Biological Effects of Cannabinoids
The main constituents of cannabis, the cannabinoids, can be found almost nowhere else in nature. There are currently about 70 known and well described naturally occurring cannabinoids in the plant. So far, the majority of biological activities attributed to cannabis have been linked to cannabinoids; specifically to THC. Additional cannabinoids, present in very minor quantities, have been discovered very recently.
The plant-derived cannabinoids, the phytocannabinoids, are accumulated in glandular hairs. While all plant parts can contain cannabinoids (except for the seeds), the highest concentrations (in % of dry weight) are found in the flowers and fruits. When grown under artificial, high yielding conditions, cannabis flowering parts can be obtained with a resin content of up to 25-30%. Among the cannabinoids, virtually all studies have focused on the effects of THC.
CBD is often considered the major non-psychotropic cannabinoid in cannabis. Of all cannabinoids, only THC has been more studied. CBD has been shown to posses anti-oxidant properties, as well as anti-inflammatory and immunomodulatory effects. Also, CBD is a modulator of some types of opioid-receptors, and has been shown to modulate sleep in rats.
In many cannabis varieties CBD is present in significant amounts. However, only recently has serious attention been placed on THC/CBD interaction. Earlier studies focusing on the effect of THC alone have generally shown the use of cannabis to be ineffective in many disease models, and such negative results unfortunately helped to shape the controversy in the discussion on the moral and ethical sides of cannabis use. It is known that CBD inhibits the metabolism of THC. This may be why CBD is known to antagonize the psychotropic effects of THC. Even though higher doses of THC are capable of inducing psychotic problems in some users, CBD seems to have an anti-psychotic effect, its presence balancing the negative impact of THC consumption.
Delta-8-THC is a positional isomer of delta-9-THC with a similar pharmacological profile and slightly lower psychoactive potency. Even though delta-8-THC has been very important for SAR studies on the classical cannabinoids, not many bioactivity studies have been done with it. It is probably not produced by plant metabolism, but rather is an artifact caused by degradation of THC. In very low concentrations (0.001 mg/kg in mice, i.p. injection) it increased food consumption, more than THC, while performance and activity of the animals were similar. This low dose is equivalent to about 0.1mg for an average human, an amount that could easily be formed by degradation of THC during the smoking of cannabis (or be already present in aged plant material).
In a rat study, it was found that behavioral suppression by delta-8-THC was mediated by activation of the arachidonic acid cascade via the CB1 receptor. This may be a useful model to study the amotivational syndrome in humans.
THC (dronabinol) is the pharmacologically and toxicologically most relevant constituent of the cannabis plant, producing a myriad of effects.
THC increases the metabolic rate in the brains of animals and humans, and it decreases body temperature, but only at high doses. The increase in heart rate observed after THC administration is dose-dependent. As a result, cardiovascular problems are generally considered a contra-indication for the medicinal use of Cannabis or THC zyban medication.
In particular in inexperienced users, THC can sometimes induce unpleasant effects including anxiety, panic, and paranoia. There are some suggestions that in a small number of cases, THC is capable of precipitating psychosis, involving delusions and hallucination. If these disorders exist they seem to be rare, most likely require very high doses of THC, the prolonged use of highly potent forms of cannabis, or a pre-existing genetic vulnerability. The causal link between cannabis use and psychosis has not been definitely proven, due in part to the large amount of parameters involved. However, there is enough reason to be cautious and communicate these suspicions in a fair and balanced way. Interestingly, many physical effects of THC are achieved below the threshold of psychological effects.
CBG is one of the major cannabinoids found in most cannabis varieties. CBG has been called ‘inactive’ when compared to THC, but it has slight affinity for CB1 receptors, approximately equal to that of CBD. However, in recent years few or no further studies have been reported on the biological activities of CBG.
In 1940, CBN was the first cannabinoid to be isolated and purified from cannabis. CBN is not produced by the plant’s metabolism, rather it is formed by THC degradation during drying, storing, and heating. As a result, it may play a significant role in several effects attributed to cannabis consumption. It has very weak psychotropic properties, and exhibits pharmacological activities that likely interact with the effects of THC.
CBC has hardly been studied at all. However, in most cannabis varieties analyzed, CBC (in the form of CBCA) can be detected in significant amounts.
Tetrahydrocannabivarin (THCV) is structurally similar to THC, and for a long time it was thought to be its slightly less potent “little brother”, exhibiting similar properties. However, quite unexpectedly, there is evidence that THCV is a CB1 and CB2 receptor antagonist.
The Acidic Cannabinoids
Isolated in 1955, CBDA was the first discovered cannabinoid acid, while CBCA was isolated from cannabis in 1968. To date, only sporadic reports have been made on CBCA or CBDA, and rarely have these pure compounds been tested for biological activity.
While not much is known about the biological effects or human metabolism of the acidic cannabinoids, older studies indicate that the most common acidic cannabinoid, THCA, is not psychoactive in monkeys. CB receptor binding assays indicate that the acidic cannabinoids, as well as their esters, are not binding. In the more potent varieties of cannabis, THCA may be present in levels of more than 20% of dry weight. However, a quantified, highly pure standard of THCA, as needed for analytical research as well as studies on biological effects, has not been available until recently. As a result, the potential value of THCA as an immuno-modulating agent has only recently been discovered. Further studies on the biological activities of THCA, and on clinical formulation of this compound, are under way.