Group 5 As many of you probably know by now, there are a lot of “legal” or “semi-legal” products out there that use analogues of cannabinoids that are not necessarily covered by the law. In recent years, this has lead to a deluge of “cannabis alternatives” (aka “designer marijuana” or “synthetic marijuana”), where synthetic cannabinoids such as cannabicyclohexanol, HU-210, JWH-018 and JW-073 are sprayed onto inert plant material. They are not at all similar to “medical marijuana“, and should probably not have the word “cannabis” attached to them in any way. Synthetic cannabinoids have very different effects, and can be dangerous. Chemical structure of synthetic cannabinoid, JWH-259. Picture from https://commons.wikimedia.org/wiki/File:JWH-259.svg These products are often sold and marketed as “incense” or “herbal blends”. Perhaps the most well-known products are K2 and Spice, both of which have received significant media attention, which lead to such products becoming illegal in many countries (they are now Schedule I substances in the US). Other common names include Black Mamba, Bombay Blue, Zohai, Bliss and probably more than can be listed here. One thing that is most notable about these products is that they seem to be more dangerous than natural cannabis. To quote from ‘Synthetic Pot: Not Your Grandfather’s Marijuana’: “SCBs are a large collection of man-made chemicals, reported in the scientific literature over decades of research to have affinity for CB1 and CB2 cannabinoid receptors. Products known as K2 or Spice contain a mixture of SCBs that have been illicitly synthesized and sprayed onto inert plant material, to mimic the appearance and psychotropic effects of Δ9-THC in marijuana. K2/Spice products are falsely marketed to adolescent and other vulnerable populations as ‘safe’ and/or ‘legal’ alternatives to marijuana, and are widely known to avoid detection in standard drug screens due to their lack of structural similarity to Δ9-THC. SCBs present in K2/Spice products produce a variety of dangerous acute and chronic adverse effects, including psychosis, seizures, tolerance, dependence, and death, with a greater severity and frequency than observed following marijuana use. Very little is known about the mechanisms underlying the distinct toxic effects of SCBs compared to Δ9-THC, but it is likely that they result from actions at both CB1 and non-CB1 cannabinoid receptor targets.” Spice – inert plant material containing synthetic cannabinoids, and now illegal in the US. Picture from https://commons.wikimedia.org/wiki/File:USMC-100201-M-3762C-001.jpg Bottom line: we do not know enough about the endocannabinoid system (ECS) yet to start messing around with synthetic, experimental analogues of delta-9 THC and other cannabinoids. The ECS is an extremely powerful system, intimately involved in homeostasis, brain development and even reproduction. Unwittingly shutting down or desensitizing one part of the ECS or the endogenous cannabinoids it produces could prove to be extremely dangerous. Essentially, the message here is: do not take these substances. They are not the same as well-grown, natural cannabis. So, why are SCBs so much more dangerous than cannabis? Well, we’ve already mentioned above that, just because a compound may be somewhat structurally similar to THC, CBD etc., it doesn’t mean that it won’t have significantly different effects. We do not know exactly how SCBs affect the body and the mechanisms by which they work. Another problem – and this is somewhat theoretical here – could be due to the “entourage effect”. Synthetic cannabis products do not have the whole gamut of cannabinoids and terpenoids that are present in the natural cannabis plant, which could negate some of the negative side-effects of other cannabinoids whilst at the same time making them potentially more useful for various ailments. Now, this is not to say “the presence of other cannabinoids and terpenoids will make SCBs safer”, but these synthetic products do not have the natural “checks and balances” that natural cannabis seems to have. Moreover, the human body seems to tolerate natural cannabinoids a lot better, and natural cannabinoids do not seem to affect the ECS in such a harmful manner. Cannabinoids: not quite the Roman Republic, but perhaps more democratic! Author: RomanHistorian. Picture from https://commons.wikimedia.org/wiki/File:Roman_Constitution.jpg We should not be too hasty in writing synthetic cannabinoids off completely when it comes to a clinical setting. Nabilone (brand name Cesamet) is a synthetic version of THC that has been used since 1981 as an antiemetic and to manage pain for patients with cancer, Parkinson’s disease, ulcerative colitis, multiple sclerosis (MS) and fibromyalgia. Dronabinol (brand name Marinol) is another synthetic form of THC that is used for chronic pain as an antiemetic for cancer and AIDS/HIV patients. Interestingly, nabilone is listed as a schedule II drug, and dronabinol is listed as a schedule III drug. Why naturally-occurring cannabinoids are treated so differently, I do not know, but it does seem to be a glaring contradiction in terms of the way in which authorities schedule substances. Another interesting point to be made is that many of these synthetic, “purified” cannabinoid-based medications are often not as well tolerated, and may in fact be less effective, due to the lack of “entourage effect”. Having other cannabinoids and terpenoids “in the mix” may well increase the therapeutic value of THC (and vice-versa), and taking these away may detract from the value of cannabinoids somewhat. Biosynthesis from THCA to THC and CBDA to CBD in the human body. The CBD-based Epidiolex by GW Pharmaceuticals is undergoing Phase III FDA-authorized clinical trials. The mouth spray Sativex (generic name naboximols), a 1:1 CBD:THC medication used primarily for MS, is another GW Pharmaceuticals product that’s available on prescription in many countries outside of the US. GW Pharmaceuticals seems to focus mostly on plant-derived cannabinoids as opposed to synthetic versions, so do not necessarily fall under the rubric of “synthetic cannabinoid medications”. There are many other whole-plant extracts out there on the market today, many of which purport to contain many other cannabinoids such as THCA, CBG, CBC, CBDA and so on. Whether or not the companies making such extracts all achieve consistent results with regards to their cannabinoid-terpenoid profiles is not certain, but I hope that this eventually becomes the case. GW Pharmaceuticals, who have the technical know-how and the licensing to do so, may well have a slightly easier time of it than those who are still working “in-between” the legal and illegal worlds, where government approval isn’t so easy to come by. Naturally-derived cannabinoids and terpenoids are often “unstable”. There are other potentially positive aspects to developing and potentially utilizing synthetic or semi-synthetic cannabinoids. Many cannabinoids are very “unstable” when out in the open and exposed to air, light, changes in temperature and so on. They start to degrade and change over time, and can end up having entirely different effects. Moreover, different cannabinoids will have different degradation points. There is little data in this area, but we can definitely be sure that the method of preparation matters. As many know by now, cannabinoids are lipophilic, meaning they love to attach themselves to lipids such as those found in coconut oil, olive oil, butter etc. Yet, even using different lipids will affect cannabinoid-terpenoid profiles, as well as how they behave when in the body (as noted by Jason David). There is still a lot of research needing to be done in this area, but it does seem that oils are one of the better ways of keeping cannabinoids stable over a longer period of time. Yet, how stable they are depends on a lot of factors, and there is still much study to be done in this area. To add some further complications, getting cannabinoids like CBDA, THCA and many of the acidic cannabinoids are notoriously difficult to keep stable. Even delta-9 THC is difficult to keep stable, so 8-THC, which is less psychotropic and expensive to prepare (‘Phytochemical and biological research of Cannabis pharmaceutical resources’), could well be another cannabinoid we could potentially utilize. However, as such compounds are often not found in huge abundance, they can become very difficult to extract. In order to get around such difficulties, synthetic and semi-synthetic cannabinoids may be a simpler and more efficient way of doing things. Adding a compound to a natural cannabinoid in order to make it more stable could be the only way of ensuring consistent dosage of CBDA, CBC and so on. Alternatively, finding out all we can about a natural cannabinoid and then creating a synthetic, well-tolerated, safe and clinically-tested “mimic” may in some instances be the only solution to getting the amount of cannabinoids we need for specific medications and conditions.Yes, naturally-derived cannabinoids and terpenoids seem to be more well-tolerated by most people, but this does not mean that there may need to be some way of “getting rid” of cannabinoids that may be potentially be harmful for some sections of the population, or using cannabinoid-based medications with very specific profiles. For example, THC could be useful for someone with MS and/or chronic pain, but someone with schizophrenia may want to avoid it, no matter how naturally-derived. Another example is cancer, where treatment must match classification (although to what extent this is the case is not actually known). We ought not to be scared of the word “synthetic” when it comes to cannabinoids, as it could mean something completely different when used in a medical and pharmaceutical setting – it is the horribly-marketed, fake, untested-synthetic-cannabinoid-sprayed plant material (once again, it shouldn’t even be called “cannabis”) that has arisen from bad regulations that we should be clamping down on. And frankly, the only way we see such products from entering the market is by cannabis legalization. Overall. Tetrahydrocannabinol (THC). Author: Yikrazuul. From https://commons.wikimedia.org/wiki/File:Tetrahydrocannabinol.svg To summarize. Synthetic and semi-synthetic cannabinoids and terpenoids that have been tested for safety and efficacy have a part to play in making novel medications. Naturally-derived cannabinoids and whole-plant extracts are generally more well-tolerated. The entourage effect is hugely important, and may well “buffer” the negative effects of other cannabinoids. At the same time, not every condition necessarily needs all the cannabinoids and terpenoids found in the cannabis plant, and some may have negative effects. This means that some form of “engineering” is required in order to get the profiles we need, whether this is through creating SCBs or genetically manipulating the plant, as we do with many fruits and vegetables in our diets. In some instances, we may need to stabilize a natural cannabinoid using semisynthetic methods. And finally, we should not be afraid of the word “synthetic” – we should be afraid of bad substances arising from bad regulations.