Despite humans having used cannabis for thousands of years, it is only recently that we have started to work out why it affects us the way that it does.
Chemicals in cannabis called cannabinoids activate receptors throughout our bodies that form the endocannabinoid system. This system is involved in regulating everything from mood to memory, and so could explain why the effects of marijuana can be so varied.
In “The anatomy of a high”, the second in our special podcast series on the science of cannabis, Christie Taylor investigates what we know about how cannabis hits our bodies and brains, how it affects our creativity and how it warps our perception of time. And it begins with an experiment in 1964 to find out which chemical in cannabis was responsible for the high…
Transcript
Christie Taylor: The year was 1964, and in a lab at the Weizmann Institute in Israel, Raphael Mechoulam had finally figured out how to get monkeys stoned. His mission for the past several years had been simple. He knew ingesting cannabis makes people euphoric, sedated, and induces a variety of interesting effects in the mind, but which of the hundreds of chemicals within the plant were responsible? So, he began a step-by-step process of isolating individual compounds called cannabinoids from hashish, which is a form of cannabis that uses very compressed, purified resins, and typically from cannabis flowers.
He then gave standard amounts to rhesus monkeys, and observed what happened. In 1963, he isolated cannabidiol, or CBD. No luck. Although, it would later turn out to be important in other ways. Meanwhile, the monkeys remained alert, unfazed, doing monkey things in their monkey cages. Then in 1964, he and his research partner Yechiel Gaoni, found the cannabinoid that actually did something. He’s surprisingly modest about it in his documentary by the Spanish non-profit Fundacion CANNA.
Raphael Mechoulam: We separate about ten, or twelve pounds, and these compounds included the only one active compound. Active, we tested at that time in monkeys. I had a colleague who worked in a nearby institute, and he had a colony of monkeys, and he and his group indeed tested these compounds in monkeys, and surprisingly found that only one compound did anything in these monkeys. It sedated them. They didn’t sleep, but they were sedated. On the basis of this particular observation, we decided there is just one active compound, and surprisingly this is true to this very day.
The science of cannabis
As the use of marijuana and its compounds rises around the world, New Scientist 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.
Christie Taylor: This compound was a tetrahydrocannabinol. You know it as THC. The main ingredient of the cannabis high. While Mechoulam speaks only of sedation in this clip, one researcher I spoke with said the lab, to quote, ‘Was like monkey Woodstock.’ After he succeeded in getting the monkeys high, Mechoulam did what any good researcher would do, he took the THC he’d isolated, asked his wife to make some cake with it, and invited some friends over.
Raphael Mechoulam: Five took only the cake without the THC, and we compared the effects. None of us had ever used cannabis before. As a matter of fact, very few people had used cannabis at that time in Israel. Only those that took the THC were affected, but surprisingly, they were affected differently. Some said, ‘Well, we just feel, kind of, strange, in a different world. We want to sit back and enjoy it.’ Another said, ‘Nothing happens,’ but he didn’t stop talking all the time. A third one said, ‘Well, nothing happens,’ but every fifteen, twenty seconds he would burst out laughing.
Christie Taylor: That was it. We had the reason for the munchies, paranoia, slow driving, and all the various euphorias of the stoned mind. I’m Christie Taylor, podcast producer for New Scientist. Welcome back to the second episode of our three part series on cannabis. How we got here, what we know, and what the future may hold. This is part of a massive months long reporting effort for more than half a dozen journalists, and you can read their work in depth over at newscientist.com/cannabis.
We’ve looked back in time to the humble origins of marijuana, the human history of intoxication, and observed the recent seismic shift in people’s attitudes. Today, we’re going to talk about what’s actually happening in your brain to make the high, and what being high really means, and why there’s still so much more we need to understand, both in the realm of medical benefits, but also the risks. There’s a certain caricature of stoners. They’re scatter-brained, absent minded, and they forget how to end the sentence that they started mere seconds ago. Definitely, don’t ask them to remember a pot influenced conversation the next day.
How much of that is a true depiction of the drug, and its effects? To understand that we need to begin with how cannabis works on the brain and body. Let’s say, for example, that you are inhaling the smoke of burning cannabis. This is the fastest way to ferry cannabinoids to your brain, and first, these compounds will cross from the lungs into your bloodstream. Red blood cells then cart them off all over your body. Now the brain, it has a membrane meant to protect it from invading organisms, viruses, bacteria, and larger molecules, but cannabinoids can cross this barrier. That’s where it gets interesting.
David Robson: Cannabis, it turns out, is made of things that your brain and body already has a whole system for. It’s called the endocannabinoid system, which basically just means a system for processing chemicals that look like cannabis, but that your body makes itself.
Christie Taylor: That’s science writer David Robson, who’s been investigating the endocannabinoid system. The endocannabinoid system has two major components. First, the brain and nervous system.
David Robson: Your body makes these endocannabinoids, you have receptors in your brain and neurons that know exactly what to do with the cannabinoids from cannabis.
Christie Taylor: These are called the CB1 receptors. CB for cannabinoid, and when they bind to the THC and other cannabis compounds in your blood they change shape and effectively turn on. They’re activated. The cannabinoids activate your CB1 receptors based on their own individual shape and chemistry. A flood of calcium is released, which is essential for the movement of certain neurotransmitters, which are your brain’s chemical messengers. Everything you feel basically is thanks to a neurotransmitter.
David Robson: It’s like a stop light. The cannabinoids, and neurotransmitters are guiding the flow of traffic in the networks of neurons that your brain contains. Depending on which region of your brain you look at, your endocannabinoid system can guide your mental, and even your physical state.
Christie Taylor: Activating the CB1 receptor immediately tamps down your stress and anxiety responses, while increasing the release of dopamine. That’s the neurotransmitter that powers your brain’s reward system. Research over the last two decades has found these receptors connected to a vast array of your body’s processes, sleep, memory, learning, pain, appetite, and even inflammation.
Now remember this is a system for recognising similar messenger chemicals that your body already makes. The exercise induced euphoria known as the runner’s high, once thought to be the produce of endorphins, actually seems to involve your endocannabinoid system, and these home-made, home cooked cannabinoids. While we haven’t found all of these endo, or internal cannabinoids, scientists have started to identify them. We found the first in 1992, also with help from Raphael Mechoulam, and its name, anandamide, derived from the Sanskrit term for euphoria, or bliss.
David Robson: What we’re now learning about the endocannabinoid system can explain, for example, why so many people seem to find pot useful for chronic pain. THC binds to CB1 receptors in the part of the brain that modulates your perception of pain. Cannabis compounds may also damp down the pain signals travelling through your nervous system. They can activate a second set of receptors in your immune system called your CB2 receptors. These seem to soothe immune responses like the inflammation around nerve endings that come with certain health conditions, and can be another source of pain.
Christie Taylor: The endocannabinoid system is ancient. It dates all the way back to before the Cambrian explosion, around 600 million years ago. There’s one in every animal, except for insects, and by every animal I mean every animal no matter how simple their nervous system. So, why aren’t we high all the time if our bodies make our own cannabinoids without any help from pot? There are enzymes for that, which rapidly break down neurotransmitters after they are released, and endocannabinoids are produced at much, much lower levels than what you might consume while smoking a joint, or just eating an edible. So, they’re just not around long enough, or in great enough amounts to create the same effect as the stuff we smoke, eat, or vape.
Grace Wade: How cannabis affects memory is a lot more complicated than the usual stereotype of stoners.
Christie Taylor: Grace Wade has been investigating the extensive research into reefer and memory. For starters, she says, “Memory is far more complicated than you think.”
Grace Wade: So, first you have long-term memory, which is where you store a memory for years, your lifetime. Then you have short-term memory, which is where you story your memory just for a few minutes. Then you have working memory, which is where we plan and carry out our behaviours.
Christie Taylor: It’s like a cognitive tool belt, or workbench. We can pull information out of our long-term memory, and use it to do mental math, process arguments, and other complex cognition. This is what acute marijuana use impairs. That’s obvious if you talk to any intoxicated person. They’re just much more likely to lose their train of thought.
Grace Wade: Researchers think that THC is to blame here. The CB1 receptors it binds to are in regions of the brain involved in memory as well. So, the hippocampus, cerebellum, and neocortex. It appears that what THC does when it triggers these receptors is block of ability to store new information. So, if you ask a group of people to memorise a list of words, and then identify those same words later, the intoxicated people are about half as accurate on average.
Christie Taylor: Good luck trying to have any important conversations. Probably better to wait until you’re sober. On the other hand, THC does appear to interfere with your ability to access things that you knew before you got high. If you memorised the words and then got stoned, you’d be much more accurate. Then there’s the interesting thing that happens when you mix THC with CBD. That’s the less psychoactive chemical that is nonetheless interesting for its calming properties.
Grace Wade: CBD seems to reduce the memory impairing effects of THC. So, if we go back one more time to those people who memorise the list of words. If you give them THC with CBD their accuracy was about the same as if they were sober. So, it may literally depend on what you’re smoking in terms of which compounds are in the stream.
Christie Taylor: This combination effect, it has a name, it’s called the entourage effect. That is how you experience one cannabinoid separately will seem to be very different from how all of the chemicals in cannabis act together on your brain, and it happens a lot. THC on its own has one effect that’s maybe a little too much, but then THC with CBD is a more balanced beneficial version. Researchers studying cannabis are still trying to understand how THC, CBD, and the dozens of other cannabinoids are working in concert on your brain, but it’s very clear that it’s a group effort.
What’s less clear about cannabis and memory is how prolonged chronic exposure to THC can affect you. It may, for example, degrade your very important CB1 receptors, and therefore reduce the number in your brain. Some studies also show that people who frequently use cannabis have worse overall long-term, short-term, and working memory than those who don’t. Especially, if they started younger, like in adolescence.
Grace Wade: The picture here is pretty complicated. There was a study back in 2007 in a small number of teenagers who had stopped consuming the drug for a month. They performed as well on a working memory task as those who had never used the drug. However, their brains appeared to be working harder to do the same tasks. So, because of that there is still worry among the research community that using cannabis while your brain is developing may change your cognitive function in a way that can’t be completely reversed.
Christie Taylor: Another key part of the stoner caricature is creativity. We associate pot smoking with ingenuity, and unconventional thought. Time itself seems to warp for some people under the influence. Music gains new layers and texture. Visual art may pop in unexpected, and entrancing ways. Ideas just seem to pour forth from the stoned mind. Scientist and author Carl Sagan said this about his experiences back in 1969.
Carl Sagan (voice actor): When I closed my eyes I was stunned to find that there was a movie going on the inside of my eyelids. Flash, a simple country scene with a red farmhouse, a blue sky, white clouds, yellow path meandering over green hills to the horizon. Flash, same scene, orange house, brown sky, red clouds, yellow path, violet fields. Flash, flash, flash. The flashes came about once a heartbeat. Each flash brought the same simple scene into view, but each time with a different set of colours, exquisitely deep hues, and astonishingly harmonious in their juxtaposition. The cannabis experience has greatly improved my appreciation for art, a subject which I had never much appreciated before. The understanding of the intent of the artist which I can achieve when high, sometimes carries over to when I’m down. A very similar improvement in my appreciation of music has occurred with cannabis. For the first time I have been able to hear the separate parts of a three-part harmony, and the richness of the counterpoint.
Christie Taylor: So, given this conception, does cannabis actually make you more creative? It turns out research finds not so much. You just think you’re more creative. The mood busting euphoria may be useful if you’re the perfectionist type plagued by writer’s block. Researchers have tried to find a link between cannabis and creative thinking, but they found that volunteers tested on this question don’t offer particularly novel ideas. They do, however, seem to rate their ideas, and those of other people, as more creative. Almost as if being in a good mood just makes you like more things. Sagan, by the way, he, like many before and after him, stood by his dazzling THC influenced thoughts.
Carl Sagan (voice actor): There is a myth about such highs. The user has an illusion of great insight, but it does not survive scrutiny in the morning. I am convinced that this is an error, and that the devastating insights achieved when high are real insights.
Christie Taylor: The time thing though, that’s mostly still a mystery. We know it happens. There’s evidence, and anecdote to shore up this experience. People who are high will move slower, take longer to answer a question. They consistently report feeling that time is moving slower. Though, occasionally, someone will also report feeling it move faster. Why does this happen? There are several theories, but in mice, not human brains, we have a clue favouring one idea in particular. Maybe THC is flooding a small section of our brain known as the suprachiasmatic nucleus, the SCN. This is like the gear that regulates our body’s internal clock, and if this is what’s happening THC maybe binding to the CB1 receptors in this region, and sending the neurons into overdrive, either speeding up, or slowing down our internal understanding of the passage of time.
There is still so much that we don’t know about how cannabis affects us, like the individual variation, how people even respond to cannabis in the first place. It’s not just about memory, or pain, but even more dramatic, and important instances. Some people, for example, have psychosis-like responses to consumption, with symptoms similar to schizophrenia.
It’s likely that the things that are good are most good for some people, but also that the risks are most risky for some people. So, how do we identify who should get a cannabis recommendation in the first place, and who should be advised to steer clear? As weed gets more potent, and more popular, researchers invested in understanding cannabis better are universally lamenting the lack of understanding we have compared to substances like alcohol, and tobacco. The number of published studies lags by an order of magnitude. If you search for cannabis in PubMed, which is database of medical research, you’ll find about 33,000 papers. If you search for alcohol that number is over 1 million. Alexis Wnuk looked at this research gap.
Alexis Wnuk: Research into cannabis really only started in earnest two decades ago. It picked up steam in the late 1990s and early 2000s, beginning with studies showing that marijuana could reduce nausea in people with HIV, and in those undergoing chemotherapy. Since then the field has exploded, but it’s still very much behind.
Christie Taylor: In the United States this gap is partly because of government limitations on how, and under what conditions you can study cannabis.
Alexis Wnuk: Researchers have to get a special licence from the Drug Enforcement Administration, and they can only study cannabis growing at licenced facilities. Prior to 2021, there was only one of these in the whole country. Some researchers have noted that this government sanctioned pot can be a lot different from what consumers are buying from dispensaries, and dealers. Namely, that it’s a lot less potent.
Christie Taylor: It’s actually remarkable in some ways that Raphael Mechoulam was able to study hash that people were actually using, which he bought, by the way, from the local police. Similar restrictions have also encumbered research in Canada. Research in the United Kingdom was limited until 2018 legalisation of medical marijuana. Even if you personally want to limit marijuana’s use to medical purposes, there’s still a value in knowing things that we currently don’t, like what’s the appropriate dose for pain versus nausea.
Alexis Wnuk: What are the long-term effects? Are the contents, and potencies listed on the label even accurate? Often, the answer to that is no. Research into CBD only products has repeatedly found that labels often under, or over estimate the amount of CBD inside. Some also contain trace amounts of THC, which isn’t good if you aren’t expecting it. How are the products produced? Is there any kind of quality control? How do people really use them? What kinds of products do they use? How much do they take? There are a lot of potentially meaningful differences between the way people use marijuana in controlled research settings, and how they use it in their regular lives.
Christie Taylor: Maybe most importantly, how does the endocannabinoid system in our bodies influence our broader health, both mental and physical. Those CB1 receptors that I mentioned earlier while we were talking about the high, those receptors are also in your liver, your fat, your reproductive tissues, your vascular tissues, even your bone. So, beyond effects in the brain and the immune system, how could cannabis affect the rest of our tissues? Cannabis is showing genuine promise to help people with autoimmune diseases like multiple sclerosis, and Crohn’s disease manage their symptoms. CBD in particular is helping treat rare forms of epilepsy.
For all the promising medical uses with decent evidence, there are many more worth exploring. Can weed work for opioid addiction, or PTSD? What about ALS, glaucoma, or migraines? There is some evidence for each of these, but a glaring lack of human clinical trials. Peter Grinspoon is a cannabis specialist who treats people with opioid use disorder, and other conditions in Boston, Massachusetts. His father, Lester Grinspoon, was one of the early researchers of cannabis in the 1960s. He says the lens through which researchers have looked in the past has also limited what we can know.
Peter Grinspoon: Over the last 50 years most of the researchers looked into harms not benefits. To be funded as a researcher to study cannabis you had to show a drop in something. You had a dropped sperm count, or IQ, you know, none of those actually turned out to be true. So, unfortunately, we don’t know as much as we would know if we were neutrally investigating cannabis not with a presupposition of, and a desire to find harm, but with a general neutral, ‘Is this harmful, or is this beneficial?’
Christie Taylor: This is about the risks as well as the benefits. Teenagers’ brains appear more vulnerable to long-term changes after chronic use, but why? I also mentioned the seeming link to schizophrenia. Research would help us better understand who is at risk, and why. There may also be a genetic component to who is at risk of cannabis use disorder, or addition, with a variety of negative consequences for their wellbeing. To understand that better we need more research. The risks of inhaling smoke, or vape are on our radar already.
Many studies have looked especially at smoke inhalation, but what about vapes, edibles, and other methods of consumption? As more ways of partaking proliferate those will need study too. Finally, there’s the question of who has the necessary expertise in what is already known. Even as research picks up a 2017 study found medical practitioners remain undereducated about the state of that research. Only one in ten medical schools at that time were offering education related to medical marijuana, which begs the question, if doctors aren’t even studying the existing science, how can we put that science into action in ways that maximise benefits, and minimise harms? I’ll let Peter Grinspoon have the last word.
Peter Grinspoon: We’ve been using cannabis, you know, through a lot of our human journey really amazingly, but the endocannabinoid system far pre-dates. The sad part is that because of the war on drugs this just hasn’t been studied. We’re very late in the learning about this. We’ve known about the other neurotransmitter systems, or many of them, for 100 years. We just are, sort of, learning about the endocannabinoid system in the 1990s. Regardless of whether you’re pro, or anti-cannabis, or neutral, or don’t care about cannabis, you have to know about the endocannabinoid system, because it’s like the traffic control system for all of our other neurotransmitters.
Christie Taylor: Researchers are catching up as governments themselves open up new avenues for science. The United States has relaxed regulations on that research, and is paving the way to provide more sources of science approved cannabis. So, as popularity soars, what does our future with this plant hold? We’ll take a look at that next time. From the climbing potency of modern pot, to the breathtaking environmental footprint of industrial cultivation, and some ways to solve it. Thanks so much to David Robson, Grace Wade, Joanna Thompson, Alexander Thompson, and Alexis Wnuk, for helping me report and write this episode. Thank you also to Timothy Revell for editing, and Jeremy Sue for his voice acting. New York Studio production is by Hugo Fonseca Suarez, and our audio and sound design is by Ollie Guillou. I’m Christie Taylor. Bye for now.
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