Raphael Mechoulam’s most important achievements in cannabis research

On 9th March, we bid farewell to someone who for most of his life went unnoticed, but who had an unimaginable role in the fight to end the stigmatisation of cannabis. A man whose drive and curiosity transformed medicine and pushed the boundaries of science. A scientist whose legacy will live on for decades and has already helped change millions of lives around the world. His name was Raphael Mechoulam, and he’ll always be remembered as a true pioneer in the field of medical marijuana.

Dr. Raphael Mechoulam was passionate about the study of the complexity of cannabis and its impact on the human body. With his firm commitment, he managed to push the boundaries of science despite the strict drug regulations that suppressed research at the time. After having become a living icon, his death at the age of 92 signifies the end of an era in the study of cannabis. In honour of Dr. Mechoulam, it is our mission to review his most important contributions so that they will never be forgotten.

Isolation of THC for the first time in history

After having been born in Bulgaria in 1930, Mr. Mechoulam was raised in Israel, where he completed his degree in Biochemistry at the Hebrew University of Jerusalem. In 1962, he and his research team at what was then the Weizmann Institute of Sciences in Israel, began to study the properties of cannabis, with a focus on understanding the chemistry of cannabinoids. Not long after, in 1964, they managed to successfully isolate THC (tetrahydrocannabinol), which is the compound responsible for the psychoactive effects of the plant. Once they were able to understand its chemical structure, they even managed to synthesise it.

Mr. Mechoulam moved to the Hebrew University of Jerusalem in 1972, where he and his team identified many other cannabinoids found in cannabis, such as cannabidiol (CBD) and cannabinol (CBN). This work put an end to a century of uncertainty: through the recognition of these other cannabinoids and their first synthesis, he laid the foundation for what became a fundamental area of biomedical research in the following decades.

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He revealed the benefits of CBD to treat epilepsy

In 1980, Dr. Mechoulam published a small scientific study whose results suggested that CBD could help reduce seizures in epileptic patients. He discovered that CBD proved more effective than a placebo, so he hoped to arouse the interest of the big pharmaceutical companies to develop CBD-based drugs for epilepsy. Thanks to his revolutionary research, THC then had to share the focus of attention with CBD, which many people initially treated with disregard, thinking that it wasn’t as important. But they certainly couldn’t have been further from the truth!

The discovery of endocannabinoids

Dr. Mechoulam’s research also led to the discovery of endocannabinoids in 1992; particularly to the discovery of anandamide, which is a compound produced by the human body that is capable of activating the CB1 receptor (i.e. the same receptor which binds to THC). Mr. Mechoulam observed that THC perfectly adapted to special receptors in the brain and the central nervous system, thereby producing their effects. Out of this emerged the theory that, if we have this complex network of receptors, then we must produce some kind of endogenous chemicals that also act as keys to unlock them.

Anandamide was the first endocannabinoid to be discovered, which signified a major milestone. Soon after, one of Mechoulam’s doctoral students, Shimon Ben-Shabat, discovered another endogenous cannabinoid: 2-AG. Not only did this finding have a great impact on cannabis research, but now we know that this molecule plays a vital role in the regulation of a wide range of physiological activities, including appetite, pain and mood. Therefore, this discovery had far-reaching benefits for the world of biology, biochemistry, medicine and general pharmacology.

He helped prove that humans have been using cannabis for millennia

A year later, in 1993, Dr. Mechoulam and his team published a study in the journal Nature which analysed the ashes found in a Roman tomb from the 4^th century, located near Beit Shemesh, about 30 kilometres west of Jerusalem. The tomb belonged to a young woman who had died during childbirth. “She was obviously given something to ease the pain or to stop the bleeding that she was apparently experiencing. We believe it might have been cannabis”, he said in an interview earlier this year. Test results showed that his hunch was right, meaning this is the first physical evidence of medical cannabis found in the ancient Middle East. “We are absolutely certain about this”, he claimed back then.

The entourage effect theory as the cornerstone of cannabis effects

Along with Dr. Shimon Ben-Shabat, Dr. Mechoulam discovered the entourage effect in 1999. This refers to the synergistic way in which cannabinoids work, enhancing mutual benefits when they’re consumed together rather than when they’re taken individually. Dr. Mechoulam and his team observed that, when certain cannabinoids were taken alone, they produced little effect or no effect at all; whereas when they were combined with THC or other cannabinoids, they were actually highly beneficial. This is especially significant, since nowadays there are lots of different ways of consuming cannabis, from CBD and THC isolates to full plant extracts. Due to the entourage effect, we know that if you want to maximise the healing properties of marijuana, it is best to take medical products that include the whole plant.

He found a more potent cannabinoid than THC.

Dr. Mechoulam continued working on his cannabis research almost up until his final days. In 2020, he discovered another compound called EPM301, which is a synthetic version of the acidic cannabinoids that are produced naturally by the cannabis plant, and which proved to be more potent than THC but without its negative secondary effects. Due to this compound’s instability, though, it took Mechoulam a while to discover it. He eventually devised a method for modifying the acids that allowed him to make it stable for a long enough period, and this facilitated its use in studies and trials.

What’s more, he found out that this compound could be useful in the treatment of nausea and anxiety, and could even possibly help with cancer, psoriasis and inflammatory bowel disease. This research provided the cannabis world with its first molecule of a cannabinoid based on synthetic acid, which, as expected, generated a lot of excitement. Raphael Mechoulam was 88 when he achieved this milestone.

There’s no doubt that the world of medical marijuana will continue to change for many years as a result of Raphael Mechoulam’s achievements. His unwavering commitment to discovering the chemical components of the plant and their possible therapeutic uses has been key to removing cannabis from the unjust obscurantism it has been subjected to over the last century. We can only hope that other pioneers like him will take up the reins to lead the way as the cannabis sector continues to develop and expand in the light of the long-awaited legalisation. Rest in peace, Dr. Raphael Mechoulam.