What’s the Deal with Synthetic Cannabinoids… Are They All Dangerous?
Ah weed, one of the most popular and lowest risk recreational substances out there. Although not without any dangers, weed itself is generally seen as one of the safest drugs to ingest with regularity. However, there’s a lot of talk about synthetic cannabinoids and their seemingly huge risk potential. So…
What’s the Deal with Synthetic Cannabinoids… Are They All Dangerous?
Risks of Delta 9-THC (Standard THC)
Before we dive into the science of synthetic cannabinoids, let’s first talk about THC’s own risk profile so we can draw a comparison and discuss why synthetics might be far more dangerous.
As most know, the primary psychoactive compound found in the marijuana plant is Delta 9-Tetrahydrocannabinol (AKA delta 9-THC, more frequently known simply as “THC”). Due to the rise in popularity of Delta 8-THC, the “Delta” descriptor might be a commonly seen word. So what does Delta specifically mean?
What does “Delta” refer to?
To understand this question, let’s first take a look at THC’s molecular structure (don’t worry you don’t really have to fully understand the chemistry here, this is just a, hopefully interesting, aside):
Delta 9-THC aka “Normal” THC
This is a picture of the delta 9-THC molecule. Notice the 3 different ring structures it has and pay special attention to the ring on the top left. Now let’s take a look at delta 8-THC.
Delta 8-THC, a Federally Legal (in the US) Minor Alt-Cannabinoid of Recent Popularity
Notice the difference in the placement of the double bond in the top left right. Delta 8 THC has the double bond at the 8th position, while Delta 9 has it at the 9th.
This minor difference in structure isn’t enough to change the effects of the molecule in any categorically different manner, but it does reduce the potency of the molecule. This is why delta 8 is a milder and less euphoric high than delta 9 and requires a higher dosage.
So with that out of the way, what are the acute risks of THC?
There are numerous deleterious effects of long term habitual ingestion of THC such as mood dis-regularity, inhibition of motivation, reduction of natural appetite, and anhedonic depression. However, today we are primarily going to focus on the acute effects since they have the most relevance to why synthetic cannabinoids can be riskier.
The primary acute risk of THC is psychosis. Although THC is incredibly safe for a healthy individual with no history nor predisposition to either anxiety or psychotic disorders, it is also simultaneously one of the most risky compounds (other than synthetic cannabinoids) for one with psychotic tendencies to ingest.
In fact, in a comparison of how likely a drug-induced First Episode Psychosis (FEP) is to convert into a full blown chronic psychotic disorder (such as schizophrenia), THC (and other THC-like cannabinoids) took first place in a solid landslide. [Note: I can’t seem to find the original paper that does the in depth break down of percentage amongst all drug classes, but THC was number 1, with hallucinogens / stimulants as a far second place] [https://ncbi.nlm.nih.gov/pmc/articles/PMC2779870/]
This tells us that: although weed is one of the safest recreational drugs out there, this is only true for those without preexisting psychosis issues (or a genetic predisposition thereof). For those suffering from psychosis or a genetic predisposition to psychotic disorders, THC could in fact be one of the most risky recreational drug to ingest!
So… Why?
THC is a cb1 receptor partial agonist (see the article on Agonism for a refresher on what a “partial agonist” is!). The cb1 receptor is involved in numerous roles in the brain including: pain relief, consummatory pleasure (they work along with endorphins and dopamine to activate the hedonic centers of the brain), reduction of nausea, and the overall mind altering “high”.
The true link between cb1 agonism and psychosis is not fully understood, but there seems to be a resultant spike in mesolimbic dopamine levels as a direct cause of cb1 agonism. (Refer back to the article on Dopamine for a refresher on the mesolimbic dopamine pathway). As mentioned in previous articles, the mesolimbic dopamine pathway deals with reward, salience (assigning importance to stimuli), and pleasure, but also lead to symptoms of delusions and psychosis when levels of dopamine become excessive. This link between cb1 agonism and increase of mesolimbic dopamine neurotransmission is potentially a cause for the increased psychosis risk. Why this effect seems more powerful than that of psychostimulants, which can directly raise mesolimbic dopamine to much higher levels, is unclear. There is some evidence of unusual cb1 receptor distribution amongst psychosis patients. [https://pubmed.ncbi.nlm.nih.gov/17349865/]
The Tempering Effects of CBD
Many probably have heard that “weed back in the day was less likely to induce psychosis”. The reason behind this assertion has to do with CBD concentrations and its softening effect on THC.
CBD (Cannabidiol) is a cannabinoid naturally found in the marijuana plant at much lower quantities than delta 9-THC. CBD is a low potency ligand for both CB1 and CB2 receptors, but due to its much lower intrinsic activity (See agonism article for more info), it acts as a partial antagonist at these receptors instead. This has the effect of reducing the intensity of the THC high and also reducing psychosis risk. Modern strains of weed tend to go for higher and higher concentrations of THC at the cost of CBD, so there is some truth in the assertion that “old school weed was healthier for mental health”.
Synthetic Cannabinoids
Ok let’s get into synthetic cannabinoids. Synthethic cannabinoids are a relatively new class of drugs that first reached popularity (or notoriety I should say) with the introduction of K2 or Spice as a legal marijuana replacement in the early 2000s [source]. These quickly developed a negative reputation once reports started coming out of otherwise healthy individuals being thrown into nightmarish psychotic episodes.
So why were these synthetic cannabinoids so much more dangerous, and is this true of all synthetics?
The primary difference is that a vast majority of synthetic cannabinoids (with the inclusion of K2/Spice) are cb1 full-agonists rather than partial-agonists. As mentioned previously, partial agonists have a ceiling-effect and “top out” on their intensity at a certain level even if you ingest an infinite amount of it. This means that delta 9-THC has lowered maximal potential subjective effects compared to full-agonists. Synthetic cb1 full agonist compounds have the potential for a much more intense high than delta 9-THC is capable of, and this is the root cause of its heightened psychosis risk.
From there we can also see that the higher risk of synthetic cannabinoids is not an intrinsic effect of it being manufactured, but rather due to the vast majority of known synthetics being full-agonists rather than partial-agonists.
Synthetic compounds that more closely match delta 9-THC’s pharmacodynamic profile are, in theory, much safer to ingest than full-agonists. But of course, ample research and caution should still be exercised regardless.
A Selection of Synthetic Cannabinoids
[attribution]
Minor Alt-cannabinoids
Alt-Cannabinoids are psychoactive cannabinoid compounds found in the marijuana plant in much lower concentrations than delta 9-THC that all contribute to the “Entourage Effect” of weed.
In recent years, these have raised in popularity due to the 2018 Farm Bill passed in the US that explicitly legalized all compounds found in hemp plant other than Delta 9-THC. The market flooded with minor cannabinoids as legal weed replacements, and examples include:
THCP, THCV, Delta 9-THC-O, Delta 8-THC-O, H4CBD, HHC, HHCO, HHCP, HHCP-O, THCPO, and numerous others. Since these are all either partial agonists or antagonists at cb1, they do not carry the same risk that most synthetic cannabinoids have.
Furthermore, some of these are not actually naturally occurring compounds and require a series of lab processes to create. Due to this, the DEA is officially categorizing the THC acetates (such as the THC-Os) as illegal synthetics not covered under the farm bill. Despite this fact, these synthetic cannabinoids are still roughly as safe as delta 9-THC, rather than being risky like K2 since they are only partial agonists (technically pro-drugs to THC).
In comparison to synthetics, naturally occurring cannabinoids are typically referred to Phytocannabinoids instead as a way to distinguish the two.
Note: THC-O and other acetates have the potential to produce harmful impurities when combusted (smoked or vaped), so it is only recommended to ingest these orally to protect ones lungs from damage.
“Smoke weed everyday”
