Synthetic Cannabinoids Flashcards
2AG action in the CNS: DSE
High-frequency presynaptic depolarisation causes excessive production of glutamate.
This leads to activation of postsynaptic NMDA and mGlu1/5 glutamate receptors.
This then causes the activation of phospholipase C (PLC) and diacylglycerol lipase (DAGL).
The endocannabinoid 2-arachidonoylglycerol (2-AG) is produced and activates presynaptic CB1 receptors.
This leads to the opening of Kir channels and a reduction in presynaptic excitability.
This is depolarisation-induced suppression of excitation (DSE).
Phytocannabinoids
Phytocannabinoids include cannabichromenic acid, cannabidiolic acid and tetrahydrocannabinolic acid.
These are naturally-occuring cyclic compounds.
Molecular targets of Phytocannabinoids
THC acts at:
- CB1 cannabinoid receptors, the highest density GPCR in the CNS. These are associated with analgesia, increased feeding, reward, etc. and appear responsible for all psychoactive effects of THC/cannabis.
- CB2 cannabinoid receptor, primarily associated with the immune system
- Glycine receptors
- PPAR𝛾
- TRP channels
Cannabis is however a mixture of lots of different compounds.
CBD has low potency at multiple targets, including:
- 5HT1A, 5HT2A agonist, 5HT3 antagonist
- PPAR𝛾
- TRP channels
CBG acts at α2-AR and TRP channels.
CBC acts at TRP channels.
The balance between THC and CBD is thought to be involved in preventing the more negative effects by limiting the action of THC at the CB1 receptor.
The issue with synthetic cannabinoids may be that this balance is lost.
Synthetic cannabinoid receptor agonists (SCRAs)
In 1964, THC was identified and in ‘88 CB1 receptors were identified. Prior to the identification of the CB1 receptor and THC radioligand binding assays, it was believed that, as THC is highly lipophilic, its psychoactivity was related to disruption of plasma membranes.
This triggered numerous medicinal chemistry programs with two intentions:
1. Producing high-potency, high-efficacy agonists able to mimic some of the desirable aspects of Cannabis/THC, such as pain relief.
2. Avoiding the negative aspects of Cannabis/THC, such as the ‘high’, memory loss and dissociation from the environment.
Many agonists with higher potency and efficacy than THC and the endocannabinoids were identified. The effects in man were very similar to the effects of higher dose THC/Cannabis.
None of these agents reached the clinic.
For example, CYP55940, generated by Pfizer, had a higher potency and efficacy than THC as the chemical modifications in the structure of THC resulted in increased hydrophilicity.
Spice as a ‘legal high’
Psyche Deli (~2005) was a company that created ‘spice’, brightly coloured bags containing a few grams of mixtures of dried and crushed plant parts (flowers, stems, leaves) from various aromatic species that the cannabinoids were added to.
Spice is a problematic description as it is not a single compound - many cannabinoid compounds are called spice and ‘spice’ is often a mix of different cannabinoids.
These complex blends became known as “herbal incense” in headshops or convenience stores and were advertised as ‘exotic incense blend which releases a rich aroma, not for human consumption’.
It was however commonly smoked through conventional Cannabis pipes or wrapped up as cigarettes. This induced euphoric effects similar to those associated with the consumption of high dose Cannabis products.
It was not detected by contemporary urine screens for drugs as the compounds have a different structure from THC.
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Unlike THC, which has a relatively large safety margin, synthetic cannabinoid use has shown many dangerous side effects and few therapeutic applications. Despite this, their use remains relatively popular, often to avoid positive drug screens. These drugs are structurally diverse and rapidly changing, driven by clandestine chemists trying to stay ahead of legal pressures.
Associated with agitation, cardiotoxicity, nausea, psychosis, seizure, and vomiting, with more frequent and severe adverse effects than cannabis, leading to a 30-fold higher relative risk for emergency medical treatment.
Street SCRAs
There is a huge variation in the constituents and levels in street SCRAs.
There is an estimate of up to 28,000 potential different SCRAs.
There are also solutions for e-cigarettes available.
SCRAs have increased potency and efficacy compared to THC. there is a rapid onset and a shorter duration of action.
Up to 10 % of US high school students (2011-13) use SCRAs.
Street names include spice, AK47, bonsai, K2, qupic and black mamba.
Compound names include: CP55940, JWH018, HU210, AM1221, XLR-11 and AB-FUBINACA.
Minor/semi-synthetic phytocannabinoids
Δ8-THC is a low abundance plant derivative less potent than Δ9-THC.
These compounds differ only in the position of a double bond.
Partial synthesis was achieved in 1941 by Adams.
In 2023, 11% of US 12th grade students (17-18 years old) had sampled Δ8-THC in the last year and 30% had sampled ‘marijuana’.
Hexahydrocannabinol (HHC) is a reduced version of THC first described in 1940 by Adams.
It can be synthesised from THC but also CBD.
It has been sold openly in headshops in Europe and North America since 2020. It was initially legal but the status has generally changed.
These compounds are not particularly potent but were abused prior to being regulated due to decreased risk of persecution.
Prevalence and legality
On 11 June 2024, the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) published the annual European Drug Report 2024 that provides an overview and assessment of the drug situation in Europe up to the end of 2023.
The report states that “cannabis consumers risk inadvertent exposure to synthetic cannabinoids”.
The 9 new cannabinoids detected, 4 of which are semi-synthetic cannabinoids, accounted for approximately ⅓ of the new substances first reported to the EU Early Warning System in 2023.
This brings the total number of cannabinoids being monitored to 254. By comparison, only 81 opioids are monitored.
Synthetic cannabinoids sometimes appear in samples of other drugs
- In May 2023 an unusual and unexpected outbreak of non-fatal poisonings involving more than 20 people was reported in Paris, caused by heroin adulterated with synthetic cannabinoids.
- In April, Lithuania reported the seizure of a similar adulterated heroin sample.
Health risks from HHC and other semi-synthetic cannabinoids remain poorly understood.
In 2022, semi-synthetic cannabinoids, not controlled under international drug laws, started to appear on the European drug market for the first time.
HHC was the first, reported in 24 European countries. HHC has been listed as a controlled drug in at least 18 EU States.
Five other semi-synthetic cannabinoids have also been identified on the European drug market.
Initially, semi-synthetic cannabinoids were trafficked from the US, but there are now signs that they are also being produced in Europe.
In 2016, the Misuse of Drugs Act of 1971 was amended to include any compound structurally related to JWH-018, in that the four sub-structures are linked together in a similar manner. This is trying to limit the exposure of the public to synthetic cannabinoids.
- The act cannot list all synthetic cannabinoids due to their widespread prevalence, so they took the four main components of one of the first synthetic cannabinoids and said that any drug that contained these, or a very similar structure, was banned.
- This was a problem as many compounds that have a similar structure have been tested against CB1 receptors and proved to have no activity - this makes registration of drugs for clinical trials more complicated.
The impact of SCRAs
Multiple SCRAs are associated with hospitalizations. There was a general decline following the 2016 amendment, but he number of hospitalisations is likely an underestimate as very few labs have the capacity to detect synthetic cannabinoids due to the huge number of such compounds.
SCRAs present a significant public health issue. This is restricted to particular subpopulations, being prevalent in the homeless and incarcerated, presumably as a mechanism to ‘fill the time’.
SCRAs are prominent in particular countries, including the UK, US and New Zealand.
Synthetic cannabinoids are a huge concern in the US. There were 130 suspected overdoses in one week in July 2016 in New York.
Also in 2016, over 33 individuals were suggested to have become intoxicated using a synthetic cannabinoid termed AMB-FUMINICA (sold as AK-47 or 24-Karat Gold). This led to a popular media description of a ‘zombie outbreak’ due to the appearance and behaviour of the intoxicated persons.
The most common clinical manifestations of SCRAs reported are CNS and CVS symptoms.
Very few studies analysed patient samples for SCRAs or their metabolites, so it’s hard to know which particular synthetic cannabinoids are associated with the most risk.
Very few studies analysed patient samples for SCRAs or their metabolites
Hard to know which particular synthetic cannabinoids are associated with the most risk. For example, rat poison was a contaminant to a synthetic cannabinoid that gave rise to significant coagulopathy.
Looking at cannabinoid-linked deaths in England and Wales, we can see that there was a spike in deaths associated with synthetic cannabinoids around 2018-2021. Deaths associated with cannabis show a slower and more steady increase. As a reference, there were 581,363 deaths in 2023 → even at their peak, synthetic cannabinoids only caused 70 deaths in 2021, but this is a huge increase from 0 in 2013.
Molecular mechanisms
There may be more reasons, besides increased potency and efficacy at the CB1 receptor, for why synthetic cannabinoids are more harmful than THC.
Looking at metabolites of JWH018, ω-hydroxylated JWH018 is also a full CB1 agonist, while the glucuronide is a competitive antagonist.
Depending on the individual’s PK profile, this combination could lead to tolerance and dependence.
- Agonist effects could be maintained or very rapidly switched off based on the metabolism of the particular individual, e.g. due to different enzyme expression levels or due to consumption of other compounds that cause induction/inhibition of metabolising enzymes.
Causes of death associated with these synthetic cannabinoids have been attributed to a mixture of CNS and cardiac events.
Some symptoms, such as renal and ocular effects and respiratory depression, are less obviously linked to CB1 receptor activation.
The precise mechanisms by which these agents elicit these effects are unclear
The involvement of CB1 receptors or off-target actions requires additional investigation.
Ion channels, such as hERG potassium and T-type calcium channels in the heart, could potentially be involved in cardiovascular effects.
Treatment of overdose is through alleviation of severe symptoms using sedation until a greater mechanistic insight allows the identification of more precise pathways.
It has been suggested that antagonists could be used, similarly to how naloxone is used to reverse opioid overdose.
Rimonabant was a CB1 receptor antagonist previously licensed (EU) as an oral therapy for metabolic disorder/obesity. It’s been withdrawn due to its tendency to induce psychiatric issues like depression and suicidal ideation, but it has never been investigated for the treatment of synthetic cannabinoid overdose.
It has been suggested that antagonists could be used, similarly to how naloxone is used to reverse opioid overdose.
Rimonabant was a CB1 receptor antagonist previously licensed (EU) as an oral therapy for metabolic disorder/obesity.
It’s been withdrawn due to its tendency to induce psychiatric issues like depression and suicidal ideation, but it has never been investigated for the treatment of synthetic cannabinoid overdose.
