Along with the popular knowledge about the beneficial properties of hemp so grows the confusion around the subject. Most consumers are already aware of the differences between hemp and marijuana, what the cannabinoids are, as well as of the role that CBD plays in the beneficial effects of cannabis. However, although the fact that CBD hemp oils are completely legal in Poland and no, they do not exhibit any psychoactive properties, some controversy is still associated with, for example, different types of CBD products and their origin, as well as with their alleged link to the “medical marijuana”. A couple of the most common myths about cannabidiol have been tackled with earlier, today we will focus on the controversial synthetic CBD. As we shall see – the issue of cannabinoids synthesized in the laboratory brings together many of the most obscure and controversial issues surrounding cannabis as such. Discussion of synthetic CBD will therefore inevitably require to revision of basics about cannabinoids and their pro-health or even therapeutic effect.
Let’s start with a quick reminder. The term “cannabinoids” refers to the group of organic compounds acting on cannabinoid receptors. Originally, the term had referred only to the compounds found in cannabis, but its meaning has widened since the discovery of endocannabinoids – substances acting on the cannabinoid receptors, but produced inside the body. The most famous endocannabinoid is anandamide.
There are more than a hundred plant cannabinoids (phytoocannabinoids). The vast majority of them are not psychoactive, yet show a beneficial effect on the human body, the effect we have only started to understand. The most famous of them are the psychoactive tetrahydrocannabinol (THC) and cannabidiol (CBD).
Following this functional approach (defining cannabinoids as a class of compounds that act on the endocannabinoid system’s receptors) we inevitably stumble across the synthetic cannabinoids – substances created in the laboratory, to a greater or lesser extent mimicking the chemical structure and effects of the natural cannabinoids.
Synthetic cannabinoids are notorious – and they to some extent have earned this status. However, they make up a huge and incredibly diverse group of compounds with different status – from illegal “designer drugs”, through registered medicines with proven therapeutic value, analogs of natural cannabinoids, up to the substances that are still in the research stage we know little about. Synthetic cannabinoids have names like 4-HTMPIPO, AM-2232 BAY 38-721, JWH-302, WIN-55212-2, and so on. Only a few of them were granted a trade name, among them Nabilone, or infamous “Spice”.
Notoriety for synthetic cannabinoids stems from the “designer drugs” in the ilk of above-mentioned “Spice”, which was responsible for at least several deaths and caused media panic around the “legal highs”. Numerous studies indicate that many of those “recreational” synthetic cannabinoids can cause serious side effects, including psychoses. At the same time the vast majority of these substances remains virtually unknown, and so are their potential effects on the human body.
But we should not forget that many of these synthetic cannabinoids are designed as medicines. The most famous is the synthetic equivalent of tetrahydrocannabinol – Nabilone, well-tested and approved for the market as an antiemetic drug also exhibiting some analgesic effect in the fight against neuropathic pain. It remains controversial whether such substances are a better measure than the natural THC and CBD or the whole-plant preparations. We will return to these questions further, dealing with the case of synthetic CBD.
The term “synthetic” is sometimes (albeit incorrectly) used in reference to isolates of individual substances. It is not a precise definition, yet as the “synthetic CBD” is unceasingly used to describe pure form cannabidiol, in this article we we’ll also broach the subject of the isolates.
“Synthetic” vs “natural”
Before we get to discuss the advantages and disadvantages of synthetic cannabidiol as such, it is worth to make a small digression. In the popular discourse, the “natural” substances are often contrasted with “synthetic” ones as allegedly “pure and beneficial,” in contrast to the allegedly harmful products of advanced chemistry and pharmacology. However, we do not want to convolute the matter ans become entangled in philosophical or technical debates in line of how many iterations of external manipulation does it take for the naturally occurring substance to lose its “natural” status and becomes “artificial.” Even less are we interested in philosophical or even metaphysical justifications behind this type of oppositions. Synthetic fertilizers have helped to feed billions of people in the postwar world, and synthetic hormones freed mankind from tedious task of evaporation tanks of urine in order to obtain a few drops of progesterone. We would like to keep a pragmatic approach and evaluate synthetic CBD only from the point of view of security, usability and convenience for the user.
As for the “naturalness” of synthetic cannabinoids defined as their similarity to the natural counterparts, it varies quite considerably. Some substances are virtually a copy of the “natural” one (in which cases they are dubbed “isolates”, yet not entirely accurately), other synthetics/analogs slightly modify the model found in the plant, while other derive far from the “prototype”.
By “synthetic CBD” we understand a group of analogues of the CBDs obtained in the laboratory. As for now, none of them differ significantly from the of natural cannabidiols in term of their structure. You may have noted that the plural form was in use above – how comel? It stems from the fact that also the plant CBD is found in seven different versions – those natural analog include compounds such as CBDA (cannabidiolic acid, CBDV (cannabidivarin), CBDVA or CBD-C4 (nor-cannabidiol).
As the “original” CBD does not exhibit any psychoactive properties, scientists studying its synthetic analogs were not seeking for any “recreational” versions of cannabidiol. Their goal was instead to develop substances that could potentially become drugs of therapeutic value. The fairly comprehensive review of the synthetic analogues of the CBD has been put together by Paula Morales and her team. New substances were tested in mice for its anti-inflammatory and antiepileptic properties, examined was also their potential to fight Crohn’s disease. The results were promising, though not spectacular. The most significant practical founding was that some of the synthetic analogues showed slightly better pharmacodynamics than plant CBD. Interestingly enough, although the natural CBD does not bind directly to the crucial CB-1 cannabinoid receptor (it affects it indirectly), at least some of its laboratory obtained analogues (namely (+) – CBD, Abn-CBD, O-1602, and few others) not only does bind with the said receptor, but seemingly stimulates other receptors as well. The consequences of such broadened scope of action have not been yet examined, none of the substances examined in the study has been also recommended for the next stage of trials.
The term “synthetic CBD” is sometimes referred to the isolate (pure CBD) – whether obtained by extraction or synthesis. It is a kind of shorthand, but the isolated cannabidiol it is worth mentioning – not only because for decades it had been the default form of CBD used in any of research of its medicinal properties, but also, as the more recent findings indicate that in one respect the isolate behaves similarly to the “proper” synthetics. This characteristics is known as the troublesome “bell curve”. In the paper published in Pharmacology & Pharmacy, Lumir Hanus reported that most studies of the CBD related to its isolates and/or synthetic CBDs administrated in their pure form, that is – without the entourage of other plant-derived compounds. Such form results, however, with a very narrow “effective window” – a very precise dose in which the CBD showed a positive effect. This problem is known to scientists studying probably the most advanced application of the CBD for medicinal purposes – its role in alleviating the symptoms of the children epilepsy. It is extremely difficult to determine the dose, wherein CBD will maintain its positive effect (plus, there is still a matter of imposing a dose which would not result in a toxicity of other drugs). The dosing’ “bell curve” phenomena was not observed after the application of the whole plant extracts.
Both in terms of isolates, as well as ot the “proper” synthetics, one thing is certain – in most applications of the cannabis’ extracts the entourage effect holds. This increasingly better understood phenomena means, in short, that a mix of cannabinoid has far better properties than any single one of them. Because the beneficial effect of the whole-plant extracts (or a mixture of cannabinoids reflecting the natural proportion) exceeds that of the hypothetical “sum” of every single one administrated individually, we are talking about “synergy.”
Observations of the beneficial effects of a mix of naturally occurring hemp compounds effectively undermine the pharmaceutical axiom of “purity.” It is worth noting, however, that the entourage effect is discussed here in the context of a general pro-health effect of cannabis, and it is possible that there are specific strictly medical cases in which the isolate/synthetic will prove a better option.
Synthetics, isolates or the whole plant extracts – which one should I choose?
It is hard to draw conclusions from the study of several synthetic versions of the CBD. On the one hand – they have not shown any dangerous side effects of such substances, which clearly distinguished the CBD derivatives from the sinister synthetic cannabinoids invented as designer drugs. Many synthetics may find specific medical applications, as they combine the advantages of the CBD with a property of binding to many different receptors. Such broad, “distributed” targeting can be a problem, however, as the authors of the referenced work pointed out. Another problem is the explained above issue of the “bell curve” in dosing, i.e. the need for precise dosage.
This dilemma, however, is purely medical. Let’s not forget, that the only form of the CBD which is legal and accessible on Polish market are dietary supplements. These include the CBD hemp oils such as CannabiGold oil. This makes the whole discourse of synthetic cannabinoids and isolates a purely academic one. Synthetic CBD is just not available on the Polish market – while some preparations containing cannabidiol’s isolates (of questionable legal status) could actually be found, the “proper” lab-grade synthetic CBD derivatives are still in the testing stage. Bearing in mind the purely theoretical comparison of the whole plant extracts, isolates and synthetics, it must be stressed that only the first exhibit entourage effect allowing a consumer to fully enjoy the beneficent properties of the whole plant. It is, of course, possible to create some kind of a “cocktail” of synthetic cannabinoids and isolates, but – at least in the context of general pro-health qualities of dietary supplements – it seems highly impractical solution in comparison to the simplest one – a whole-plant extract.
As we wrote above, our opinion about the advantages of extracts of whole plants is not due to ideologically motivated beliefs in the superiority of “natural” over “artificial.” In the case of pro-health dietary supplements the good quality hemp extracts are just much more practical, safer and more effective. “The entourage effect” is a fact.
By the way, it is worth to recall that for this effect to persist, it is necessary to preserve the full cannabinoid profile of the extracted plants, which can be guaranteed only by use of elaborate extraction procedure – one that does not pollute the final product solvents, does not damage the precious cannabinoids and does not draw from hemp heavy metals and other substances. It is also particularly important in the context of the alleged “purity” of synthetics and isolates. Yes, this type retain one hundred percent purity of the substance, but at the cost of weeding out many beneficial compounds and forgoing their synergies. Meanwhile, good quality CBD hemp oil obtained from the whole plant can preserve a complete profile of the plant, while maintaining the purity of the final product, yet only when produced under appropriate conditions and using the best method of extraction. Currently, the best method is the supercritical CO2 extraction, which in conjunction with meticulous quality control processes allows for the production of CBD hemp oil with the preferred composition of the natural compounds.
Law and others: Notes from the Field: Increase in Reported Adverse Health Effects Related to Synthetic Cannabinoid Use – United States
Gallily R., Z. Yekhtin, LO Hanus: Overcoming the Bell-Shaped Dose-Response of Cannabidiol to Using Cannabis Extract Enriched in Cannabidiol
P.Morales, Reggio PH, N. Jagerovic: An Overview on Medicinal Chemistry of Synthetic and Natural Derivatives of Cannabidiol