3. Synthetic cannabinoid antagonists
4. Peripherally restrictedagonists
6. Water-soluble cannabinoids
7. Allosteric cannabinoid receptor modulators
8. Inhibitors of endocannabinoid metabolizing enzymes
9. Endocannabinoid reuptake inhibitors
The possibility that a woman could have painless labor became an idÃ©e fixe of H. L. (“Doc”) Humes, a literary wunderkind and MIT science prodigy who developed some intriguing theories about cannabis. When his wife was giving birth at their home on July 4, 1977, they tried an experiment involving marijuana, breathing exercises, and massage. Humes gave her some marijuana to inhale just before each contraction and this helped her immensely.
Marijuana is “among the most forgiving medicines we know,” said Humes, who described cannabis as a “neurological laxative” that “acts to surface anxiety which the user holds within himself.” Doc touted the weed as the best remedy for stress, “the necessary medicine for the nation’s anxiety-tension problem.” “America is so sick,” he declared, “and cannabis is the specific medicine for the disease that afflicts us.”
Chronic “anxiety-tension,” Humes explained, “is a state of general blockage that shows up most obviously at an individual’s ‘weakest link,’ so it can have a wide variety of physical and emotional symptoms, as well as being generally debilitating … Most of the common elements from which people suffer are really symptoms of anxiety-tension, including headache, backache, insomnia, fatigue, irritability, GI disturbances such as constipation and ulcers, overweight, arthritis, and so on. Anxiety-tension has also been very clearly implicated in more deadly disorders such as high blood pressure, heart disease, cancer proneness, and premature aging … Depression is frequently a symptom of anxiety-tension.”
Related Story: Stress Can Kill You: Marijuana Can Help Kill Stress
Ganja’s biphasic qualities allowed smokers to “equilibrate” the nervous system, according to Humes. Consumed in appropriate quantities, the herb could calm the hyper or invigorate the sluggish. The medical use of cannabis depends precisely on managing its psychoactive properties,” Doc counseled. “In heavy dosage, it functions like a hypnotic. In a light dosage it functions like an illuminant.”
Humes saw early on that the widespread “recreational use of cannabis is also a form of self-medication,” even if most marijuana smokers did not acknowledge this to themselves. He lamented the fact that hundreds of thousands of young people are arrested each year for using the most efficacious and least harmful medication available to cope with the stress of living in the modern world.
Source: H. L. Humes, “Notes on Painless Detoxification from Narcotics Addiction,” unpublished manuscript.
An excerpt from Smoke Signals: A Social History of Marijuana – Medical, Recreational and Scientific by Martin A. Lee
It doesn’t get you high, but it’s causing quite a buzz among medical scientists and patients. The past year has seen a surge of interest in marijuana’s CBD, a non-intoxicating cannabis compound with significant therapeutic properties. Numerous commercial start-ups and internet retailers have jumped on the CBD bandwagon, touting CBD derived from industrial hemp as the next big thing, a miracle oil that can shrink tumors, quell seizures, and ease chronic pain — without making people feel “stoned.” But along with a growing awareness of cannabidiol as a potential health aid there has been a proliferation of misconceptions about CBD.
Project CBD receives many inquiries from around the world and oftentimes people say they are seeking “CBD, the medical part” of the plant, “not THC, the recreational part” that gets you high. Actually, THC, “The High Causer,” has awesome therapeutic properties. Scientists at the Scripps Research Center in San Diego reported that THC inhibits an enzyme implicated in the formation of beta-amyloid plaque, the hallmark of Alzheimer’s-related dementia.
Related Story: The Only CBD User’s Manual You Need
The federal government recognizes single-molecule THC (Marinol) as an anti-nausea compound and appetite booster, deeming it a Schedule III drug, a category reserved for medicinal substances with little abuse potential. But whole plant marijuana, the only natural source of THC, continues to be classified as a dangerous Schedule I drug with no medical value.
2. “THC Is The Bad Cannabinoid. CBD Is The Good Cannabinoid.”
The drug warrior’s strategic retreat: Give ground on CBD while continuing to demonize THC. Diehard marijuana prohibitionists are exploiting the good news about CBD to further stigmatize high-THCcannabis, casting tetrahydrocannabinol as the bad cannabinoid, whereas CBD is framed as the good cannabinoid. Why? Because CBD doesn’t make you high like THC does.
Project CBD categorically rejects this moralistic, reefer madness dichotomy in favor of whole plant cannabis therapeutics. (Read the foundational science paper: A Tale of Two Cannabinoids.)
THC and CBD are the power couple of cannabis compounds — they work best together. Scientific studies have established that CBD and THC interact synergistically to enhance each other’s therapeutic effects. British researchers have shown that CBD potentiates THC’s anti-inflammatory properties in an animal model of colitis.
Related Story: How Marijuana’s CBD Works In The Body According To Science
Scientists at the California Pacific Medical Center in San Francisco determined that a combination of CBD and THC has a more potent anti-tumoral effect than either compound alone when tested on brain cancer and breast cancer cell lines. And extensive clinical research has demonstrated that CBDcombined with THC is more beneficial for neuropathic pain than either compound as a single molecule.
4. “Single-Molecule Pharmaceuticals Are Superior To ‘Crude’ Whole-Plant Medicinals.”
According to the federal government, specific components of the marijuana plant (THC, CBD) have medical value, but the plant itself does not have medical value. Uncle Sam’s single-molecule blinders reflect a cultural and political bias that privileges Big Pharma products. Single-molecule medicine is the predominant corporate way, the FDA-approved way, but it’s not the only way, and it’s not necessarily the optimal way to benefit from cannabis therapeutics.
Cannabis contains several hundred compounds, including various flavonoids, aromatic terpenes, and many minor cannabinoids in addition to THC and CBD. Each of these compounds has specific healing attributes, but when combined they create what scientists refer to as a holistic “entourage effect,” so that the therapeutic impact of the whole plant is greater than the sum of its single-molecule parts. The Food and Drug Administration, however, isn’t in the business of approving plants as medicine. (See the scientific evidence.)
5. “Psychoactivity Is Inherently An Adverse Side Effect.”
According to politically correct drug war catechism, the marijuana high is an unwanted side effect. Big Pharma is keen on synthesizing medically active marijuana-like molecules that don’t make people high — although it’s not obvious why mild euphoric feelings are intrinsically negative for a sick person or a healthy person, for that matter.
In ancient Greece, the word euphoria meant “having health,” a state of well-being. The euphoric qualities of cannabis, far from being an unwholesome side effect, are deeply implicated in the therapeutic value of the plant.
“We should be thinking of cannabis as a medicine first,” said Dr. Tod Mikuriya, “that happens to have some psychoactive properties, as many medicines do, rather than as an intoxicant that happens to have a few therapeutic properties on the side.”
6. “CBD Is Legal In All 50 States.”
Purveyors of imported, CBD-infused hemp oil claim it’s legal to market their wares anywhere in the United States as long as the oil contains less than 0.3 percent THC. Actually, it’s not so simple.
Federal law prohibits U.S. farmers from growing hemp as a commercial crop, but the sale of imported, low-THC, industrial hemp products is permitted in the United States as long as these products are derived from the seed or stalk of the plant, not from the leaves and flowers. Here’s the catch: Cannabidiol can’t be pressed or extracted from hempseed. CBD can be extracted from the flower, leaves, and, only to a very minor extent, from the stalk of the hemp plant. Hemp oil start-ups lack credibility when they say their CBD comes from hempseed and stalk.
7. “CBD-Only’ Laws Adequately Serve The Patient Population.”
Some U.S. state legislatures have passed “CBD only” (or, more accurately, “low THC”) laws, and other states are poised to follow suit. Some states restrict the sources of CBD-rich products and specify the diseases for which CBD can be accessed; others do not. Ostensibly these laws allow the use of CBD-infused oil derived from hemp or cannabis that measures less than 0.3 percent THC.
But a CBD-rich remedy with little THC doesn’t work for everyone. Parents of epileptic children have found that adding some THC (or THCA, the raw unheated version of THC) helps with seizure control in many instances. For some epileptics, THC-dominant strains are more effective than CBD-rich products.
The vast majority of patients are not well served by CBD-only laws. They need access to a broad spectrum of whole plant cannabis remedies, not just the low THC medicine. One size doesn’t fit all with respect to cannabis therapeutics, and neither does one compound or one product or one strain. (Read more: Prohibition’s Last Gasp: “CBD Only.”)
8. “CBD Is CBD—It Doesn’t Matter Where It Comes From.”
Yes it does matter. The flower-tops and leaves of some industrial hemp strains may be a viable source of CBD (legal issues notwithstanding), but hemp is by no means an optimal source of cannabidiol. Industrial hemp typically contains far less cannabidiol than CBD-rich cannabis. Huge amounts of industrial hemp are required to extract a small amount of CBD, thereby raising the risk of toxic contaminants because hemp is a “bio-accumulator” that draws heavy metals from the soil.
Single-molecule CBD synthesized in a lab or extracted and refined from industrial hemp lacks critical medicinal terpenes and secondary cannabinoids found in cannabis strains. These compounds interact with CBD and THC to enhance their therapeutic benefits.
Back to court
Pharma versus farmer
Cannabis has been a friend to humankind since before the written word, providing fiber for cordage and cloth, seeds for nutrition, and roots, leaves and flowers for ritual and healing. During the Neolithic period, our ancestors discovered uses for every part of cannabis, which was one of the first agricultural crops, perhaps the first, ever to be grown and harvested some 12,000 years ago.
Agriculture, strictly speaking, is not a natural phenomenon. It is an expression of human ingenuity, an invention that has been described as the basis – literally the ground – of modern civilization. “The onset of agriculture was probably one of the most dramatic and important developments in human history,” writes Swiss scientist JÃ¼rg Gertsch, who explores the profound consequences of dietary changes brought on by food cultivation in a recent article in the British Journal of Pharmacology, entitled “Cannabimimetic phytochemicals in the diet – an evolutionary link to food selection and metabolic stress adaptation?”
Gertsch’s provocative thesis is that chronic metabolic disorders, currently a worldwide pandemic, are rooted in “a mismatch between ancient genes and high caloric diets” that ensued with the introduction of agriculture. “The multimillion year evolutionary process during which nearly all genetic change reflected the life circumstances of our ancestors [was] suddenly disturbed” when “carbohydrate farming” supplanted the “hunter-gatherer diet rich in animal food,” says Gertsch, who maintains that “the interplay between diet and the endocannabinoid system” is key to understanding today’s obesity/diabetes crisis and its potential remediation.
The endocannabinoid system, an ancient biological signaling network, regulates numerous physiological processes, including intestinal function, glucose metabolism, and the stress response. A dysregulated endocannabinoid system is implicated in metabolic and bowel pathologies and many other diseases. Gertsch discusses the different, yet complementary, roles of the cannabinoid receptors – CB1 and CB2 – pertaining to diet, digestion, and energy metabolism.
Mammalian CB1 receptors are concentrated in the brain and the central nervous system. They are also present in taste buds and the enteric nervous system (the gut-brain axis). Tetrahydrocannabinol (THC), marijuana’s main psychoactive component, boosts appetite and food intake by binding to the CB1 receptor – a phenomenon playfully known as “the munchies.” But CB1 receptors, as Gertsch points out, “can exert paradoxical effects on food intake,” facilitating essential nourishment as well as metabolic imbalance.
CB1 receptor signaling triggers a newborn’s suckling instinct. Mother’s milk is well endowed with arachidonic acid, a basic building block of the brain’s own marijuana-like compounds, anandamide and 2AG. These endogenous cannabinoid compounds bind to the same cell receptors – CB1 and CB2 – that mediate many of the effects of marijuana. Found in eggs, meat, and dairy products, arachidonic acid intake increases endocannabinoid levels in different tissues and is crucial for pre- and post-natal brain development.
Early hominids lived a precarious wilderness existence, requiring significant physical exertion (hunting and gathering) for survival. Famine, microbial infection, traumatic encounters with predators, fight or flight – all were hallmarks of a pre-agriculturist, subsistence lifestyle. Given the metabolic demands of their large brains and strenuous daily activities, our ancestors needed to consume energy-dense, nutrient-rich food.
In addition to heightening one’s sense of smell and stimulating appetite, CB1 receptor signaling “may facilitate survival after excessive physical activity, stress and trauma by restoring homeostasis, suppressing negative memories and reducing anxiety at the level of the central nervous system,” writes Gertsch, who explains that “CB1 receptor activation is associated with increased energy intake and decreased energy expenditure by controlling neural pathways.”
And CB1 taketh away
Combined with rigorous, day-to-day aerobics, the hunter-gatherer diet did not engender obesity, metabolic problems or cardiovascular disease. But the high-fat hunter-gatherer diet, which served our ancestors well, changed significantly with the advent of cultivated food. “Carbohydrate farming incited the most important dietary transition, which is still ongoing to the present day,” says Gertsch. There is a continuum, he maintains, between plant carbohydrate cultivation of yore and today’s over-starched, over-sweetened and over-processed Western diet.
Grain, carbs, sugar, alcohol, high fructose corn syrup: What started as the basis of civilization has spiraled into a mass-marketed refined sugar binge. “Dietary carbohydrates once essential for the cognitive and social development of Paleolithic humans gradually turned into a metabolic stress factor as a function of their glycemic indices,” Gertsch explains. “Epidemiological evidence points toward a pandemic diet-induced glucose toxicity due to excess sugar intake.”
The endocannabinoid system is deeply implicated in this unhealthy worldwide trajectory. Linked to both motivation and reward, CB1 receptor signaling encourages sugar consumption by enhancing neural responses to sweet flavors. It has been shown that chronic CB1 receptor activation in mice causes obesity-related insulin resistance. Aberrant CB1 activity reinforces a metabolically skewed feedback loop: In obese humans, high endocannabinoid levels are found in the liver, pancreas, adipose tissue, and skeletal muscle, where they contribute to insulin resistance, decreased glucose uptake, oxygen depletion, and cardiometabolic distress.
“The generation and excess use of sugars could be seen in analogy to the detrimental impact of the first distilled alcohol on humans. The sudden availability of excess sugars in combination with fats in diet may have led to a collision of genes that evolved to cope with high energy demands due to constant physical activity,” says Gertsch. “Excessive consumption of high-energy palatable food without physical activity contributes to obesity.” Which, in turn, leads to metabolic syndrome, heart disease, and other degenerative conditions.
CB2 to the rescue
CB1 receptors and CB2 cannabinoid receptors play different roles with respect to diet and nutrition. In animal studies, CB2 receptor activation generally causes the opposite effects of CB1. Whereas CB1 receptors promote appetite and food consumption, CB2 receptors tend to inhibit food intake.1
Expressed primarily in immune cells, adipose (fatty) tissue, and the peripheral nervous system, CB2 receptors confer broad anti-inflammatory effects in various disease models. Noting that obesity is a low-grade inflammatory condition, Gertsch discusses the “protective role of CB2 receptors in diet-induced metabolic malignancies.” Preclinical research indicates that CB2 receptor activity can prevent or ameliorate diabetes-associated peripheral neuropathy and pro-inflammatory obesity. CB2 signaling is also protective against brain damage from strokes, concussions, and neurodegenerative ailments.
Gertsch suggests that the contemporary “mismatch between ancient genes and high caloric diets” might be reconciled in part by CB2’s ability to mediate the effects of secondary plant metabolites (terpenes, flavonoids and other polyphenolic compounds) that are found in kitchen spices, leafy greens, and other vegetables. “Dietary secondary metabolites from vegetables and spices are able to enhance the activity of CB2 receptors and may provide adaptive metabolic advantages and counteract inflammation,” Gertsch reports.
Beta-caryophyllene (BCP), for example, is a seemingly ubiquitous aromatic terpene present in many spices (black pepper, cloves, rosemary, etc.) and bitter greens, as well as in numerous cannabis varietals. This versatile plant compound conveys significant health benefits by directly activating the CB2 receptor and via other molecular pathways. BCP has been shown to stimulate insulin production and inhibit tumor growth in human cell lines. Mounting evidence suggests that a steady diet of BCP-rich foods could prevent or mitigate non-alcoholic fatty liver disease through CB2-mediated channels. Eating green leafy vegetables and spices rich in essential oils “may counteract metabolic stress induced by excessive carbohydrate intake,” Gertsch advises.
Healthy fats, healthy people
Several scientific studies have explored the link between the intake of polyunsaturated fatty acids (PUFAs) and the endocannabinoid system. Docosahexaenoic acid (DHA), an omega-3 fatty acid, is the principal long chain PUFA found in the human brain. (Omega oils are considered “essential” fatty acids because they can’t be produced by the body in sufficient amounts and therefore must be ingested.) Dietary DHA and eicosapentaenoic acid (EPA), another long chain PUFA, support neurological function, retinal development, and overall health by up-regulating CB1 receptor gene expression.2 Preclinical research has shown that administering DHA and EPA prevented glucose intolerance and low-grade inflammation of white adipose tissue in obese mice.
The manifold health benefits of omega-3 PUFAs – prominent in oily fish, walnuts, flax and hempseeds, for example – include the prevention of heart disease, dementia, cancer cell proliferation, insulin resistance, and depression. Low levels of DHA and EPA can lead to premature aging, as well as mental illness. Nutritional omega-3 dietary deficiency “abolishes endocannabinoid-mediated neuronal functions” and is associated with neuropsychiatric disease, according to a 2011 report in Nature Neuroscience. Alzheimer’s sufferers and children with attention deficit hyperactivity disorder tend to be deficient in omega-3 fatty acids.
A healthy balance of omega-3 fatty acids and grain-derived omega-6 fatty acids is fundamental for preventing and managing obesity and metabolic syndrome. But a well-balanced ratio of PUFAs is typically lacking in a carb-heavy Western diet that favors greater omega-6 intake at the expense of omega-3. Gertsch suggests that it is possible “to reprogram energy metabolism” by increasing omega-3 and decreasing the amount of omega-6 in one’s diet: “Generally a lower omega-6 to omega-3 ratio is desirable in reducing the risk of many of the chronic diseases of high prevalence in industrial society or societies with high carbohydrate intake.”
A 2014 paper by Japanese scientists reported that the ratio of dietary omega-6 to omega-3 fatty acids influences how CB1 cannabinoid receptors regulate fear memory. The upshot is that altering the omega-6/omega-3 ratio in one’s diet could improve treatment regimens for anxiety and PTSD, as well as for metabolic disorders. Human beings have evolved in such a way as to have “an advanced capacity to digest and metabolize higher fat diets,” says Gertsch, who concludes that a “low-carb, high fat diet should be the most effective measure against obesity” – with the caveat that a high fat diet must be combined with regular physical exercise, much like in the hunter-gatherer days before agriculture.
Given what scientists know about how the endocannabinoid system functions, there is a strong basis for adopting a high fat, low carb diet with lots of fresh vegetables and spices, both as a general health practice and a remedy for many maladies.