Humans have used drugs derived from plants such as the opium poppy for thousands of years to lessen pain and produce euphoria. In 1973, scientists discovered the brain receptors that interact with these opiates, which include opium, morphine, and heroin. In 1975, the first of the brain's natural chemicals that bind with these receptors was identified. The similarity of this chemical, enkephalin, to morphine suggested opiate drugs work primarily by mimicking natural opiate-like molecules. The discovery of this endorphin (a term meaning endogenous morphine) system helped explain the effects of opiate drugs and opened the door to the development of powerful new therapeutic drugs that revolutionized pain management.

Similarly, humans have used the cannabis plant for thousands of years to reduce pain, control nausea, stimulate appetite, control anxiety, and produce feelings of euphoria. The first cannabinoid was isolated in 1899, but it wasn't until 1964 that THC was isolated. Since the discovery of THC, researchers have made new discoveries that help us better understand not just why and how cannabis works so well for so many people but its full therapeutic potential.

The therapeutic benefits of cannabis are derived from the interactions of cannabinoids and the human body's endocannabinoid system (ECS), identified in 1984. The ECS is a sophisticated group of ligands (such as the natural cannabinoid anandamide), their receptors, and signaling pathways involved in regulating a variety of physiological processes including movement, mood, memory, appetite, and pain.

One of the leading modern cannabinoid researchers, Dr. Ethan Russo, offers this comprehensive description of the ECS and its importance to a variety of physiological functions:

“The analgesic and palliative effects of the cannabis and cannabinoid preparations have been amply reported over the past generation.  In essence, the effects result from a combination of receptor and non-receptor mediated mechanisms. THC and other cannabinoids exert many actions through cannabinoid receptors, G-protein-coupled membrane receptors that are extremely densely represented in central, spinal, and peripheral nociceptive pathways. Endogenous cannabinoids (endocannabinoids) even regulate integrative pain structures such as the periaqueductal gray matter. 

The endocannabinoid system also interacts in numerous ways with the endogenous opioid and vanilloid systems that that can modulate analgesia and with a myriad of other neurotransmitter systems such as the serotonergic, dopaminergic, glutamatergic, etc, pertinent to pain. Research has shown that the addition of cannabinoid agonists to opiates enhances analgesic efficacy markedly in experimental animals, helps diminish the likelihood of the development of opiate tolerance, and prevents opiate withdrawal. Researchers have suggested that a clinical endocannabinoid deficiency may underlie the pathogenesis of migraine, fibromyalgia, idiopathic bowel syndrome, and numerous other painful conditions that defy modern pathophysiological explanation or adequate treatment.”

More than 20 years since researchers began developing an understanding of the ECS, two types of cannabinoid receptors, CB1 and CB2, have been identified, setting the stage for discoveries that have dramatically increased our understanding of how cannabis and its many constituent cannabinoids affect the human body.

CB1 receptors are found in the central nervous system, particularly the brain, and in other organs and tissues such as the eyes, lungs, kidneys, liver, and digestive tract. In fact, the brain's receptors for cannabinoids far outnumber the presence of all other neurotransmitter receptors combined, yet they are highly localized. The relative safety of cannabis is in part explained by the fact that cannabinoid receptors are virtually absent from those regions at the base of the brain (i.e., brain stem) that are responsible for such vital functions as breathing and heart control. CB2 receptors are primarily located in tissues associated with immune function, such as the spleen, thymus, tonsils, bone marrow, and white blood cells.

Research is helping scientists and physicians understand the role of the ECS in regulating a variety of bodily functions. As noted by Raphael Mechoulam, the researcher who first identified THC, the discovery of the ECS has generated a great deal of interest in identifying opportunities for the development of a wide variety of cannabis-based and other cannabinoid therapeutic drugs.

Locating accurate information about the safety and therapeutic value of cannabis can be difficult. An unfortunate result of the federal prohibition of cannabis has been limited clinical research to investigate the safety and efficacy of cannabis to control symptoms of serious and chronic illness. Many scientists have noted research is “hindered by a complicated federal approval process, limited availability of research grade marijuana, and the debate over legalization.”

Nonetheless, the documented use of cannabis as a safe and effective therapeutic botanical dates to 2700 BC14. Between 1840 and 1900, European and American journals of medicine published more than 100 articles on the therapeutic use of cannabis. In fact, cannabis was part of the American pharmacopoeia until 1942, and is currently available by prescription in Canada, the Netherlands, Israel, Germany, and soon Australia.

The political interference with cannabis research and its use as a medicine originated with the Marihuana Tax Act of 1937. The United States Congress passed this first federal law restricting access to cannabis, even for medical and research purposes, over the objections of the American Medical Association. Since then, numerous reviews by local, federal, and international commissions have confirmed the relative safety and efficacy of cannabis as a medicine. In recent decades, research studies have further shown cannabis has the potential to treat a variety of debilitating conditions for which conventional treatments are lacking. Yet the use of cannabis remains completely prohibited by federal law—even for medical purposes.

To date, more than 30,000 modern peer-reviewed scientific articles on the chemistry and pharmacology of cannabis and cannabinoids have been published, and more than 1,500 articles investigating the body's natural endocannabinoids are published every year. In recent years, more placebo-controlled human trials have also been conducted.

A 2009 review of clinical studies conducted over a 38-year period found that “nearly all of the 33 published controlled clinical trials conducted in the United States have shown significant and measurable benefits in subjects receiving the treatment.” The review's authors note that cannabinoids have the capacity for analgesia through neuromodulation in ascending and descending pain pathways, neuroprotection, and anti-inflammatory mechanisms—all of which indicates that the cannabinoids found in cannabis have applications in managing chronic pain, muscle spasticity, cachexia, and other debilitating conditions.

Currently, cannabis is most often recommended as complementary or adjunct medicine. But there is a substantial consensus among experts in the relevant disciplines, including the American College of Physicians, that cannabis and cannabis-based medicines have therapeutic properties that could potentially treat a variety of serious and chronic illness. What follows is a brief, annotated compilation of the emerging clinical data that support the therapeutic use of cannabis.

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Unlike prescription medications, cannabis therapeutics do not come with a specific dose. Successful use of herbal medicines such as cannabis requires active patient engagement, awareness, and feedback. Products and dosages that work for one patient may not work for another. The good news is that, unlike most prescription drugs, the patient has more personal control over the dose (self-titration), and there are a variety of delivery methods (routes of administration) that a patient can use to find the optimal treatment of symptoms. Experimentation may be necessary to determine the therapeutic threshold and preferred delivery methods.

Emerging regulations in some states, such as lab testing and labeling requirements, are creating more tools for patients to make educated decisions about product selection. Healthcare professionals and medical cannabis providers may play a bigger role in helping legal patients establish dose and delivery method as clinical research, experience, and the regulatory environment develop. In the meantime, however, patients must take the lead in finding the best solution.