The discovery of cannabis鈥檚 principal active ingredient is the stuff of scientific legend. In the early 1960s, a scientist in Israel named Raphael Mechoulam obtained some high-quality hashish from the police, who had confiscated the stash from smugglers. He isolated the components and then tested their effects, one by one, on monkeys in his lab. Mechoulam, who died in March of this year, knew he had found his target as soon as he administered tetrahydrocannabinol, commonly known as THC. 鈥淚t made them act like they were all at Woodstock,鈥� says , a physician at Massachusetts General Hospital and author of Seeing Through the Smoke: A cannabis specialist untangles the truth about marijuana.
Mechoulam was hopeful that his discovery would . But it was another two decades before scientists began to come to grips with the ways that THC works its magic.
This research in turn led to the discovery of the 鈥渆ndocannabinoid system鈥� (ECS) 鈥� an ancient cell signalling network that helps maintain an organism鈥檚 homeostasis. 鈥淚t keeps the body in balance,鈥� says Grinspoon. The vital role of this system quickly became clear, but the legal and logistical challenges of studying cannabis meant research progress has been slow there, too.
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That is finally starting to change, in large part thanks to shifting views and laws about cannabis. Research is now starting to unravel long-standing mysteries of the ECS 鈥� as well as the ways its dysfunction may be implicated in a host of diseases, from chronic pain and irritable bowel syndrome to Parkinson鈥檚, Alzheimer鈥檚 and multiple sclerosis.
Why has progress been so slow? In a word: politics. 鈥淭he US government funds 80 to 90 per cent of drug research worldwide,鈥� explains Grinspoon. 鈥淎nd when the War on Drugs intensified in the 1970s, they were only focused on the harms of cannabis.鈥� Even basic research on the fundamental mechanisms of the drug was discouraged at this time. This was quite absurd, says Grinspoon, whose father, Lester Grinspoon, was one of the few cannabis researchers in the 1960s. The drug was clearly acting on an important biological pathway that might have been useful for other medical insights. 鈥淎nd even if you think cannabis is the Devil鈥檚 lettuce, you need to understand the [biological basis] to explain why it鈥檚 bad for people.鈥�
The first breakthrough came in the late 1980s with the discovery of a cellular receptor that responds to cannabinoid compounds, dubbed CB1. A second receptor, CB2, was discovered shortly after. Soon, scientists started identifying the endogenous 鈥� internally produced 鈥� messenger chemicals that activate these receptors, which we call endocannabinoids. The first was named , after the Sanskrit term for internal bliss.
The science of cannabis
As the use of marijuana and its compounds rises around the world, 快猫短视频 explores the latest research on the medical potential of cannabis, how it is grown and its environmental impact, the way cannabis affects our bodies and minds and what the marijuana of the future will look like.
This signalling system evolved long before our ancestors started lighting up joints and munching edibles. What evidence we do have suggests humans started using cannabis for medicinal or psychoactive purposes between 2500 and 2800 years ago. The ECS, in contrast, emerged in an animal ancestor around 600 million years ago, just before the Cambrian explosion. Cannabinoid receptors can even be found in Hydra vulgaris, the fresh-water polyp thought to have the simplest nervous system of any known organism.
So what does the ECS do? In truth, it might be simpler to say what it 诲辞别蝉苍鈥檛 do, since research over the last two decades implicates it in a host of processes, including sleep, memory and learning, pain, appetite and inflammation.
As you would expect from the mind-altering effects of cannabis, much of this takes place in the brain. CB1 receptors are primarily found around the junctions between neurons, or synapses, where information is passed between cells. The activation of CB1 receptors regulates the influx of calcium, which is essential for the release of certain neurotransmitters during the cell鈥檚 electrical signalling. You can almost think of them as stoplights, guiding the flow of traffic in our neural networks. By tuning the activity in a particular region, the ECS can therefore guide our physical and mental state, whether that is perception, mood, sleep or appetite.
CB2 receptors are primarily located in components of the immune system. When these receptors are activated, immune cells return to their resting state and stop producing inflammatory molecules that act as a first line of protection against pathogens. In this way, a well-functioning endocannabinoid system can prevent the body鈥檚 defences from going into overdrive and causing undue damage to our own tissue. Once again, it is acting as a controller that gives the green or red light to further action.
Someone鈥檚 natural levels of endocannabinoids will be much lower than the levels of cannabinoids consumed during recreational drug use. 鈥淎nd when we produce endocannabinoids, those are rapidly broken down by certain enzymes,鈥� says at the University of South Carolina. 鈥淭hat鈥檚 why we鈥檙e not high all the time.鈥�
Wide-ranging effects
The difficulty is that the fine details of these processes are still unknown, even as it is becoming clear that the ECS may play an important role in multiple medical conditions. Consider certain forms of chronic pain. The ECS can influence levels of , the transmission of pain signals through the nervous system and how the brain processes those signals. If any of this goes awry, people may begin to experience enormous discomfort.
Tellingly, people with certain forms of chronic pain appear to have than people without these conditions. One possible explanation for why for some people with chronic pain is that it is actually correcting for the imbalance in their ECS.
The ECS is similarly important for stress management, as endocannabinoids mute neural activity associated with fear and anxiety. 鈥淭hey basically tell the neurons to calm down, 聽鈥榶ou don鈥檛 need to show as much of a stress response鈥�,鈥� says at Wayne State University in Michigan.
Various lines of evidence suggest that a malfunctioning ECS may also contribute to certain neurodegenerative diseases. In 2020, , then at the Max Delbr眉ck Center for Molecular Medicine in Germany, and his colleagues found that the APOE4 gene variant associated with Alzheimer鈥檚 can , for instance. And in June last year, Zhenhua Liu at the US National Institute on Aging in Maryland and his colleagues identified a gene associated with endocannabinoid synthesis that appears to .
In each case, problems in the ECS could lead to faulty neuronal function and increased brain inflammation 鈥� both of which might damage brain tissue in the long term. 聽Nagarkatti points out that runaway inflammation can even play a role in psychiatric conditions like . 鈥淐hronic inflammation is currently believed to be the underlying cause of pretty much all major clinical disorders,鈥� he explains.
The ECS could be particularly pertinent for autoimmune diseases. In people with multiple sclerosis, for instance, immune cells go into overdrive and begin attacking the body鈥檚 nerve cells, stripping them of the insulating myelin sheath that enhances the transmission of electrical signals. 鈥淚n autoimmune diseases, people may not be producing enough endocannabinoids to send the immune cells into their resting state,鈥� says Nagarkatti.
The wide-ranging influence of the ECS may explain why people with such a broad range of conditions say that they find relief with medical marijuana. Because it has been so difficult to study cannabis, so far, Grinspoon says, people have been experimenting on their own without any specialised knowledge of the ECS. 鈥淲hat blows my mind is that most of this happened organically without their doctors knowing anything about it,鈥� he says.
The entourage effect
There is still much more to discover. It is not yet clear, for instance, how the other compounds in cannabis 鈥� such as cannabidiol, or CBD 鈥� interact with the cannabinoid receptors, which may have multiple binding sites. CBD does not appear to bind to CB1 through the main site, which may explain why it 诲辞别蝉苍鈥檛 alter perception and mood in the same way that THC does. But it may lock onto the receptor at another spot. We need a much better understanding of the ways that these different compounds act on the body and 鈥� equally importantly 鈥� how they influence each other鈥檚 effects, says Grinspoon.
The interaction of different cannabis compounds is known as the 鈥渆ntourage effect鈥�, and it may explain why people who have taken THC on its own often claim not to feel the same benefits as when they have tried taking whole-plant cannabis. (There is also some evidence that CBD alongside THC , such as the racing heartbeat, for instance.) Greater knowledge of these processes may also help health practitioners to determine which strains (or chemovars, as they are officially known) of medical marijuana are most suitable for a particular patient.
When it comes to potential medical therapies, though, ingesting cannabinoids isn鈥檛 the only way to impact the ECS. Nagarkatti suggests that there may be other kinds of drugs that could increase the body鈥檚 production of endocannabinoids, for instance.
Alternatively, we may also be able to raise people鈥檚 levels of endocannabinoids by targeting the enzymes that naturally break them down. Nagarkatti鈥檚 ongoing research examining production of an enzyme called 鈥渇atty acid amide hydrolase鈥� in mice supports this idea. He and his team found that making genetic modifications in mice that blocked production of this enzyme led them to produce much . That, in turn, appeared to offer significant protection against autoimmune conditions compared with mice without these genetic changes. 鈥淭hese mice are now more resistant to developing an autoimmune disease,鈥� Nagarkatti says. It is early days for this kind of work, but the potential is clear.
Runner鈥檚 high
We are also starting to learn more about far less invasive ways to alter endocannabinoid production. Exercise is a good place to start. In the past, the euphoria, or 鈥渞unner鈥檚 high鈥�, that comes from physical activity was thought to arise from the release of endogenous opioids called endorphins, which act along the same pathway as morphine. But Marusak鈥檚 recent research suggests that it 鈥� the 鈥渂liss molecule鈥� 鈥� and another endocannabinoid called 2-arachidonoylglycerol (2-AG).
In laboratory experiments, drugs that prevent endorphins from docking with their receptors in the brain tend to have little effect on people鈥檚 mood after exercise. 鈥淏ut if you block the endocannabinoid system, you don鈥檛 get the runner鈥檚 high effect,鈥� says Marusak. This makes sense when you look at the chemistry of the respective compounds, she says. 鈥淓ndorphins are really big molecules, and so they don鈥檛 easily cross the blood-brain barrier, whereas cannabinoids are really tiny lipid molecules, and they really love fatty brain tissue.鈥�
In the future, scientists may be able to identify compounds that preferentially activate or block receptors in particular parts of the brain or body governed by the ECS. A weight-loss drug, for example, may block the cannabinoid receptors in the networks controlling appetite without influencing those associated with mood. That type of precision control would make all the difference. It鈥檚 worth noting that the effective weight loss drug Rimonabant, which targeted CB1 receptors, was in the EU when it was discovered that it had severe side effects including increased risk of adverse psychiatric events. 鈥淚 think we鈥檙e going to be able to target the therapy much better,鈥� says Grinspoon. Research into the ECS is still at such an early stage that we may also discover new cannabinoid receptors that perform entirely unknown functions.
For now, both Grinspoon and Marusak believe that a primary objective should be education, since few doctors currently have a detailed up-to-date knowledge of the ECS and the ways that cannabinoids influence our health. 聽鈥淲e hear almost nothing about it at graduate school and medical school, despite the fact that cannabinoid receptors are one of the most pervasive types of receptors in the brain,鈥� Marusak says. This may be a sign of just how quickly the field is moving: the latest findings haven鈥檛 yet trickled down into the university syllabi.
Grinspoon points to a study showing just currently offer content on medical marijuana and its biological mechanisms. A recent survey of medical education in Quebec, Canada, supported that estimate. In it, most medical students rated their knowledge of cannabis-related issues as 鈥渓ow鈥� to 鈥渧ery low鈥�. That is starting to change, but there is quite a distance to go, Grinspoon says. 鈥淣ow that we understand how central the endocannabinoid system is, it鈥檚 mind-blowing that we鈥檙e not teaching it.鈥�
is the author of The Expectation Effect: How your mindset can transform your life.
