Last Updated on April 26, 2021 by Maxwell Harris

The discovery of cannabinoids and the endocannabinoid system

In 1964, tetrahydrocannabinol (THC) saw the light of day, so to speak, when it was discovered by Israeli chemist Raphael Mechoulam as the active ingredient in the hemp plant. In the years that followed, he identified other substances of the plant, which he placed in the same category, although chemically they do not belong to a uniform group of substances. Because of their origin from the cannabis plant, they were given the name cannabinoids.

In the meantime, more than 80 of these substances have been identified, but only THC and cannabidiol (CBD) occur in larger quantities in the plant. The substances are produced on the plant surface by resin glands. The resin serves as protection against plant-eating insects and fungal attack. In numerous laboratory studies, Mechoulam was able to demonstrate early on the positive effects of THC in particular in the area of health. However, he lacked proof of the key through which these effects are spread in the body. This was provided years later by an American researcher with the discovery of receptors to which the cannabinoids docked.

It was immediately clear to the scientists that there are no specific structures in the body that react exclusively to plant substances. Mechoulam himself, in 1992, was consequently able to identify endogenous substances that docked to the receptors, the endocannabinoids. In the same period, the scientists found that these specific synapses were not only isolated, but distributed throughout the body, in some regions with a particularly high receptor density. Thus, the so-called endocannabinoid system was discovered, although its functioning is still not understood in all details. So far, two receptor types have been identified beyond doubt, the endocannabinoid receptor 1 (CB1) and the endocannabinoid receptor 2 (CB2).

These have a high affinity for certain endocannabinoids, which are released on demand and dock to them in a targeted manner, whereas THC comes into contact with them more by chance. CB1 is found primarily in the brain and the rest of the nervous system, while CB2 is found on the cell membranes of immune cells and bone-forming cells.

The discovery of THC led to a real hype in the drug field in the following years, while CBD and the other cannabinoids remained unnoticed for a long time. Cannabis had been used as a drug for a very long time, but only now had the substance responsible for the intoxicating effect been identified. This also aroused the interest of the pharmaceutical industry and medical research, because an active ingredient emerged that could be highly interesting for medical purposes. These activities resulted in the development and production of synthetically produced cannabinoids.

The different types of cannabinoids

The active ingredients of the cannabis plant are also called phytocannabinoids, according to their origin. This not only conceptually distinguishes them from the endocannabinoids produced by the body and the synthetically produced substances. Rather, the mode of action of the various substances is also very difficult, although many relationships in this area are not yet completely understood. At the moment, a picture emerges in which similar and supportive as well as modulating or even antagonistic effects are observed at the same receptors.

Endocannabinoids

The best known endocannabinoids are anandamide (derived from the Sanskrit word ananda = bliss), 2-arachidonylglycerol (2-AG), and O-arachidonylethanolamide (virodhamine). They have strong affinities for endocannabinoid receptors 1 or 2 and thus can initiate various reactions in different parts of the body.

These can be health effects, but also, as in the case of anandamide, the intoxicating effect, which is similar to that of THC. However, unlike THC, which is deposited in fatty tissue for up to weeks, it breaks down very quickly.

Anandamide activates the CB 1 receptor and can thus cause reactions in the brain and the rest of the nervous system. It can be very finely tuned by the body, so the direct effects are not as drastic as THC. It can induce feelings of pleasure and euphoria, even to the point of the “runners high” described by cross-country runners. However, anandamide also interacts with the CB 2 receptor and is involved in the regulation of pain and appetite through this channel. It has a very significant role in breast cancer.

A 2012 study was able to confirm that the administration of anandamide reduced breast cancer growth. Specifically, it reduces cancer cell survival. Arachidonylglycerol spreads similar effects to anandamide in the brain and nervous system via the CB 1 receptor. In addition, it has been shown to be neuroprotective in animal studies of brain injury. Via the CB 2 receptor, it is predominantly involved in stimulating bone growth. In the brain, virodhamine acts antagonistically to the other two representatives of the endocannabinoids and can thus suppress or modulate the intoxicating effect. At the CB 2 receptor, on the other hand, it has agonistic significance.

Phytocannabinoids

The best known phytocannabinoid is undoubtedly THC. This, of course, has to do with its psychoactive effects, although this classification does not do justice to the plant compound. Many pieces of research and smaller studies have also shown its health potential. The positive effects in pain relief and relaxation are well known and often correlate with the mind and perception enhancing reactions. The effect depends strongly on the dose, on the physical and mental condition of the user and on the daily form. Taking into account these parameters, the following effects are possible:

  • Anti-inflammation
  • Appetite stimulation
  • Dilatation of blood vessels
  • hypoallergenic
  • Anxiety reduction
  • Anxiety enhancement
  • Euphoria and other changes in mood.

Tetrahydro-cannabivarin (THCV)

Tetrahydro-cannabivarin (THCV) is structurally very similar to THC and is also psychoactive. Its effects have not been widely researched, which is certainly due to the fact that its content in the cannabis plant is very low. It is said to have anti-inflammatory and anti-epileptic properties. Possible beneficial influences on the reduction of glucose intolerance in diabetic patients have yet to be scientifically clarified.

Cannabidiol (CBD)

The second cannabinoid commonly found in the cannabis plant is cannabidiol. Although it was discovered almost simultaneously with THC, it has long been ignored by scientists. This is due to the fact that it has no psychotropic effect and therefore at first glance does not produce very spectacular effects.

Read more: CBD vs THC: What is the difference?

Since the 2000s, its health potency has first come to the public’s attention, mainly due to the spread of countless testimonials from users through the modern media. Since then, it has really taken off and is also increasingly attracting the interest of researchers. Some small studies have been able to prove its effectiveness in specific diseases. In some cases, this has led to its approval as a drug, for example in the U.S. as an anticonvulsant for MS and as an antiepileptic for Dravet syndrome.

In Germany, it has been listed in the “Arzneimittelverordnung” since 2017 and can be prescribed by doctors in cases of severe illness or severe chronic pain. It is also used as an additive in classic cancer therapies and, on the one hand, helps to alleviate side effects such as nausea and vomiting. On the other hand, many affected patients have found that it complements conventional medical care very well. Some affected people even describe that they were able to reduce or even discontinue the cancer drugs, which are afflicted with very strong side effects. Thus, CBD combines two key advantages. It has no intoxicating effects and almost no side effects, but it has a huge health potential, as the following incomplete list shows:

  • Pain relief
  • Anti-inflammation
  • Strengthening of the immune system
  • Neuroprotection
  • Antidepressant
  • Antipsychotic
  • Anxiety relieving
  • Relaxing
  • Sleep promoting
  • Anticonvulsant
  • Antiepileptic

CBD is antagonist of THC and anandamide at the CB 1 receptor and therefore able to attenuate and regulate their psychoactive effects. At the CB 2 receptor and several other receptors, which can probably also be attributed to the endocannabinoid system, it is agonistically active. This probably explains its wide spectrum of action.

Cannabidivarin (CBDV) and Cannabigerol (CBG)

Cannabidivarin (CBDV) and Cannabigerol (CBG) are similar to CBD in their chemical structure. Therefore, their spectrum of action could also be the same. However, it has been little researched so far, which is probably also related to the small amount in the cannabis plant.

Cannabichromene (CBC)

Another interesting cannabinoid seems to be cannabichromene (CBC). It is not psychoactive itself, but can probably enhance this effect of THC and anandamide at the CB 1 receptor. It has already been shown in animal studies to produce analgesic and sedative effects when combined with THC. However, the full health potential of CBC is not yet known or studied.

Other cannabinoids include:

  • CBDA (cannabidiolic acid)
  • CBN (cannabinol)
  • CBL (cannabicyclol)
  • CBV (cannabivarin)
  • THCC (tetrahydrocannabiorcol)
  • THCP (tetrahydrocannabiphorol)
  • CBCV (cannabichromevarin)
  • CBGV (cannabigerovarin)
  • CBGM (cannabigerol monomethyl ether)
  • CBE (cannabielsoin)
  • CBT (cannabicitran)

Synthetic cannabinoids

Synthetic cannabinoids can be produced fully synthetically or semi-synthetically from components of the phytocannabinoids. They are used primarily in medical research to test their effects on brain functions and eventually to develop drugs for neurological disorders and other health problems. Synthetic cannabinoids are also used in the skincare industry.

Conclusion

Cannabinoids are a heterogeneous group of highly potent substances that disseminate their information through the so-called endocannabinoid system. There are three cannabinoid classes, the phytocannabinoids derived from the cannabis plant, the endogenous endocannabinoids, and synthetically produced cannabinoids.

Some of the hormone-like substances have psychoactive effects, including the very well-known THC, endogenous anandamide, and most synthetic compounds. In the last 2 decades, the health potential has come to the fore especially of THC and the non-psychoactive CBD. The positive findings in this area are mainly based on laboratory studies and many reports of users’ experiences. Individual studies prove this, but further scientific work must follow in order to uncover the complete spectrum of effects.

Sources:

Laezza, C., D’Alessandro, A., Paladino, S., Malfitano, A. M., Proto, M. C., Gazzerro, P., … & Endocannabinoid Research Group. (2012). Anandamide inhibits the Wnt/β-catenin signalling pathway in human breast cancer MDA MB 231 cells. European Journal of Cancer48(16), 3112-3122.

Wikipedia. Raphael Mechoulam. https://en.wikipedia.org/wiki/Raphael_Mechoulam

Chen, J. W., Borgelt, L. M., & Blackmer, A. B. (2019). Cannabidiol: a new hope for patients with Dravet or Lennox-Gastaut syndromesAnnals of Pharmacotherapy53(6), 603-611.

Hemppedia. The Endocannabinoid System. (2018) – Hemppedia.org

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