Acids and Cannabinoids
The scientific name for marijuana is cannabis. Cannabis plants contain more than 60 acids which are not found in any other species. They have very strong anti-inflammatory action, and since the beginning of written history, people have ground the plant up and plastered it on bruises and swollen knees. Inflammation is a problem today, but we don’t use these medicines because of something else that one of them does. When they are heated, they all undergo a chemical change. Carbon dioxide is released, and what’s left are 60 new compounds – cannabinoids. One of the cannabinoids – THC – can get you high. In clinical terms, it causes a state known as “mild euphoria”.
THC was identified in 1964 by Raphael Mechoulam at Hebrew University in Jerusalem. His team found many of the acids and cannabinoids, and showed that out of all of them, only THC has a psychoactive effect. The rest of the world figured they had found “the active ingredient” of marijuana. Dr. Mechoulam and other scientists continued to investigate.
Marijuana Activates a Body Wide Protective System.
Knowing that THC was the agent, biologists could watch where it goes in the body. They found that THC attaches to receptors – proteins on cells that recognize changes in the environment and trigger the cell’s response. Reasoning that if a receptor exists there must be a signaling molecule that matches it, they looked to see what else besides THC binds to those receptors. They found a family of signaling molecules – the endogenous, or “endocannabinoids”. AEA was the first of these to be found. THC is very similar to AEA in its action at the receptors. Another endocannabinoid, 2AG – is stronger than either AEA or THC.
So by the middle 1990’s, scientists had a rough picture of the biochemistry of cannabis signaling – the messenger molecules and receptors. They asked the next logical question – what does this signaling do? In seeking the answer to that, they uncovered a previously unknown, body-wide protective system.
The first clue to the importance of the endocannabinoids is how early they appeared in animal evolution. So far as we know, every animal that has a nervous system produces AEA and 2AG. They are found in jellyfish, the most primitive animals that have skin and nerves. AEA is involved in their feeding, and 2AG serves as an anti-oxidant.
Animal life depends on processing a lot of oxygen, and oxygen is a very toxic substance, so our cells perform a continuous balancing act, running a high level of oxidation, and struggling to control it. Many of the cannabinoids are very strong anti-oxidants. 2AG is produced when cells are under stress, and it immediately protects the cell from oxidative damage.
The cannabis receptors evolved later. The first cannabis receptor appeared in an ancestor of the vertebrates. Jellyfish don’t have them, nor do invertebrates like worms and insects. But everything that has a nerve down its backside has cannabis receptors – mammals, birds, reptiles, fish, even sea squirts, that came before fish [photo by Stephen Chow].
Since cells produce 2AG in response to stress, a cell with cannabis receptors can tell when one of its neighbors is under stress. So vertebrate cells can signal to each other about stress states. And every part of you that is different from a sea squirt evolved with this capability already in place.
Where in the body can cells find a use for this kind of signaling? Almost everywhere. According to a recent review, “Changes in endocannabinoid levels and/or CB2 receptor expressions have been reported in almost all diseases affecting humans, ranging from cardiovascular, gastrointestinal, liver, kidney, neurodegenerative, psychiatric, bone, skin, autoimmune, lung disorders, to pain and cancer, and modulating CB2 receptor activity holds tremendous therapeutic potential in these pathologies.”
For example, bone density is maintained by two kinds of cells – osteoblasts that create bone and osteoclasts that remove it. Both of them have cannabis receptors. Stimulating the receptors activates osteoblasts and inhibits osteoclasts. So in this little system, cannabis signaling causes bone growth. Invertebrates, which do not have these receptors, do not have our flexibility in skeletal growth.
Osteoporosis is a failure of bone growth, so could a cannabis based medicine treat osteoporosis? It’s been tried in mice, and it works. Normally, the next step would be clinical trials on humans, but there has been no next step. All of the preclinical evidence is positive, but there cannot be clinical trials, because it is illegal to study any possible benefits of marijuana.
The Federal Prohibition on Research
NIDA, the National Institute on Drug Abuse, has veto power over marijuana research in America, and NIDA only allows research if it is designed to show harmful effects of the plant. If your purpose is to find any benefit from this plant, you can’t do research in the U.S.
Now, if you want to study cell chemistry, you can be fuzzy about your reasons, but if you want to do clinical trials on a medicine for humans, you have to admit that you’re looking for a benefit from the plant. And if you admit that, you can’t do the research.
Cannabis based medicines are unique in being blocked this way. Even for heroin or cocaine you only need Food and Drug Administration approval to do research. But FDA approval is not enough to do research on marijuana. The FDA has approved clinical trials for cannabis medicine twice, once for migraine and again for PTSD. In both cases NIDA vetoed the study.
A Body Wide System
Cannabis receptors are very common in the brain. They are also found in the intestines, liver, kidneys, bones, the linings of our blood vessels, and our reproductive organs. The egg and sperm use cannabis signaling to find each other and manage conception. Then the fertilized ovum uses cannabis signaling toimplant itself on the mother’s uterine wall. Arguably, your first act as a genetic individual was to initiate cannabis signaling. That’s how deeply it is built into human physiology.
Regulating the Immune Response
Signaling about cell damage is necessary for the immune system to work, so every cell in the immune system has cannabis receptors. The most prominent thing that the immune system does with cannabis signaling is to control inflammation and plaques. Plaques are small plates or blankets, made of a protein or a fat like cholesterol. When the body is attacked or injured, the immune system responds by promoting inflammation and building plaques and fibrous mats. This stops infection, but if this first line of defense is not carefully controlled we get autoimmune diseases – low level inflammation causes tissue damage, accompanied by plaques and fibrosis. This process is a major health problem. It is common to Alzheimer’s, hardening of the arteries, multiple sclerosis,rheumatoid arthritis, Crohn’s disease and many others. And there is plenty of evidence that marijuana can help with all of these conditions, from biochemistry, animal models, and patient testimony. But we can’t get scientific proof that it works in humans because clinical trials are blocked by the federal prohibition.
How well would you guess this kind of science is working for us? For a good case study, let’s look at cancer.
Marijuana and Cancer
Almost 40 years ago, in 1974, researchers at the National Cancer Institute discovered that two plant-based cannabinoids, THC and CBN, could slow the growth of tumors and extend the lives of mice with cancer. This happens for a number of reasons, in particular, cannabis signaling is involved in initiating programmed cell death, or apoptosis. Apoptosis fails in cancer cells, so they don’t die when they should. Cannabinoids can restore one of the biological pathways leading to apoptosis, causing the tumor cells to self destruct. Since cannabis signaling is merely restoring normal biochemistry, it does not damage nearby healthy cells.
You would think that a cheap medicine that selectively kills cancer cells would be worth investigating, but there was no follow up to this research – it was effectively suppressed for 24 years. To repeat, Congress decided that the plant is bad, so NIDA does not allow research into possible benefits of the plant.
The ability of cannabis to kill cancer cells was rediscovered in 1998 in Spain. At Complutense University in Madrid, a team led by Manuel Guzman, Guillermo Velasco and Christina Sanchez wanted to study the biochemistry of cannabis metabolism. They decided to work with cancer cells because you can buy cancer cell lines from a laboratory supply company. These cell lines are cheap and once you have them they just go on reproducing and never die. But when Dr. Sanchez put cannabinoids on the cancer cells, they died. After verifying that it was the cannabis that was killing them, the Spanish researchers looked into the scientific literature, where they learned that the U.S. Government had found the same thing 24 years earlier.
The Spanish researchers did what American scientists did not – they began looking for ways to turn this laboratory result into a treatment. For study, they chose glioblastoma multiforme, a brain cancer that has no cure. THC slowed the growth of these tumors, but did not stop them. In this regard, THC is the same as other, approved anti-cancer drugs. The best we can do today is slow these tumors down and extend the patient’s life by a few months.
But looking at the biochemistry, the Spanish team found that THC complements the action of an approved drug, Temazolomide. Working with mice, they tested a combination of THC and Temazolomide. The two drugs together not only stopped tumor growth – the cancers began to shrink. The following graph shows the size of the tumors over time. The rapidly climbing line on top shows how tumors grow when they are left untreated. The two lines in the middle show growth under each medicine alone. The line at the bottom shows the tumors shrinking, when THC and TMZ are used together.
This is what it does in mice. Would it work on humans? We don’t know. The law is, no good can come from this plant. Last year 571,950 Americans died of cancer. This same story is repeated for disease after disease. Cannabis medicine slows the progression of atherosclerosis in mice. The evidence is strong enough that for any other substance, clinical trials would have begun long ago. Last year about 870,000 Americans died of atherosclerosis. More than 2 million suffered osteoporosis fractures. How many of these people are victims of the war on drugs?
The Knowledge Gets Out
While clinical science is blocked, the medical marijuana community has responded to these findings. A key development was the realization that THC is not the only “active ingredient” in the plant.
First there are the raw plant acids, which have anti-inflammatory action even though they are not psychoactive. In fact, much of the historical use of cannabis as medicine has been as raw plant extract, in poultices, teas and tinctures.
Raw plant extract has been championed by Dr. William Courtney in northern California, who says “Cannabis is a vegetable, and a dietary essential.” Dr. Courtney’s patients make juice from young plants and drink it daily. Using the plant this way, there is 60 times less effect on the mind, so these patients can take large doses without getting stoned.
Then, when the acids are converted, it turns out that THC is not the only active cannabinoid. The most abundant cannabinoid in wild plants is CBD. CBD was thought to be inactive because it doesn’t get people high. But once the biochemistry could be investigated, it was discovered that CBD is a partial antagonist at the cannabis receptors. It blocks the effect of THC, so a plant can contain THC and still not be psychoactive, if it also has enough CBD.
With THC stimulating the receptors, and CBD blocking them, different strains of marijuana can have opposite effects. For example, one of the longstanding mysteries of marijuana has been its effect on anxiety. Users consistently report that smoking relaxes them, but anxiety attacks (“paranoia”) also happen. How can a medicine reduce anxiety sometimes, and increase it other times? We now know part of the answer – it isn’t just one medicine. THC increases anxiety, CBD reduces it. Mixing the two produces a variety of energizing and calming states. It’s important to know the chemistry of the individual plant.
With CBD we can start to think about more sophisticated tuning of the endocannabinoid system. CBD is an anti-convulsant, an anti-psychotic, and it prevents diabetes in mice. THC and CBD can work together – in England, GW Pharmaceuticals has shown that a 1 to 1 balance of THC and CBD is better for multiple sclerosis than either chemical alone.
The Dispensaries Respond to Knowledge
The dispensaries and cannabis physicians in California responded to these discoveries by starting ProjectCBD. The state’s largest dispensary, Harborside Health Center in Oakland, began testing to measure the percentage of THC and CBD in the marijuana they sold. A search began for high CBD varieties. With reliable and consistent testing, it became possible to survey patients to find out which cannabinoid profiles are effective for which conditions. Down the street from Harborside, Oaksterdam University emerged as a focus for spreading this information.
The Government Responds to Knowledge
On April 2, 2012, federal agents raided Oaksterdam University and seized computers and records. Oaksterdam is not a dispensary and did not distribute marijuana – they do training. The government “would not comment on the purpose of the raid”.
In July, the US Attorney moved to shut down Harborside Health Center by seizing the buildings where Harborside operates. Harborside has been a leader in making this medicine safe and in helping patients to know what they are getting. Harborside pioneered testing for cannabinoid profiles, and before that they pioneered testing for fungus and insecticides. The prohibition police are deliberately targeting the people who do it right. This is a war on medical knowledge.