxiety, decreased appetite, aggressive

• precipitated withdrawal seen in animals with high doses (e.g. paw tremor - similar to opiates)

what about dependence - what are the risks

• impaired control over cannabis use and difficulty stopping

• risk about 10% - increases to 50% if daily use (higher than heroin, nicotine, cocaine)

what is the risk for psychosis

• 6-8% of schizophenia could be prevented if cannabis use removed from young adults and adolescents

• cannabis use execerbates psychotic symptoms in those already experience them