Cannabis Flashcards
(12 cards)
History and background
The Cannabis plant is one of the oldest plants we can track as moving with human migration.
10,000 BCE China shows evidence of cultivation.
In 2000 BCE India/Egypt, there is evidence of medicinal use.
In the 1600s there was extensive use of hemp in Europe and the US.
In the 1840s the medicinal value of Indian hemp was described. It became a ‘middle class’ tonic and there were some suggestions of queen Victoria using it.
In the 1920/30s there was legal restriction of Cannabis in UK and US
In 1964 THC was identified. This is the psychoactive compound.
In 1987, a behavioural tetrad including analgesia, catalepsy, hypolocomotion and hypothermia was identified in responses to THC-like compounds.
In 1990 the CB1 cannabinoid receptor was identified.
In 1992 endogenous cannabinoid ligands were identified.
The Cannabis plant
The Cannabis plant is a tall (up to 2.5-3.5 m) dioecious entity, so there are separate male and female versions.
It is very efficient at converting sunlight into biomass.
Hemp fibres have been used for centuries as rope and cloth. They have also been used in composites in the building and automotive industries.
Seeds are used for biofuel, animal feed and as bait in freshwater fishing.
The cannabis plant is often described as different species: Cannabis sativa/indica/ruderalis. It is suggested that sativa is more active, indica more mellow and ruderalis does not have much psychoactivity. There is however no clear-cut separation in commercial varieties due to extensive historical crossbreeding.
It is the most widely abused illicit substance in the world.
The cannabis leaf is called herbal Cannabis or marijuana. However ‘marijuana’ was invented in the 1920s to deliberately associate it with Mexicans, so the use of this word is not preferred.
Cannabis resin is called Hashish, a coarse resinous extract from the buds
Cannabinoids are Cannabis-derived compounds (up to 114 unique chemicals).
Other names for Cannabis include: hashish, Mary Jane, puff, charas, grass, herb, kif, dagga, ganja, sinsemilla, wacky baccy, reefer, spliff, doobie, bhang, dope, pot, blow, weed, skunk, roach, etc.
The female plants have sticky buds arranged around the plant, where the resin is secreted. This is where the phytocannabinoids are concentrated. This is compacted to generate the hashish.
Cannabinoids are also found in the leaves and stem but not the roots.
Non-medicinal Cannabis consumption
Most commonly smoked as ‘joints’ or in a bong using dried leaves and flower buds, often mixed with tobacco.
Hashish can also be crumbled into tobacco. This was historically more common in the UK as Cannabis was mainly imported as resin.
Smoking causes decarboxylation of tetrahydrocannabinolic acid (THCA-A) and pyrolysis (~70 %) of THC.
- THCA-A is a precursor of tetrahydrocannabinol (THC).
- Raw cannabis plant material typically has low levels of Δ9-THC compared to its precursor tetrahydrocannabinolic acid (THCA). Heating cannabis decarboxylates THCA to psychoactive Δ9-THC, explaining traditional methods of consumption like smoking, baking, or vaporising.
There is a move towards vaporisers. Hot plates or e-cigarettes with tinctures are used. This is referred to as dabbing in the US.
Cannabis can also be consumed orally. This takes multiple forms:
- ‘Baked’ in ‘hash brownies’ or ‘cannabutter’
- An infusion like tea - compounds are quite hydrophobic so extraction may be poor
- A tincture added to drinks
- Sublingual
- Juicing into a kind of smoothie using fresh leaves. Popular in California, does not cause psychoactivity as heat is required to produce THC.
Smoking and vaping provide a relatively rapid ‘hit’. Symptoms are noticeable in less than 5 min, lasting 30-120 min.
Oral ingestion has a much longer and more variable latency to onset but with an apparently extended duration of action. Noticeable effects occur after 30-40 min, lasting up to 240 min. This is an issue in naive users as they might take a second dose if they do not notice effects within the first 15 minutes, leading to them being hit by a large effect at once.
For all these methods, the actual bioavailability of metabolites, particularly THC, is poor (5-10 %) and very variable
Symptoms of Cannabis consumption
Objective symptoms include: Transient increase in HR, increased pain tolerance, conjunctival reddening. There is no change in pupillary diameter or respiratory rate.
Subjective symptoms are much more variable. There is usually an initial period of euphory (high) followed by a period of drowsiness (dope). There is an altered sense of time passing and dissociation from the environment/depersonalization as a result of short-term memory impairment. There may be mild visual distortions or hallucinations and less frequently depressive or psychotic episodes. Dysphoria can occur at high doses (skunk) or with naïve users.
All of these symptoms are unpredictable. There is also major context sensitivity, but this is true for a lot of psychoactive substances.
There is a limited understanding of the chronic effects of cannabis.
Tolerance is displayed to cardiac and psychoactive effects.
Dependence is seen in 10% of heavy users (10-20 joints/day). By comparison, >50% of heavy opioid users develop dependence.
Use may be associated with panic attacks, depression, mania and schizophrenia.
- Adolescent (<25 y) exposure increases the risk of schizophrenia development, but it is important to consider that diagnosis is usually around this age anyway.
Respiratory disorders may occur but this is not as severe as expected.
There is a mild withdrawal syndrome manifesting as irritability, sleep disturbance, nausea, vomiting, excessive sweating and salivation. THC accumulates in adipose tissue and is eliminated slowly, which may be why symptoms are so mild.
Cannabinoids
There is a unique enzyme and metabolite set in Cannabis, such as Tetrahydrocannabinolic acid synthase.
100+ unique metabolites, and the majority are resorcinols
Δ9-tetrahydrocannabinol, THC, is the most famous. It’s apparently solely responsible for the well-recognised psychotropic effects
These metabolites may have an “immune” role in the plant
Cannabinoids with reported “bioactivity” include:
- THC - tetrahydrocannabinol: THCA-A (Δ9-tetrahydrocannabinolic acid) and THCV (Δ9-tetrahydrocannabivarin)
- CBD - cannabidiol: CBDA (cannabidiolic acid) and CBDV (cannabidivarin)
- CBG – cannabigerol: CBGA (cannabigerolic acid)
- CBN – cannabinol
- CBC - cannabichromene
Phytocannabinoids show structural similarity with steroids. They are all acids - different profile from other psychoactive substances .
Molecular targets
THC acts at CB1 cannabinoid receptors.
These are the highest density GPCR in the CNS, associated with analgesia, increased feeding, reward, etc.
CB1 appears to be responsible for all the psychoactive effects of THC/cannabis.
The CB2 cannabinoid receptor is primarily associated with the immune system. People with IBS experience a worsening of symptoms if they consume cannabis.
THC also acts at glycine receptors, PPAR𝛾 and TRP channels.
It is harder to determine the molecular targets of CBD. It shows low potency at multiple targets.
- 5HT1A, 5HT2A agonist, 5HT3 antagonist
- PPAR𝛾
- TRP channels
CBG acts at α2-AR and TRP channels
CBC acts at TRP channels.
2AG action in the CNS - depolarisation-induced suppression of excitation
High-frequency presynaptic depolarisation causes an excessive production of glutamate.
This causes activation of postsynaptic NMDA and mGlu1/5 glutamate receptors and also perisynaptic PLC and DAGL.
This leads to production of 2AG and activation of presynaptic CB1 receptors.
- The signalling molecule travels backwards, but it is unknown if this is random or if there is an active retrograde transport mechanism.
This causes opening of Kir channels and a reduction of presynaptic excitability.
This is depolarisation-induced suppression of excitation.
This may cause the short-term memory impairment associated with cannabis use.
Rimonabant
Rimonabant is a CB1-selective antagonist/inverse agonist developed by Sanofi-Aventis, licensed in Europe in 2006 (but not in the US) as a treatment of obesity-related diabetes or for metabolic disorders.
It was an effective weight-loss treatment, but it was withdrawn in 2008 due to an incidence of depression and suicidal ideation in patients without previous symptoms.
Medicinal Cannabis and derivatives
In states like Oregon, a lot of income is generated from taxing cannabis as this is legal for any use.
Cannabis is legal for medical use when authorised by a physician in the UK since 2018, but not many prescriptions are given out, so there is an issue with accessibility.
Medicinal use of Cannabis (including THC) include:
- Emesis/nausea, but 5-HT3 receptor antagonists, like ondansetron, are now preferred. Cannabinoid hyperemesis syndrome (CHS), characterised by severe nausea and vomiting in regular users, is a paradoxical adverse effect.
- Glaucoma - reduces intraocular pressure
- Multiple sclerosis adjunct therapy
- Epilepsy, particularly childhood epilepsy
- Cachexia (weight loss) in AIDS/cancer - improves quality of life by stimulating the consumption of palatable food and preventing weight loss
- Pain/analgesia
- Migraine and cluster headaches
- Anxiety & PTSD. Memory loss effects beneficial in these condition, however some long-term users develop anxiety, so it’s difficult to stratify patients into who the treatment would be beneficial for.
- Harm reduction - a lot of addicts would use cannabis to mellow the effects of withdrawal from other drugs such as opioids, synthetic cannabinoids or ‘Bazooka’ (remnants left after cocaine extraction).
THC is also being investigated for anorexia nervosa, agitation in dementia, and Tourette’s syndrome.
Low doses of Δ9-THC have shown potential in reversing age-related cognitive impairments and protecting against toxic insults in rodents.
However, the intoxicating effects of Δ9-THC can be a barrier to widespread therapeutic use.
THC is available as a regulated pharmaceutical in products like Marinol, Sativex, and Namisol.
Why isn’t the evidence more convincing?
Evidence for the medicinal use of Cannabis may not be acceptable due to the huge variation in metabolite content in commercial preparation.
THC content has increased over the years in both herbal cannabis and cannabis resin.
Intrinsic variability
Cannabis is a natural product, so there is an inevitable variability in genetic background, growth conditions, harvesting times, preparation handling, etc. Think of it as wine: there is a difference in taste of different varieties, which comes down to differences in intrinsic chemical composition.
The quality control of Cannabis preparations is limited at best for those locations where the non-medicinal sale is legal.
Where the sale is illegal (most of the world), there is huge variation in the chemical constituents.
This means that the balance between desirable and undesirable properties of the chemical constituents is highly unpredictable.
Commercial suppliers of Cannabis-derived medicinal preparations however identify the content of principal cannabinoids.
Statistics
Cannabis is the most widely used illicit drug globally, with an estimated 192 million users.
In England and Wales, around 30% of the population has used cannabis between 2000 and 2024. However, use by young people has gone down since the 2000s, so people may start using it later in life.
10% of the population takes cannabis daily.
Cannabis is a class B drug, so it is associated with penalties for supply and possession.
- Possession: <5 yrs prison and/or fine
- Supply: <14 yrs prison and/or fine
Looking at deaths where selected substances were mentioned on the death certificate in England and Wales between 2014-23, opioids are associated with the most deaths and cocaine has had a rise in the last 5 years. Cannabis only causes 20-30 deaths per year, out of half a million annual deaths in the UK. Most of these are not caused by cannabis alone as cannabis is often consumed with other substances.
Cannabis is not associated with acute toxicity, but that doesn’t mean it is ‘safe’.
In the UK, ‘home-growers’ have selected Cannabis strains/cultivars with higher THC content/lower CBD content, called ‘skunk’.
This is associated with increased reports of negative effects on ingestion, including paranoia, anxiety, psychotic episodes and long-lasting depression.
‘Street’ Cannabis is often adulterated with other substances to increase the impact.
