The 1960s was a big decade for cannabis: images of flower power, the summer of love, and Woodstock wouldn't be complete without a joint hanging from someone's mouth. In the early '60s, however, scientists knew surprisingly little about the plant. When Raphael Meshulam, then a young chemist in his early 30s at Israel's Weizmann Institute of Science, went looking for interesting natural products to research, he saw a tantalizing gap in knowledge about the hippie weed: the chemical structure of its active ingredients had not been worked out.
Meshulam set to work. The first hurdle was simply getting some cannabis, given that it was illegal.
Meshulam set to work. The first hurdle was simply getting some cannabis, given that it was illegal.
«I was lucky. The administrative head of my institute knew a police officer and I just went to the police department, had a cup of coffee with the police officer in charge of illegal drug possession and got 5 kilograms of confiscated hashish, presumably smuggled from Lebanon» — Meshulam says in a personal chronicle of his life's work, published this month in the Annual Review of Pharmacology and Toxicology.
By 1964, Meshulam and his colleagues had first determined the complete structure of both delta-9-tetrahydrocannabinol, better known to the world as THC (responsible for marijuana's psychoactive «high»), and cannabidiol (CBD).
This chemical coup opened the door for cannabis research. Over the next decades, researchers, including Meshulam, identified more than 140 active compounds called cannabinoids in the cannabis plant and learned how to produce many of them in the laboratory. Meshulam helped discover that the human body produces its own natural versions of similar chemicals, called endocannabinoids, which can shape our moods and even our personality. And scientists have now created hundreds of new synthetic cannabinoids, some of which are more effective than anything found in nature.
Today, researchers are studying a myriad of known cannabinoids — old and new, found in plants or humans, natural and synthetic — for possible pharmaceutical use. But at the same time, synthetic cannabinoids have become a hot trend in recreational drugs with potentially devastating consequences.
For most synthetic cannabinoids produced so far, the side effects tend to outweigh their medical uses, says biologist João Pedro Silva of the University of Porto in Portugal, who studies the toxicology of substance abuse and co-authored a 2023 assessment of the pros and cons of these drugs in the Annual Review of Pharmacology and Toxicology. But, he adds, that doesn't mean there won't be something better.
This chemical coup opened the door for cannabis research. Over the next decades, researchers, including Meshulam, identified more than 140 active compounds called cannabinoids in the cannabis plant and learned how to produce many of them in the laboratory. Meshulam helped discover that the human body produces its own natural versions of similar chemicals, called endocannabinoids, which can shape our moods and even our personality. And scientists have now created hundreds of new synthetic cannabinoids, some of which are more effective than anything found in nature.
Today, researchers are studying a myriad of known cannabinoids — old and new, found in plants or humans, natural and synthetic — for possible pharmaceutical use. But at the same time, synthetic cannabinoids have become a hot trend in recreational drugs with potentially devastating consequences.
For most synthetic cannabinoids produced so far, the side effects tend to outweigh their medical uses, says biologist João Pedro Silva of the University of Porto in Portugal, who studies the toxicology of substance abuse and co-authored a 2023 assessment of the pros and cons of these drugs in the Annual Review of Pharmacology and Toxicology. But, he adds, that doesn't mean there won't be something better.
Finding medical applications for cannabinoids requires understanding their pharmacology and comparing their pros and cons. Meshulam played a role in the early days of research into possible clinical applications of cannabis. Based on anecdotal reports dating back to ancient times that cannabis helps with seizures, he and his colleagues studied the effects of THC and CBD on epilepsy. They started with mice and, because CBD showed no toxicity or side effects, moved on to humans.
In 1980, then at the Hebrew University in Jerusalem, Meshulam jointly published the results of a 4.5-month small study of patients with epilepsy who were not helped by modern drugs. The results seemed promising: of the eight people taking CBD, four had almost no seizures throughout the study, and three showed partial improvement. Only one patient was not helped at all.
«We assumed that pharmaceutical companies would extend these findings, but nothing happened for more than 30 years. In the four decades since our initial publication, thousands of patients could have been helped» — Meshulam writes in his autobiographical article. It wasn't until 2018 that the FDA approved Epidiolex to treat epileptic seizures in people with certain rare and severe conditions.
Drug approval is an inevitably long process, but for cannabis, there have been additional hurdles in the form of legal hurdles, as well as difficulties in obtaining patent protection for natural compounds. The latter makes it difficult for a pharmaceutical company to financially justify expensive human trials and the lengthy FDA approval process.
To date, the FDA has only licensed a handful of cannabinoid-based medicines, and so far they are only based on THC and CBD. Along with Epidiolex, the FDA has approved a synthetic THC and THC-like compound to combat nausea in patients undergoing chemotherapy and for weight loss in patients with cancer or AIDS. But there are hints of many other possible uses. The National Institutes of Health's Clinical Trials Registry lists hundreds of efforts around the world to study the effects of cannabinoids on autism, sleep, Huntington's disease, pain management and more.
In recent years, interest has moved beyond THC and CBD to other cannabis compounds such as cannabigerol (CBG), which was discovered as early as 1964. Later, derivatives of CBD were created that have anti-inflammatory and analgesic properties in mice (for example, reducing pain felt in a swollen paw) and can prevent obesity in mice fed a high-fat diet.
This year, a small clinical trial of the effects of CBG on attention deficit hyperactivity disorder is underway. The methyl ester form of another chemical, cannabidiolic acid, also seems very promising — in rats, it can suppress nausea and anxiety and act as an antidepressant in an animal model of mood disorders. But while the list of possible benefits of all the many cannabinoids is huge, the hard work of proving their usefulness remains to be done.
In recent years, interest has moved beyond THC and CBD to other cannabis compounds such as cannabigerol (CBG), which was discovered as early as 1964. Later, derivatives of CBD were created that have anti-inflammatory and analgesic properties in mice (for example, reducing pain felt in a swollen paw) and can prevent obesity in mice fed a high-fat diet.
This year, a small clinical trial of the effects of CBG on attention deficit hyperactivity disorder is underway. The methyl ester form of another chemical, cannabidiolic acid, also seems very promising — in rats, it can suppress nausea and anxiety and act as an antidepressant in an animal model of mood disorders. But while the list of possible benefits of all the many cannabinoids is huge, the hard work of proving their usefulness remains to be done.
These endocannabinoids, as they're called, can alter our moods and affect our health, even if we don't even get close to a joint. Some speculate that endocannabinoids may be responsible for personality quirks, personality disorders or differences in temperament, among other things.
Animal and cell studies hint that modulation of the endocannabinoid system could have a huge range of possible applications, from obesity and diabetes to neurodegeneration, inflammatory diseases, gastrointestinal and skin problems, pain and cancer.
Studies have shown that endocannabinoids, or synthetic creations similar to natural compounds, can help mice recover from brain injury, unblock arteries in rats, fight antibiotic-resistant bacteria in petri dishes and alleviate opiate addiction in rats. But the endocannabinoid system is complex and not yet fully understood; no one has yet administered endocannabinoids to humans, leaving what Meshulam sees as a gaping hole in knowledge, and a huge opportunity.
It's a truly understudied area of research, and one day it could lead to useful pharmaceuticals. For now, however, most clinical trials are focused on understanding how endocannabinoids and their receptors work in our bodies (including how everything from probiotics to yoga affects chemical levels).
Since the discovery of CB1 and CB2, many researchers have focused on developing new synthetic molecules that bind to these receptors even more strongly than plant cannabinoids. Pharmaceutical companies have been pursuing such synthetic cannabinoids for decades, but so far without much success — and with some missteps.
A drug called Rimonabant, which bound firmly to the CB1 receptor but acted in opposition to the usual CB1 effect, was approved in Europe and elsewhere (but not in the U.S.) in the early 2000s to reduce appetite and thus fight obesity. It was withdrawn worldwide in 2008 due to serious psychotic side effects, including provoking depression and suicidal thoughts.
Some of the synthetic substances originally invented by scientists and pharmaceutical companies ended up in recreational drugs such as Spice and K2. Such drugs are thriving and new chemical formulas continue to emerge, with 224 different ones spotted in Europe since 2008. These compounds, chemically altered to maximize psychoactive effects, can cause everything from headaches and paranoia to heart palpitations, liver failure and death. They have very toxic effects.
A drug called Rimonabant, which bound firmly to the CB1 receptor but acted in opposition to the usual CB1 effect, was approved in Europe and elsewhere (but not in the U.S.) in the early 2000s to reduce appetite and thus fight obesity. It was withdrawn worldwide in 2008 due to serious psychotic side effects, including provoking depression and suicidal thoughts.
Some of the synthetic substances originally invented by scientists and pharmaceutical companies ended up in recreational drugs such as Spice and K2. Such drugs are thriving and new chemical formulas continue to emerge, with 224 different ones spotted in Europe since 2008. These compounds, chemically altered to maximize psychoactive effects, can cause everything from headaches and paranoia to heart palpitations, liver failure and death. They have very toxic effects.
Given all this work that's being done on the chemistry of these compounds and how they work in the human body, there's going to be a big explosion in understanding the physiology of the endocannabinoid system. And with that, we're likely to have a lot of new drugs.
In Austria, cannabis was recognized as a medicinal plant of the year, which stimulated a review of scientific research by many scientists in the field. Since the widespread legalization of medical cannabis, the amount of information about the previously banned plant has increased significantly. Numerous studies confirm what patients already knew beforehand, some refute old myths, and others surprise even the most experienced cannabis experts.
This article is only a small part of current cannabis research. Ultimately, the current state of research is not as bad as is often assumed. Back in 2010, NORML's director, Paul Armentano, called cannabis one of the most studied substances. In this context, he was referring to the more than 20,000 studies and scientific papers on cannabis. At this point more than 10 years (as of this writing at the end of December 2024) have passed and still the frequency and volume of research on cannabis is increasing.
Сannabinoid researcher Ethan Russo presented his third study at the IACM Cannabinoid Congress in Cologne, demonstrating that the classification of cannabis into Sativa and Indica varieties has no scientific basis. Jeffrey Raber was the first to express doubts about this classification in 2013. Raber, owner of a medical marijuana research lab in California, argued that after analyzing more than 1,000 varieties of cannabis, there is no scientific basis for the different effects of cannabis. «OG Kush» from cannabis dispensary «X» is significantly different from «OG Kush» from dispensary «Y».
The study presented by Dr. Russo of Dalhousie University, which was conducted in collaboration with Bedrocan, confirms Raber's findings and an earlier study conducted by Dalhousie University in 2015. In the current study, scientists were not able to detect genetic differences between the Indica and Sativa samples. However, thanks to the terpene profiles from the study, it was possible to draw conclusions about the origin of the individual strains. «It is more likely that strains are classified based on their varied flavors rather than on their genetic origin» the study's press release noted.
The study presented by Dr. Russo of Dalhousie University, which was conducted in collaboration with Bedrocan, confirms Raber's findings and an earlier study conducted by Dalhousie University in 2015. In the current study, scientists were not able to detect genetic differences between the Indica and Sativa samples. However, thanks to the terpene profiles from the study, it was possible to draw conclusions about the origin of the individual strains. «It is more likely that strains are classified based on their varied flavors rather than on their genetic origin» the study's press release noted.
The American company Seedo conducted a study to determine, among other things, the potential tax revenue from cannabis, based on average per capita consumption. What are the results? In Berlin the tax authorities could receive 92 million euros annually; in Hamburg and Munich the city budgets could be bolstered by an additional 40 million euros. The world leader in these statistics is Cairo, with a theoretical tax revenue of 307 million euros from cannabis. There are serious problems with prescription painkillers in the United States. Each day about 90 people die from an overdose of hard drugs. According to a study published by the American Medical Association, opioid-related deaths have decreased significantly in U.S. states thanks to the medical cannabis program (cannabinoid substitution therapy).
The study indicates that the U.S. can reduce the abuse of highly addictive narcotic painkillers by expanding such programs and, as a result, reducing opioid-related deaths. According to a 2017 study published by Indiana University, medical cannabis can save up to 47,500 lives each year nationwide and is now already preventing between 17,400 and 38,500 premature deaths annually.
The study indicates that the U.S. can reduce the abuse of highly addictive narcotic painkillers by expanding such programs and, as a result, reducing opioid-related deaths. According to a 2017 study published by Indiana University, medical cannabis can save up to 47,500 lives each year nationwide and is now already preventing between 17,400 and 38,500 premature deaths annually.
The overall frequency of seizures decreased by 41% compared with 14% in the group that took placebo. Moreover, patients or their caregivers often reported an improvement in their general condition. A U.S. study of drug use and health found that cannabis is becoming increasingly popular among older adults. Data from 2006 to 2013 were estimated. The relative increase among adults ages 50 to 64 was 58.4 percent. The relative increase among those over 65 was the largest among all age groups at 250%.
Unlike older people, young people don't seem to be curious or open to experimenting with cannabis, even with a controlled market. In Colorado, where the effects of legalization have been carefully regulated for five years, the opposite is actually true. According to the Colorado Department of Health, the 30-day prevalence of cannabis use among young people declined slightly in 2016 compared to 2011. The 21.2% of young cannabis users was slightly lower than the 2016 United States average of 22 percent 30-day prevalence among young people that year. Thus, Colorado is reinforcing this trend for the second year in a row.
According to a study published in the British Journal of Pharmacology, Δ9-tetrahydrocannabinol has neuroprotective properties. It is the most common cannabinoid in the cannabis plant. A Spanish study by the Instituto Maimónides de Investigacion Biomedica de Córdoba looks at Δ9-THCA as a possible treatment option for people with debilitating and degenerative diseases. In a study published in the Journal of Sexual Medicine, researchers at Stanford University analyzed the results of a survey of 50,000 men and women between the ages of 25 and 45 regarding their health in the United States.
https://journals.lww.com/aidsonline...nabis_users_have_lower_circulating.97348.aspx
As MSU study lead author Norbert Kaminski notes in the AIDS Journal, the cognitive function of many people with HIV is reduced due to chronic inflammation in the brain caused by constant stimulation of the immune system to fight disease. A comparative analysis of cannabis and non-cannabis patients showed that non-cannabis patients had a lot of inflamed cells. At the same time, those who used cannabis had significantly lower levels of inflammation. According to Kaminski, the study leader, the level of inflammation in cannabis patients was close to that of a healthy non-HIV-positive person.
According to a long-term study, violent crime is declining in U.S. states bordering Mexico with a medical cannabis program. After laws were passed, violent crimes dropped by an average of 13 percent. Much of the cannabis consumed in the U.S. comes from Mexico, where seven major cartels control the illegal drug trade. Economist Evelina Gavrilova, one of the authors of the study, told the Guardian newspaper in Britain that laws allowing legal cannabis cultivation in California allow local farmers to grow cannabis, which can then be sold to medical facilities legally. These growers are in direct competition with Mexican drug cartels who smuggle cannabis into the United States. As a result, the cartels make far less profit.
As MSU study lead author Norbert Kaminski notes in the AIDS Journal, the cognitive function of many people with HIV is reduced due to chronic inflammation in the brain caused by constant stimulation of the immune system to fight disease. A comparative analysis of cannabis and non-cannabis patients showed that non-cannabis patients had a lot of inflamed cells. At the same time, those who used cannabis had significantly lower levels of inflammation. According to Kaminski, the study leader, the level of inflammation in cannabis patients was close to that of a healthy non-HIV-positive person.
According to a long-term study, violent crime is declining in U.S. states bordering Mexico with a medical cannabis program. After laws were passed, violent crimes dropped by an average of 13 percent. Much of the cannabis consumed in the U.S. comes from Mexico, where seven major cartels control the illegal drug trade. Economist Evelina Gavrilova, one of the authors of the study, told the Guardian newspaper in Britain that laws allowing legal cannabis cultivation in California allow local farmers to grow cannabis, which can then be sold to medical facilities legally. These growers are in direct competition with Mexican drug cartels who smuggle cannabis into the United States. As a result, the cartels make far less profit.
A study by Gavrilova and her colleagues based on FBI data from 1994 to 2012 found that changes in the law had the greatest impact in California. Here there was a 15 percent drop in violent crime, while Arizona recorded the lowest drop of any state with legal medical cannabis at 7 percent. According to the study, violent robberies dropped by 19 percent after medical cannabis was legalized, and homicides in the states in question fell by an average of 10 percent. Drug-related homicides were the most notable, with a 41% decrease.