Here is an article I posted waaaaaaaay back in the day (1998 I think) on overgrow in the cannabis knowledge thread. Pre shutdown days. Enjoy.
Just a few centimeters behind your eyes is a living computer a billion times more complex and wondrous than the most sophisticated machines on the planet.
Humans speculate about the existence of souls, spirits and past lives, but there’s one thing I’m sure of: my thoughts, dreams, memories, feelings, and consciousness are somehow contained in the billions of neurons inside my skull.
I am my brain. Without my brain, I couldn’t write this, and you couldn’t read it. We couldn’t get stoned… we couldn’t get anything.
Brain salad surgery
Ingesting marijuana or other entheogens is a deliberate act of consciousness evolution. Physiologically, it can accurately be described as temporary neurosurgery: using cannabis as a tool, you reach inside your head, you literally alter your mind. Let’s face it, “mind-altering drug” is not a metaphorical term.
How so? As far as science can determine, your mind is your brain. Your brain is billions of cells, called neurons, which function as individual units, but are intimately networked with every other brain neuron.
Cells contain fluid and intracellular structures. They also contain ions of calcium, sodium, potassium, protein, and chloride. Ions have positive or negative electrical charges. Positive and negative ions repel or attract each other, like the poles of magnets. The repulsions and attractions of cellular ions allow cells to engage in electrochemical exchange; this exchange allows cells to communicate with each other. Scientists call this communication “neural transmission.”
Cells communicate via inflow and outflow of ions; they also communicate using neurotransmitters, which are body-manufactured chemicals created and stored inside cells. Neurotransmitters are released into gaps between cells, called synaptic clefts. When neurotransmitters bridge those clefts and contact other cells, intercellular communication takes place. Without ion exchanges and neurotransmitters, the brain cannot speak to itself – it’s dead.
So this is why “mind-altering drugs” is a literal term: drugs affect neurons, ions, neurotransmitters, and cellular communication. Some drugs, like alcohol, make neurons more fluid, which decreases their ability to communicate. Cocaine interferes with the “sodium channels” that permit positively charged sodium ions to enter and leave cells. Most psychoactive drugs severely alter normal patterns of production, release and absorption of neurotransmitters.
To put it bluntly, putting drugs inside your brain is serious business, and an act of faith.
Locks and keys
Dr Roger Pertwee, an Oxford-educated professor of neuropharmacology at the University of Aberdeen in Scotland, has spent a good portion of his life trying to figure out how marijuana affects brains and other body systems.
He started doing cannabis research in 1968, when cannabis tinctures were still legally available as medicine in the United Kingdom. In 1997-98, he was president of the International Cannabinoid Research Society (ICRS), a group founded in 1991. The ICRS has hundreds of member-researchers studying “cannabinoids,” which are marijuana’s most interesting ingredients.
Pertwee is still an ICRS leader; he’s currently the organization’s international secretary. He’s also a highly regarded expert whose cannabis research has been lauded by the International Union of Pharmacology and The Rowett Research Institute. He was author, co-author or a contributor to four recent reports on cannabis and cannabinoids: one for the British Medical Association, one for the House of Lords Select Committee on Science and Technology, one for the National Health Service, and one for the Royal Society and Academy of Medical Sciences.
Like many pot researchers, Pertwee is a cannabis specialist who has never used marijuana.
“Surprisingly, I’ve never taken it,” he said during an interview at his office in Scotland. “It’s very ironic perhaps, but it’s perfectly true. I don’t know how I’ve avoided it all these years, and it’s quite amazing- even when I was at university, I never came across it. And now I quite honestly prefer to have a drink rather than think of taking cannabis. I am not interested in taking it.”
So why is Pertwee interested in studying cannabis?
“I was nearly finished with my Ph.D. in the late 60’s, and almost everyone was taking cannabis, but virtually nothing was known about how it worked in people,” he explained. “It began to get really exciting in the late 1980s and in 1990, with the discovery that cannabinoids were linked with a newly-discovered system of receptors.”
“Receptors” are a hot item in pharmacological research, Pertwee explained. Cells have specific sites – the receptors – which interact with specific compounds in the same way that locks and keys work together. The receptor can be viewed as the lock. Substances that fit into receptors can be viewed as keys.
Some of these “keys” are produced in the body. They include hormones and neurotransmitters, classified as “ligands,” that bind with receptors. But it isn’t enough just to bind with cell receptors; if ligands bind with and activate a receptor, causing cellular changes, they’re called “agonists.”
Ligands made inside the body are called endogenous agonists. Agonists that come from outside the body are called exogenous agonists. Marijuana contains exogenous agonists – cannabinoids – that bind to receptor sites in the brain. The changes that result from the interaction of cannabinoids, receptor sites, and cells are what stoners experience when they feel high.
Blissful discoveries
Pertwee and his colleagues are excited about cannabis because it contains an exogenous version of an endogenous agonist called anandamide, the first endogenous cannabinoid discovered by scientists. Anandamide derives its name from “ananda,” a Sanscrit term that means “bliss.” Scientists suspect that anandamide plays an important role in pain suppression, and may be crucial to other life-support functions as well.
“The discovery of anandamide answered some questions,” Pertwee said. "We had hypothesized that if the receptors were there, they must be there for a purpose. Humans don’t evolve receptors so they can smoke a plant. The plant contains substances that activate receptors already present in the body. Presumably these receptors were there because there was an endogenous chemical that interacted with them. And it was exciting to actually find the chemical, which was done by Professor Raphael Mechoulam’s group in Israel in 1992.
“They sent us some of the material so we could do the pharmacology on it. We demonstrated that anandamide had properties that were pharmacologically similar to exogenous cannabinoids.”
Almost sheepishly, Pertwee admitted that early samples of anandamide had been obtained from a rather unusual source.
“The first sample from Israel had been extracted from pig brain,” he said, "They sent just a few micrograms in a little glass vial; we couldn’t actually see it because there was so little of it. And we didn’t know what kind of chemical it was, how to dissolve it, or how much to give to our tissues to get an effect. We had the world’s entire supply, so we had to be very careful, but it turned out OK because we picked the right dose and the right solution to dissolve it in.
“The cannabinoids are very fat-soluble, but have very little water solubility; that’s a big problem when you want to work with them. You have to use some kind of vehicle, some kind of solvent to dissolve them, but one that won’t destroy the sample or the tissue. Anandamide is now made in laboratories, so it’s easier to obtain for research.”
Pertwee says it’s wrong to think that tetrahydrocannabinol (THC), the primary psychoactive ingredient in marijuana, is exactly like anandamide.
“The two are quite different. Anandamide isn’t the same chemical that is in the plant. Anandamide and THC structurally look quite different, but anandamide is a flexible molecule and can take the same three-dimensional shape as THC. This is similar to the situation with opiates and morphine-like drugs. Morphine comes from poppies, and it acts like an endogenous morphine-like substance made in the body, although it is chemically different from that endogenous substance. With anandamide and THC, there’s quite a molecular difference, but they both bind with the same receptors, so we view them as analogous to each other.”
Cannabinoid networks
Unlocking the secrets of endogenous and exogenous cannabinoids fascinates Pertwee, and for good reason: cannabinoids apparently affect a wide range of important body functions, and the system by which they do this is complex and mysterious, offering intrigue and challenge for researchers.
“Our bodies contain the endogenous cannabinoid system, otherwise known as the endo-cannabinoid system, consisting of chemical messengers and receptors these chemical messengers interact with,” he said. “There are two types of receptors in this system. One is the CB1 receptor, found primarily on nerve cells in the brain, spinal cord and peripheral nervous system. The second type of receptor, CB2, is found mainly in immune system cells. These two types are affected by some of the chemicals in cannabis, particularly Delta-9 THC. Delta-9 produces effects by acting on CB1 and CB2 receptors, but its recreational effects are probably mediated only by the CB1 receptor.”
“The CB1 receptor is present at synapses,” explained Pertwee, when I asked how THC changes brain function. “Synapses are tiny gaps in between nerves. The nerves release chemical messengers that act on other nerves, and that process constitutes neurotransmission. The CB1 receptor seems to control release of a range of neurotransmitters. In general, cannabinoid-receptor interactions produce a suppressant effect, but this doesn’t mean that cannabis is a relaxant. It just means that it tends to inhibit cells from releasing a variety of neurotransmitters.”
Cannabinoids simultaneously produce stimulating and relaxing effects by affecting neurotransmitter release, and by changing a nerve’s ability to respond to neurotransmitters.
Pertwee patiently provided me with a crash course in neurobiology, which I needed it if I was to understand how pot can be both a stimulant and a relaxant.
“People spend years at university trying to figure out this stuff,” he said. “Some neurotransmitters are inhibitory; they limit cell behavior. So if a cannabinoid inhibits their release, it removes their inhibitory effect, which produces an excitatory effect. Cannabinoids also inhibit release of excitatory neurotransmitters. When you remove the excitatory effect, you end up with an inhibitory effect. Hence, cannabinoids can produce a mixed excitant and depressant effect.”
Cannabinoids are powerful brain-changers because they influence release and uptake of the brain’s most important neurotransmitters, including dopamine, glutamate and serotonin.
Cannabinoid interactions with serotonin are especially interesting, because serotonin is widely believed to be a mood-moderating neurotransmitter. Many prescription anti-depressants, and alternative depression therapies such as the herb St. John’s Wort, are based on increasing serotonin levels.
Scientists are now asking if cannabinoids can be used as targeted chemical messengers, to affect specific neurotransmitters and alter brain networks like a conductor calling out different instruments during a symphony.
Not yet, says Pertwee.
“It is very difficult at this point to determine what the cannabinoids are doing in regards to specific neurotransmitters,” he said. "A wide range of neurotransmitters is affected in many different brain areas and outside the brain in the peripheral nervous system.
"It’s also very difficult to study CB2 receptors, which are found mainly in immune cells; they’re at very high concentrations in human tonsils. There’s tremendous interest in CB2 function, especially from drug companies. If you find drugs that activate only the CB2 receptors you’re likely to retain some cannabinoid effects while deleting recreational, psychoactive effects that come from CB1 receptors. But for the recreational users, turning on CB2 without affecting CB1 would probably be a rather disappointing psychoactive experience. "
I mentioned that anti-pot propagandists often claim that marijuana negatively affects immune function.
Pertwee noted that Marinol (synthetic THC) is often given to AIDS patients to boost their appetites, even though AIDS patients obviously have a compromised immune system. He said it’s hard to evaluate the effect of cannabis on the immune system, in part because THC interacts much more weakly with CB2 receptors than with CB1 receptors.
Psychonautics
When I told a friend I was writing an article about neurobiology for Cannabis Culture, she laughingly responded, “Stoners won’t read it. They have a short attention span and aren’t looking for a science lesson.”
I hope her condescending stereotype is untrue. Most “potheads” I know are interested in psychonautics – the exploration of inner space.
Any pot user reading this will realize that using marijuana is akin to playing god with the hardware and software of their brain. I hope they’ll want to know how Pertwee’s research can be useful in their quest for safe, intense highs.
It is useful to understand that stoners and Pertwee are different members of the same team. Like Pertwee, pot-people are fascinated with cannabinoids and perform experiments with them. Of course, there are important differences: Pertwee’s research happens in laboratories, with eight researchers assisting him. His tests are conducted on animal tissues and “cultured” cells. Potheads conduct experiments on themselves, dosing their brains with a mixture of cannabinoids and other substances not designed or created in a lab, but created inside a living plant and ingested as a dried, smoked or eaten herb.
Pot users monitor effects from inside the experiment, noticing from a participatory perspective the perceptual results of neurochemical shifts that Pertwee sees through microscopes and statistical analysis.
Pertwee says cannabis users should keep themselves informed about scientific cannabinoid research, if only to keep abreast of the latest ideas about marijuana’s effect on cognition, longevity, and medical conditions.
“From a medical point of view, I’m against recreational use,” he says. "Cannabis can produce serious unwanted effects, such as an exacerbation of schizophrenia in people who are prone to schizophrenia. Cannabis can trigger a paranoid attack, and there may be other harms it causes.
"But I also believe some sort of public inquiry is needed to look at all aspects of the plant. We’ve had inquiries, including the recent US Institute of Medicine report and the 1998 House of Lords report, but those looked only at the medical side of it – they didn’t look at other issues, such as the effects of police tactics, or ethical and social issues.
“Although a strictly medical approach might warn against side effects of recreational cannabis use, there might be other aspects that more than counterbalance those warnings. Overall, it might be better to legalize it. But nobody can give you a definitive answer because a comprehensive inquiry has never been held.”
Even though Pertwee believes further study is needed before scientists can say whether or not recreational cannabis use is relatively safe, he is already certain that medically-supervised use of cannabis for targeted aliments should be allowed.
“I agree with the IOM and the House of Lords who recommended that cannabis should be available now for patients,” he said. "The known adverse effects of marijuana are no worse than those of drugs already used for similar problems, and in some cases marijuana appears to be less harmful than prescription drugs.
"I see no reason why doctors shouldn’t be allowed to prescribe it now. After all, it was a medicine until 1971 in this country. I’ve kept a couple of bottles of cannabis tincture from back then, prepared for the National Health Service. People used to take it orally for various ailments.
"Now that I think about it, it’s surprising how recently it became banned. It was the World Health Organization that pushed the ban; our government just went along with it. At that time there was no obvious use for cannabis as a medicine; it was considered an outdated medicine, used only for general aches and pains. No connection had really been made with chronic pain or multiple sclerosis or whatever. We bought up hundreds of bottles of this tincture, and used it for research.
“I understand why some people want to ban cannabis and cannabis research. They seem to be worried about abuse among children and the like, but I ask why should that prevent patients from getting a drug that might be the only drug that works for them. If it is something like severe pain or spasticity, then surely that is good enough reason for allowing the patient to take cannabis.”
Future directions
I asked Pertwee if anandamide could be used recreationally. He said he’d be interested in knowing if it could be, but no human experiments have yet been carried out, “perhaps due to ethical concerns.”
One of the raging debates that could be resolved by Pertwee’s research centers on whether THC alone can produce the same effects as ingestion of a “natural” cannabinoid profile from raw marijuana, which includes other cannabinoids (such as CBD and CBN), along with THC.
“Our lab uses synthetic THC,” Pertwee commented. "We also get THC from GW Pharmaceuticals, which is a British company now growing cannabis for medical research. It’s unlikely that pure Delta-9 THC in the lab is different from pure Delta-9 THC extracted from cannabis, but a real possibility of difference exists in comparing a single cannabinoid’s effects with that of a cannabinoid mixture.
"It may be preferable to give someone a mixture of cannabinoids rather than a single cannabinoid. You could administer the profile extracted from a raw plant, or extract individual constituents and recombine a dozen, or maybe just two or three, constituents. When we set up a committee to design a clinical trial with cannabinoids for multiple sclerosis, to determine if cannabinoids are truly effective against some of its symptoms, we decided that it was very important to include raw cannabis as well as THC in the study, and to do a comparison to see if there are differences.
"But I am a scientist, not a medic, so most of our work is in collaboration with medicinal chemists, looking for new compounds that affect CB1 and CB2 receptors. We’ve studying the effects of drugs that activate the CB1 or CB2 receptors selectively, or act as blockers of CB1 or CB2. And we’re interested in agonists, in seeing if they are full agonists, or what we call partial agonists. This is analogous to morphine and codeine: morphine is what we call a full agonist, whereas codeine is a partial agonist. Morphine will have a big receptor effect, but codeine only a partial one, so even at maximum doses codeine can only relieve modest pain, not severe pain.
“We’re also interested in drugs we call ‘inverse agonists’ which are drugs that actually produce effects opposite in direction to agonists. So, we’re interested in those being possible therapeutic compounds for use medically, and also as experimental tools. We’re also trying to find if there are cannabinoid receptors other than just CB1 and CB2. Are there maybe CB1-like and CB2-like? There is some evidence that there are some CB2-like already, or CB3… another completely different set of cannabinoid receptors. This could give us new targets for medicines.”
God bless the UK
Pertwee is lucky that he is doing research in the United Kingdom, rather than in the United States. The American government rarely grants permission or provides test materials for cannabis experiments.
“Our government,” Pertwee says, "in giving Dr Guy [of GW Pharmaceuticals] permission to grow his cannabis, suggests it is sympathetic to the idea of medical cannabis, and that they genuinely are saying ‘Show us evidence and then we’ll do something about it, but we’re not convinced at the moment… we need more evidence.’ But the fact that they’ve gone along with Dr Guy, and the fact that they’ve allowed him to grow his cannabis, is really quite a big step and very encouraging.
"I don’t get attacked for doing cannabis research over here. I’ve been on radio and television programs and in the newspapers, and the impression I get over here is that people are really very sensible about it.
“Even the ones who campaign against recreational use, admit, at least over here, that they would be prepared for cannabis to be available for medical use. And the average man in the street is really quite educated about it because it appears quite a lot in the media, that they can distinguish between recreational and medical use. And they may well be against the recreational use, but very, very often, I would say the majority of people interviewed are in favor of medical cannabis use.”
As for the future?
"Well, we’re going to know much more about how the cannabinoid system is involved in things like pain,’ Pertwee speculates, "working out exactly where cannabinoids are acting to relieve pain, what kind of pain that they can relieve, and so on. We’ll know much more about the role of anandamide and other endogenous cannabinoids and their receptors, and maybe with any luck we’ll start finding out what the CB2 side of things is doing. And maybe there will be discoveries of additional types or sub-types of cannabinoid receptors.
"For example, there’s a recent paper in Nature demonstrating that anandamide will activate what are called vanilloid receptors. These are receptors also acted upon by capsaicin, which comes from hot peppers; these receptors are present on sensory neurons in the periphery and are presumably involved in feeling pain. So here we have anandamide, not THC, but only anandamide, acting on this possibly endogenous type of receptors.
"We need more clinical studies to demonstrate that cannabis really does work, or doesn’t as the case may be, so regulatory authorities and drug companies can be convinced to take cannabis seriously. The Medical Research Council, a UK government funding agency, has agreed to provide a substantial sum to fund a large multi-centre clinical study that will compare cannabis and THC in MS patients.
“One of the biggest problems is how to administer the medicine to the patient. Smoking is not an acceptable way to deliver medicine, and orally delivered cannabis is absorbed unreliably and changed by the liver into a more potent metabolite. There are experiments with inhalers, and some people have developed a suppository version. But I don’t think people here and in the States are very keen on suppositories. On the other hand, on the Continent they don’t mind at all. A lot of their drugs are taken as suppositories. In France it’s quite a usual method. It’s cultural differences. When you take it at that end, you avoid the liver metabolism, because the blood supply bypasses the liver. It may be quite a challenge, marketing cannabis suppositories!”
Sinister uses?
Pertwee is a brilliant, precise, patient and pleasant man. Although many scientists with less qualifications than Pertwee refused to be interviewed for Cannabis Culture, because they are afraid of, or prejudiced against, pro-marijuana publications, Pertwee freely gave many hours of his valuable time explaining science and concepts to me.
But Pertwee’s cannabinoid research does not occur in a vacuum. He accepts funding from agencies that traditionally have been unfriendly to marijuana, such as the US National Institute on Drug Abuse (NIDA). Pharmaceutical companies also fund him.
I told Pertwee I was worried about his work with inverse agonists, because hard-line anti-marijuana fascists talk about secretly administering inverse agonists to teenagers, to people arrested for marijuana, and to medical marijuana users. Inverse agonists could literally prevent cannabinoids from binding with their receptor sites. They would prevent people from getting high.
I also shared concerns that the medicalization of marijuana might feed into increased prohibitionism and persecution of recreational users.
Some medical marijuana researchers, for example, are developing genetic and chemical methods of removing THC from the plant and medical pot products. They believe that non-THC cannabinoids, which do not produce a psychoactive effect, are as medically useful as THC. Most medical marijuana scientists and pharmaceutical developers are trying to design marijuana-based medicines that do not cause mood alteration. And in general, scientific cannabinoid researchers frown on recreational use and and are not themselves recreational users.
And the UK’s very own drug czar, a former constable from Yorkshire, has proclaimed that since UK researchers allegedly devised marijuana that has a full range of medicinal uses without recreational effects, the issue of legalizing the whole plant is moot. Ironically, the czar recently admitted that the UK’s anti-pot policies were misguided, and that less emphasis should be placed on arresting marijuana users.
Pertwee acknowledged my concerns, but said that he has not encountered scientists who do biased cannabis research. He asserted instead that biased organizations, pressure groups, and individuals distort research results for political purposes.
He says he is proud of the ICRS: “We’re all strictly scientists. We’re extremely open-minded. All we want is to find out the facts and report them. The lack of a political agenda makes us very credible and very useful.”
When I asked if it troubled him that anti-marijuana forces might use his discoveries to prevent peoples’ brains from being affected by THC, Pertwee replied, “How our published discoveries are used by others is outside our control – that is so throughout science.”
Still, no matter how others may pervert or misuse his research, I see Pertwee as a gentleman and an innocent, an honorable man fascinated by the wonders of nature. He ended our conversations by saying that his interest in cannabinoids has as much to do with his interest in the origins of life as it does in pure science and medicine.
“I am excited about cannabinoids because they reveal that we have these marvelous systems in our bodies,” he said “Where do they come from? Why are they there? The endogenous cannabinoid system, with its vast network of receptors and chemical messengers, deals with pain, muscle, motor function, thought, and mood. It’s been detected in very primitive organisms, and yet it has survived evolution from very early on and therefore it must be quite an important system for us to have. It’s a wonderful system to study.”