Cannabis & Psychedelics Flashcards
Where is cannabis collected from?
What did O’Shaughnessy’s experiment with low dose Indian Hemp show in the old gentleman?
Larger dose?
What were the characteristic effects of cannabis that he discovered?
What was cannabis mixed with & what was it used to treat?
When was cannabis prohibited in the UK & US?
Why did its medical use wane?
Where are the trends of legalisation & illegalisation?
Hemp plant
Talkative, musical, fell asleep soundly
Powerful sedative, stimulating digestive system, exciting cerebral system
Euphoria
intoxication
* Fine motor control dysfunction or sedation (dose
dependent)
* Anxiolysis/ anxiogenesis (dose dependent)
* Appetite stimulation («the munchies»)
* Anti-emesis
* Increased heart rate & vasodilation
* Deficits in memory & attention
alcohol - fever, inflammation, rheumatism (arthritis), nausea, muscle spasms
UK = 1928, US = 1937
Aspirin & vaccines for tetanus
Legalisation in Western world - mainly for medical use but also any use in parts of America & Canada
Illegalisation - Asia & Africa (except south africa)
What are the medicinal properties of cannabis?
What is Ganja?
Bhang?
Hashish?
What are the two biologically active compounds in cannabis?
What happened when monkeys were given with higher dosage THC?
What were the results from 25 cannabis users Wachtel et al 2002 with high/low dose of THC administered orally & smoking?
What does this conclude?
What is the rising trend in cannabis content?
What type of molecules are CBD/THC?
anti-inflammatory, anti-spasmodic, analgesic
Small leaves & stems from non-flowering plant
Dried leaves, flowering shoots & buds
Resinous exudes from flower tops - trichomes
Cannabidiol CBD & tetrahydrocannabinol THC
Decrease hypolocomotion, increased hypothermia, increased catalepsy (seizure & loss sensation/consciousness) & increased analgesia with similar potency to morphine - also mood, cognition (but main 4 are psychoactive effects)
Sedation & intoxication feelings were dose dependent but administration make little difference
Psychoactive effects of marijuana due to THC dose
Increasing THC:CBD content - as major cannabinoids share a metabolic pathway such that increasing THC content decreases CBD content
tricyclic phytocannabinoids
What is the most significant cannibinoid receptor in the brain?
What kind of receptor is it?
Where is it densely labelled & what are these areas involved with? 4
Why is there low toxicity (unlike opioids)?
CB1 - cannabinoid receptor
G-protein coupled receptor - with Gi/o
- basal ganglia (reward, emotion, & motor function), cerebellum (motor)
- hippocampus & cortex (memory, cognition, & emotion)
- pain-associated regions (PAG, RVM, spinal cord dorsal horn), striatum (reward),
- amygdala (fear/anxiety), & hypothalamus (appetite)
Low expression of CB1 in respiratory centres of medullary brainstem
What is the second receptor & where is it located?
When is CB2 expression upregulated?
What effects are these receptors responsible for?
What is anandamide? AEA
2-arachidonyl glycerol (2-AG)?
What are they both called?
CB2 - spleen & immune cells of periphery & glial cells of CNS (maybe neurones) but not in the brain
Immune response, pain states, neurodegenerative disease
anti-oedemic (build up fluid), antiinflammatory, neuroprotective - immune effects of cannibinoids
Partial agonist of CB1 & weak agonist of CB2 & full agonist of TRPV1 at high concentration
Full agonist of CB1 & CB2
Endocannabinoids
What is the second receptor & where is it located?
When is CB2 expression upregulated?
What effects are these receptors responsible for?
What is anandamide? AEA
2-arachidonyl glycerol (2-AG)?
What are they both called?
CB2 - spleen & immune cells of periphery & glial cells of CNS (maybe neurones) but not in the brain
Immune response, pain states, neurodegenerative disease
anti-oedemic (build up fluid), antiinflammatory, neuroprotective - immune effects of cannibinoids
Partial agonist of CB1 & weak agonist of CB2 & full agonist of TRPV1 at high concentration
Full agonist of CB1 & CB2
Endocannabinoids
What did the identification of CB1 allow for? 4
What did Katona et al demonstrate in 1999?
2006?
What does this explain?
Therefore, what is CB1 responsible for?
What is the mechanism behind cellular effects of CB1?
What NTs are affected?
What does cannabis use also lead to?
- Cloning & expression in heterologous cell systems
* Probing intracellular signalling pathways
* Development of synthetic agonists & antagonists
* Production of antibodies for localisation in brain
CB1 expressed at high levels presynaptically on inhibitory axon terminals e.g GABA
CB1 at low levels on excitatory synapses close to transmitter release sites.
biphasic (2) effects of THC
Activation of CB1 receptors reduces neurotransmitter release from axon terminals
Gi/Go causes inhibition adenylyl cyclase & cAMP formation & inhibition of Ca2+ voltage gated channels & activation of K+ channels (into cell) - since CB1 on presynaptic terminals, exerts powerful inhibitory effect on NT release
ACh, DA, NA, 5-HT, GABA & glutamate
Activation of MAPK pathway & DNA methylation (long-term)
What are endocannabinoids?
What are their properties?
When is 2-AG release triggered?
How does it overcome this?
What are both ECs broken down by? 3
Where are ECs synthesised?
Cannibinoid receptor agonists synthesised by the body
Very lipid soluble - synthesised when needed as too soluble to be stored in vesicles
Rise in intracellular Ca2+ levels (caused by opening of Ca2+ channels or NMDA receptor channels in membrane or release of Ca2+ from intracellular stores from DAG)
Agonist binds to CB1 - results in Gi/Go & inhibition of Ca2+ voltage gated channels
Anandamide - fatty acid amide hydrolase FAAH
2-AG - monoacyl-glycerol lipase MAGL
Both - cyclooxygenase-2 COX2 (process in inflammation)
Postsynaptic element e.g dendritic spine
What is the retrograde signalling mechanism?
What is the non-retrograde signalling mechanism?
What is the neurone-astrocyte signalling mechanism?
What are the 3 causes of eCB signalling in neurones and why?
2-AG synthesised in postsynaptic element diffuses & activates CB1 receptors on presynaptic terminal inhibits Ca2+ mediated neurotransmitter release
Anandamide remains in postsynaptic cell & activates a cannibinoid receptor or TRPV1 (nonspecific cation channels) - increased Ca2+ in cell = stimulate release NTs & sensation of spiciness
eCB activates CB1 on astrocytes - inducing glutamate release
- Protection - Prevents excitotoxicity & neuroprotective in epilepsy & stroke
- Pain relief - CB1 similar to opioid signalling & eCBs reduce pain signalling
- Pleasure - CB1 on inhibitory neurones in reward pathways - block tonic inhibition so more dopamine release
What does the retrograde signalling mechanism actually involve in excitatory glutamate synapses? 4 steps
What does MAGL do?
What is tonic inhibition?
- Glutamate release from presynaptic nerve terminal activates mGluR5 in membrane of dendritic spine (postsynaptic)
- mGluR5 (metabotropic) Gq leads to activation of PLC-beta - increasing levels of PIP2 & DAG
- DGLa converts DAG into AG-2 & is released into extracellular space & diffuses to nerve terminals to activate CB1 on presynaptic terminal
- CB1 inhibits opening of Ca2+ voltage gated channels & thus reducing glutamate release from that terminal
Hydrolyses 2-AG into arachidonate & glycerol
GABA release & binding to GABA-A to cause inhibition
Therefore, how do ECs play a part in Depolarisation-induced suppression of inhibition (DSI) and synapse plasticity?
How does THC interfere?
What ECs are expressed in pain states?
How can you prevent EC levels from dropping?
What happened in experiments with pain when patients were given JZL184 (MAGL inhibitor) and also with a CB1 antagonist?
What does this experiment suggest?
When the Von Frey test was done on mice with different doses & repeats of JZL184, what were the results? What does this show?
What happens with chronic cannabis use?
Why is the EC system dynamic?
DSI = transient suppression of inhibitory input following strong activation (GABA) - reducing tonic inhibition allow long-term potentiation & synapse strengthening - memory & learning
Tonic inhibition produced by THC disrupts short-term memory
AEA decreases when there’s pain & 2-AG increases in pain relief
Inhibit FAAH or MAGL
Tail immersion test - latency was longer with only JZL184 & not with it & cb1 antagonist
ECs decreases pain sensitivity and that THC increases pain sensitivity
Didn’t alter withdrawal thresholds significantly
Fewer CB1 receptors
Due to CB1 receptor expression, activity of synthetic & degradative enzymes
What does EC signalling depend on?
What can these sites be used for?
What does this explain?
Which parts of the brain are involved with pain? 4
What happens to the brain after repeated exposure to THC/cannibinoids/drugs?
Site of high EC activity - produces different effects
Used to target pain
Individual responses to CB1 activation/THC is different - where EC system is most active the effect will be greatest (e.g emotion centres, reward, motor centres, pain pathways etc)
PFC, amygdala, cerebellum, hippocampus** main one
Adaptive changes - resulting in lower CB1 expression
How is 2-AG involved in neurodevelopment?
How does THC therefore interfere with neurodevelopment?
What can this affect?
What other way does EC signalling affect neurodevelopment?
What can THC exposure do to adolescents & adults?
Neurones use 2-AG when growing towards synaptic partners but 2-AG signalling terminates when the synapses are formed (MAGL)
THC is not degraded by MAGL - can alter neuronal connections with long-lasting repercussions - decreases number of synaptic connections (embryonic dev/postnatal)
Learning, skill, memory, concentration
Myelination & synapse changes in late adolescence & prefrontal cortex involved in decision making
Adolescents - impaired abstract & visual reasoning & impaired visuoperceptial functioning
Adults - altered functioning in visuo-spatial memory
What is Dronabinol & Nabilone?
Sativex (nabiximols)?
Epidiolex?
What kind of pain is cannabis good for & bad for treating?
Adjuvant? (used to increase efficacy/potency of another drug)
EC-therapies?
THC in capsule form for chemotherapy-induced nausea & appetite simulation for AIDS wasting disease
Oromucosal spray with equal THC:CBD & other phytocannabinoids - treat multiple sclerosis spasticity & chronic cancer pain in Israel but not US
Liquid extract of CBD approved for childhood epilepsy syndromes but not CB1 mediated more likely TRPV1/GPR55 with gaba signalling
Some efficacy of chronic non-cancer pain, but not acute, cancer or rheumatic pain
Failed clinical trials - cannabinoids & opioids & cannibis to treat opioid withdrawal
Inhibitors of EC metabolism effective pre-clinically but all have failed clinically for pain but good relieving tourettes & cannabis withdrawal syndrome
How can cannabis be used to treat the following:
PTSD
Parkinson’s
Alzheimer’s
Problem with these?
Traumatic Brain Injury & Stroke
Tourette’s
Cannabinoids to extinguish recurrent aversive memories & reductions in recurrent nightmares
Loss of dopaminergic neurones linked to increased CB1 receptor expression - CBD/THC (CB1 agonists) improve quality of life & dyskinesia (reduce CB1 expression)
CB1/CB2 mediates reduced inflammation & neuroprotection - Nabilone reduces agitation
Cannabinoids cause motor dysfunction & memory impairment
Anti-inflammatory & neuroprotective effects - sativex for post-stroke spasticity
Reducing tics by inhibiting excessive recurrent activity in neuronal networks - FAAH inhibitor in clinical trials
What are the risks with cannabis use? 6
Psychosis, neuropsychiatric effects (neuropsychological decline), anxiety (biphasic - high dose/prolonged use), abuse/tolerance/dependence (prolonged use), risks of pulmonary disease with smoking & deficits in concentration/motor function
