What we need in medical marijuana research

For marijuana, establishment medicine has failed. We need real science controlled by patients.

The tool we cannot learn to use

A mountain of studies and patient reports shows that marijuana is medicine. But these are not clinical trials — double-blind, placebo-controlled experiments on humans, that follow the three phase FDA process. Clinical trials are required by law in order to call something a medicine in the United States and they are prohibited for medical marijuana. As long as clinical trials can be prevented, the political class can say there is “no evidence” that marijuana is medicine, despite the mountain of actual evidence.

Even in medical marijuana states, as long as clinical trials are prevented, most doctors will not be comfortable using this medicine. Cannabis will not be widely used by doctors until we have precise treatment guidelines based on human studies. Precise guidelines means we need to know two things — dosage and which cannabinoids to use for any given condition. Unfortunately, both are complicated.

Dosage

Dosage is the simpler of the two, and it isn’t simple. For many conditions, there is an optimal dose that has to be just right — too little doesn’t work but neither does too much. Worse yet, for some problems different doses can actually have opposite effects. This is true for THC and anxiety: most users consider a small toke to be relaxing but a big cookie can cause anxiety so severe that we call it paranoia. The same is true for memory: at high doses I can’t remember why I walked into a room, but low doses improve memory in elderly mice and in Alzheimer’s patients. These “biphasic effects” have been found for pain. feeding, and novelty seeking.

These dosage problems lead to a basic rule which is “start low and titrate up slowly”. For pain and inflammation, “low” means 2 mg or less — a single toke rather than a pipe full. If that doesn’t work the rule says “titrate up”, that is, slowly raise the dose until you get a beneficial effect. It is common among practitioners to raise the dose every three days.

The titration rule solves the complexity of cannabis dosing, and “gradually increase until you’ve had enough” is what patients naturally do when they smoke. So until now medical marijuana has been successful when patients could self-titrate, that is, decide for themselves how much to use. In medical practice when they want you to self-titrate they say “take as needed”.

This works for symptoms because they are what people can feel, so most use of medical marijuana is for symptom relief. In Oregon, for example, the most common conditions given on medical marijuana card applications were pain, spasms, PTSD and nausea. Pain, spasms, and nausea are clearly symptoms, while the use of cannabis for PTSD is to reduce depression and take the edge off of panic attacks. Symptoms are titratable — the patient knows when the spasms have stopped, so the complexities of cannabis dosage are not a problem. Today the patient community knows a lot about using cannabis for symptom relief, but we don’t know as much about long term healing.

To promote healing, some patients and caregivers take a more radical approach. In 2003 Rick Simpson, a Canadian engineer, went for the moonshot and succeeded — he cured himself of skin cancer using a concentrated cannabis extract. His protocol has been used to treat a wide variety of cancers. It uses more than 700mg of THC per day — 70 times what pot smokers would consider a normal dose and 700 times as much as the smallest microdose. There are numerous testimonials and case studies of people who have been cured of advanced cancers, often very quickly. These large doses have become common among practitioners trying to cure really serious conditions. We don’t have published evidence of how often it works, perhaps because practitioners would jeopardize their licenses by talking too much, but at least occasional miracle cures are happening.

So across all the conditions marijuana is being used to treat, there is a 700 fold variation in the recommended dose, there’s often an optimum dose that you don’t want to exceed and you may get opposite effects at low and high doses. All these problems are manageable if patients can self-titrate, and at least a few people have saved their own lives by taking a blind stab.

Cannabis pharmacopoeia

Dosage is hard but it’s just part of a bigger question — which cannabis medicines to use for any given condition. The plant medicines work with the human endocannabinoid system, which has been evolving for something like 800 million years. It has several signaling molecules with dozens of targets. Its effects are highly articulated. For example, different parts of the hippocampus have different CB1 expression. The body exploits this to control what gets written into memory. This is why cannabis has opposite effects on memory at low and high doses — if you change the dose you activate a different part of the brain.

The plant is equally creative. Across its genetic range, marijuana produces about 100 cannabinoid acids. When they are heated, they reduce to a neutral form. THC is the neutral form of the acid THCA, which is in the plant. So counting acid and neutral forms there are about 200 plant cannabinoids, each of which probably has a unique effect on the body. THC causes a high and helps with depression, THCA reduces inflammation and protects brain cells, CBD does twenty different things, THCV improves pancreatic function in Type II diabetes and on and on. These plants produce a family of medicines, that differ from each other the way novocane differs from cocaine.

Synergy between these different compounds is so common that it has a name — the entourage effect. When whole plant extracts are tested against an isolated “active ingredient” like THC, whole plant medicine consistently works better. In 2002 GW Pharmaceuticals, now part of Bayer, showed that a mix of plant extracts containing 1:1 ratio of CBD and THC is more effective for multiple sclerosis than either chemical alone. Researchers in Israel found that a plant strain must have three specific cannabinoids to be effective against an aggressive breast cancer, and one of those is so exotic that it doesn’t even have a name. Most patients and practitioners of cannabis medicine prefer plant extracts to chemical isolates. The plant also produces terpenes, which are mainstays of aromatherapy, and flavonoids which have been shown to have medical potential.

On the pharmaceutical side there are synthetic cannabinoids, drugs that block cannabis receptors, and drugs that block the production or breakdown of endocannabinoids. Some of these are very interesting, for example, HU-308 is specific for the CB2 receptors. Other synthetics have killed people, on the streets and in clinics.

Federal regulation of science has failed

In this situation researchers are stuck on an endless treadmill, forever fighting to get permission to conduct experiments to show that cannabis is any kind of medicine at all. This is a political battle which has nothing to do with facts, science, or medical benefit.

We are not going to get permission to do FDA trials until politics change. Furthermore, FDA trials are largely irrelevant to cannabis. What would we learn from a standard clinical trial comparing a placebo to a fixed dose of some synthetic chemical isolate? Who wants to wait years for that? Phase I and II trials can take 3 years. They are required in order to prove that the medicine is safe for humans to consume. Seriously?

We need to bypass the corrupt, politicized federal process and move immediately to building a public understanding of how to use cannabis as medicine. Rather than endlessly litigating the catch-22s laid down by thugs, we should find out how to use the medicine by comparing different treatment protocols.

The research we need

Letting research be guided by politicians, medical boards, corporations or any other established authority has not worked. The experts have failed us. Here are some principles to guide the studies:

1. We need scientifically rigorous dose-response studies, comparing different plant extracts and combinations of cannabinoids. This means double blind assignment to treatment groups, pre and post testing, primary and secondary measures, and professional oversight. The primary measures must include independent observation, patient self reports are necessary but not sufficient. It’s important to record side effects, changes in comorbid conditions, and other drugs the patient is using.
2. A panel of experienced medical marijuana practitioners should advise on the conditions and treatments to be studied.
3. Comparing whole plant medicines is more important than studying chemical isolates.
4. Plant medicines have to be reproducible, so we need plants with known genetics, and extraction and processing documented. We need lab results giving the cannabinoid and terpene profiles of the medicine.
5. Short term studies to detect symptom relief should be part of long term studies that look for healing.
6. For symptoms that patients can self-titrate, at least one group in each experiment should be allowed to do so. If the patients use cannabis outside of the study, this should be measured and treated as self-titration.
7. An organization to undertake this research should be under the control of patients who are using the medicine.

Using these principles, we can design experiments that will give us real knowledge of how to use medical marijuana, without spending years fighting the powers that don’t want us to succeed.