CBD : The Cinderella Molecule, Martin A. LEE, projectCBD.org, 2017

Martin A. Lee

On February 09, 2017
Originally published in High Times (Feb. 2017)
High Times cover story by Martin A Lee highlights the breakthrough research on CBD, and how it has revolutionized the story of cannabis medicine.

“This changes everything!” That was the immediate reaction of Bay Area journalist Fred Gardner as he stood in the office of Steep Hill Laboratory in Oakland and eyed a chromatogram showing the unusual cannabinoid content of a hitherto unknown marijuana strain. The year was 2009, and the strain of interest, an oddity called Soma A-Plus, didn’t top the charts with THC (tetrahydrocannabinol), aka The High Causer, unlike several thousand other bud samples that Steep Hill had previously tested for California medical marijuana dispensaries and growers.

Soma A-Plus was the first of a handful of soon-to-be discovered cannabis strains imbued with a significant amount of cannabidiol (CBD), a compound with intriguing medical attributes. One of these strains, Women’s Collective Stinky Purple, tipped the scales at over ten percent CBD by dry weight with little THC. This genetic anomaly wasn’t hemp—it was a drug plant, a high resin CBD-rich marijuana strain brimming with medicated goo. But anyone who smoked it or consumed it as an edible wouldn’t get high because CBD is not psychoactive like THC. CBD can actually lessen or neutralize the THC high depending on how much of each compound is in a given strain or product.

Traditionally, cannabis grown for hashish contained roughly equal amounts of THC and CBD. Since the late 1970s, however, cannabis genetics has changed as renegade breeders in Northern California catered to consumer demand for stonier THC-dominant varietals. Consequently, CBD nearly vanished from the grassroots gene pool in the Emerald Triangle, America’s cannabis breadbasket.

When Californians passed Prop 215, the statewide ballot measure that legalized cannabis for medical use, few people knew about CBD. It wasn’t on anyone’s radar, except for a small group of scientific pioneers who were probing marijuana’s molecular mechanisms and healing potential. Early studies indicated that CBD had noteworthy anti-inflammatory, anti-tumoral, antipsychotic, and anticonvulsant properties with no known adverse side effects.

Fred Gardner had been covering the CBD science story in O’Shaughnessy’s, the journal of cannabis in clinical practice. In 2010, he and I would launch Project CBD, an educational nonprofit that reported on the entire CBD phenomenon—the research, the patients, the doctors, new strains and products, the business angles. Right from the start we sensed that CBD could be a game-changer for the medical marijuana movement. We thought it might be the key to liberating marijuana from the confines of the drug abuse paradigm. How could the pretzel logicians in the drug czar’s office justify the ongoing prohibition of CBD-rich cannabis, a safe medicinal substance with no adverse side effects that doesn’t even get you high?

The advent of CBD-infused products meant that a lot more people—including those who aren’t into getting stoned—would be open to using marijuana for health reasons. Not everyone enjoys the THC high; some folks get edgy and anxious on weed. CBD-rich cannabis might be the answer for those who want to experience marijuana’s health benefits without the buzz. We referred to it as “CBD-rich” (rather than “high CBD”) cannabis to get away from the stoner connotation — and that designation has since been adopted by medical scientists in peer-reviewed publications.

A Tipping Point

The serendipitous rediscovery of CBD in Northern California would upset everyone’s applecart—stoners as well as cops—and usher in a new era of cannabis therapeutics. The crucial tipping point came in the summer of 2013, when CNN broadcast Sanjay Gupta’s special on medical marijuana that featured the now famous case of Charlotte Figi, a young girl from Colorado who suffered from Dravet’s Syndrome.

Little Charlotte was having hundreds of epileptic seizures a week and pharmaceuticals weren’t helping. Her parents thought they had run out of options when they heard about a boy with Dravet’s in California who responded well to CBD-rich cannabis oil. They found a high CBD/low THC strain at a Colorado cannabis dispensary and it worked like a charm for their daughter, reducing her seizures to a couple a month. That strain is now called Charlotte’s Web in her honor.

Suddenly, the CBD genie was out of the bottle. A national television audience was stunned by what they saw and heard: Marijuana, once slandered as “the Assassin of Youth,” could save the lives of desperately ill children. And what’s more, kids and grown-ups don’t have to get stoned to get better if they use medical marijuana. The idea that it might be possible to access the therapeutic upside of marijuana sans euphoria or dysphoria would prove irresistible to a lot of people after the CNN special.

But along with a growing awareness of cannabidiol as a potential health aide, there has also been a proliferation of misconceptions about CBD-rich cannabis, a remarkable botanical that befriended humankind before the written word. Cannabis has a rich history as a source of fiber, food and medicine in many countries going back thousands of years. But our ancient connection with this plant and our knowledge of its utility as a versatile folk medicine was broken by marijuana prohibition. Thus, we’ve had to recreate a rapport with cannabis and relearn how to use it for maximum therapeutic benefit.

Some might wonder: Why not just spark a phatty and inhale? That seems to do the trick for a lot of people. Actually, it’s gotten a lot more complicated now that there are potent cannabis oil extracts with different ratios of THC and CBD to choose from and various ways to administer them. Figuring out how to harness the curative qualities of cannabis is still a work in progress. It’s the driving force behind the great laboratory experiment in democracy known as medical marijuana that’s been unfolding state-by-state in recent years.

The Big Breakthrough

For a long time, the illegality of marijuana has acted as a deterrent to scientific research in the United States. Ironically, it was President Ronald Reagan who advanced our understanding of the scientific basis of cannabis therapeutics when he escalated and militarized the war on drugs in the 1980s. The Reagan administration poured tens of millions of dollars into research that would prove once and for all that marijuana damages the brain—or so they thought. After all, this was the Evil Weed and it was an article of faith within the drug war establishment that smoking marijuana caused brain damage.

But rather than showing how marijuana harms the brain, the Reagan administration ended up subsidizing a series of studies that culminated in the discovery of “the endocannabinoid system,” which actually protects the brain when activated by plant cannabinoids like THC and CBD. This major scientific breakthrough opened up whole new vistas of understanding human biology and went a long way toward explaining how and why cannabis is such a multifaceted medicine—and why it’s the most popular illicit herb on the planet.

By the mid-1990s, the endocannabinoid system had emerged as a hot topic among scientists around the world who shared their findings in highly technical peer-reviewed journals and at annual meetings of the recently formed International Cannabinoid Research Society. There ensued an avalanche of scientific data attesting to the jaw-dropping therapeutic potential of CBD and other cannabinoid compounds.

A 1998 preclinical study funded by the National Institutes of Health became the basis for a U.S. government patent on the antioxidant and neuroprotective properties of CBD and THC, which were found to limit “neurological damage following ischemic insults, such as stroke and trauma.” Both compounds were described as having “particular application… in the treatment of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and HIV dementia.”

And that’s just for starters when it comes to cannabidiol. Some highlights from the exploding field of cannabis therapeutics:

  • Cancer: Scientists at the California Pacific Medical Center showed that CBD reduces breast cancer cell proliferation, invasion and metastasis in human cell line experiments.
  • Diabetes: Israeli researchers reported that CBD “lowers incidence of diabetes in non-obese diabetic mice.”
  • Epilepsy: British scientists noted that CBD exerts anti-convulsant effects in animal models of epilepsy.
  • Mood disorders: Brazilian investigators explored CBD’s potent anti-psychotic and anti-anxiety properties.
  • Acne: The Journal of Clinical Investigation (2014) reports that “CBD has potential as a promising therapeutic agent for the treatment of acne vulgaris.”
  • Irregular heartbeat: The British Journal of Pharmacology (2010) disclosed that CBD suppresses stroke-induced cardiac arrhythmia in animals and reduces the size of brain damage.
  • Stem cell neurogenesis: German scientists discovered that CBD stimulates the growth of new brain cells in adult mammals.
  • Antibacterial: According to the Journal of Natural Products (2008) published by the American Chemical Society, CBD “showed potent activity against a variety of methicillin-resistant Staph (MRSA) strains.” The World Health Organization has identified antibiotic resistant bacteria as a major global health crisis.
  • Mad Cow Disease: There is no known cure for Mad Cow, a deadly infectious brain disease transmitted by misshaped proteins called “prions,” but French scientists reported in the Journal of Neuroscience that “CBD may protect neurons against the multiple molecular and cellular factors involved in the different steps of the neurodegenerative process, which takes place during prion infection.”

Mad fucking cow disease!

And the list goes on: Rheumatism, PTSD, depression, gut issues, obesity, alcoholism, liver disease… Extensive preclinical research and mounting anecdotal reports suggest that these and many other conditions may be responsive to CBD-rich remedies.

Power Couple : CBD & THC

There’s a lot of excitement about cannabidiol—with good reason. Thus far, however, clinical trials that could “prove” CBD’s therapeutic utility have gotten short shrift in the United States because of the war on drugs. Consequently, most of what scientists know about CBD is based largely on preclinical lab research—animal studies, molecular probes, test tube experiments, etc.—rather than human studies. Some of this research has yielded important insights into the endocannabinoid system and its crucial role in health and disease. But data from animal models are not always applicable to human experience.

Outside the United States, CBD-rich remedies have been subjected to rigorous clinical trials and approved for therapeutic use in more than two-dozen countries. Sativex, a sublingual cannabis spray that contains equal amounts of CBD and THC, is available by prescription (though not yet in the U.S.) for treating neuropathic pain and spasms associated with multiple sclerosis. GW Pharmaceuticals, the British firm that produces Sativex, determined that a combination of CBD and THC is more effective than either compound alone for pain management.

Simply put, CBD and THC are the power couple of cannabis therapeutics; they work best together. CBD and THC amplify each other’s curative qualities by activating different receptors in the brain. This synergistic dynamic is all-important for medical patients. It’s the reason why THC is key to maximizing the therapeutic potential of CBD, and vice versa.

Cannabis oil concentrates with varying CBD:THC ratios are available in medical marijuana dispensaries so patients can adjust or eliminate psychoactive effects to suit their needs. When present in roughly equal amounts in a cannabis strain or product, CBD will prolong the THC buzz while lowering the ceiling on THC’s psychoactivity. These days, cannabis patients also have the option of healing without the high by using a CBD product with only a small amount of THC. But a low THC oil or flower, while not intoxicating, is not necessarily the best treatment modality.

One’s sensitivity to THC is a major factor in determining the optimal ratio and dosage of CBD-rich medicine. There’s no single ratio or dosage that’s right for everyone. Cannabis therapeutics is personalized medicine. Patients may need to experiment, dial in, and, if need be, adjust their treatment regimen until they find their own sweet spot with the right balance of CBD and THC. In essence, the goal is to administer consistent, measurable doses of a CBD-rich remedy that includes as much THC as a person is comfortable with.

If you are lucky enough to live in a state with a robust medical marijuana program, there are lots of possibilities if want to use CBD-rich cannabis without smoking it. CBD-rich cannabis—like the stony stuff—comes in many non-smokable forms: edibles, lozenges, beverages, gel caps, sublingual sprays, tinctures, topical ointments, transdermal patches, suppositories, and more. All the different choices can be confusing, especially for those who are newcomers to cannabis.

Product safety is a major concern given that the marijuana industry is still largely unregulated. Unfortunately, many cannabis farmers use pesticides and dubious plant hormone boosters to increase cannabinoid content and crop yield. Look for CBD-rich products that are lab tested and are verified as being free of mold, pesticides, solvent residues and other contaminants. Better, if possible, to avoid cannabis oil that’s been extracted with butane, hexane and other toxic solvents; opt for safer extraction methods, such as food-grade ethanol or supercritical CO2. A high quality, CBD-rich product should include only high quality ingredients: no corn syrup, transfats, preservatives, and other artificial additives. Products should have clear labels showing the quantity of CBD and THC per dose. Keep in mind that the CBD:THC ratio is not an indication of how much of each compound is actually in the product.

Industrial Hemp

What about CBD oil extracted from industrial hemp? Internet storefronts are peddling unregulated hemp-derived CBD products to all fifty states, despite that fact that cannabidiol is not a FDA-approved dietary supplement. For many people, particularly those living in states where medical marijuana is not yet legal, hemp-derived CBD may be their only practical option for now, even though it’s technically still a Schedule One controlled substance.

The federal government arbitrarily defines hemp—as distinct from marijuana—as a cannabis plant with 0.3 percent THC or less. What actually distinguishes hemp from marijuana is resin content: Hemp is low resin cannabis; marijuana is high resin cannabis. CBD and THC are contained in the resin. High resin drug plants include euphoric THC-rich plants and non-euphoric CBD-rich plants (as well as various combinations of both).

Low resin industrial hemp is not an optimal source of CBD-rich oil. Fiber hemp is basically useless for extracting CBD, as there is hardy any resin on the stalk. The skimpy foliage of industrial hemp grown for nutritious seed oil (and other uses) maxes out at about 3.5 percent CBD by dry weight, but there’s no CBD or THC in the seeds themselves. Compare this to the ACDC strain, a non-euphoric, high resin marijuana varietal widely grown in California, which contains 20 percent CBD by dry weight.

The 0.3 percent THC legal limit for industrial hemp is an impractical, scientifically baseless distinction designed to maintain marijuana prohibition. In an effort to circumvent the law, some farmers in Colorado and other states are growing high resin CBD-rich marijuana and calling it hemp; they harvest their crop early to minimize THC content. Growing industrial hemp outside the parameters of strictly implemented, state-sanctioned pilot research is still forbidden by the federal government.

For hemp farmers abroad, CBD paste is typically a byproduct of industrial hemp grown for another purpose. Farmers sell leftover hemp biomass to businesses that extract CBD oil. It’s not great starter material for making a CBD product because huge amounts of low resin hemp refuse are required to extract a small amount of CBD. The more plant material one extracts from, the greater the risk of contaminants because hemp is a “bio-accumulator” that draws toxins from the soil. That’s a great feature for cleaning up a poisoned environment—hemp was planted near Chernobyl after the nuclear disaster for this purpose — but it’s exactly what you don’t want in a medicine.

Thus far, CBD commerce proliferates online with little interference from the federal government other than FDA warning letters to several CBD hemp oil retailers for mislabeling products and making unproven medical claims. Some CBD products tested by the FDA had little or no CBD. Even more disconcerting is what’s actually in these items. Many if not most CBD hemp oil vape cartridges contain propylene glycol, a thinning agent that is carcinogenic when overheated and inhaled. Flavoring agents are also ubiquitous in CBD hemp oil cartridges, yet few of these ingestible food additives have been safety tested for inhalation. Some are known to be toxic.

You might find serviceable products marketed as CBD hemp oil if you’re willing to take a chance on the vagaries of online meds. It’s somewhat of a crapshoot, but some of these products may provide health benefits. Low THC cannabis oil extracts have been a godsend for a number of children with intractable seizure disorders. There are accounts of epileptic kids who experience a near complete cessation of seizures when they utilize CBD oil products. But for many other seizure disorder sufferers, adults as well as children, CBD doesn’t do the trick. It’s not a miracle cure for everyone.

The therapeutic range of CBD hemp oil is significantly limited by the small amount of THC and other cannabinoids contained therein. Many medical marijuana patients have learned through trial and error that augmenting CBD-rich oil by adding some THC — or THCA, the unheated, non-psychoactive form of THC that’s present in raw cannabis flowers and leaves—helps to keep seizures and other symptoms at bay. Low-THC cannabis oil products don’t work for everyone. People of all ages need access to a full spectrum of whole plant cannabis remedies, not just low-THC oil.

Molecule Versus Plant

CBD will soon become a single-molecule pharmaceutical. When Epidiolex, an almost-pure CBD anti-seizure remedy developed by GW Pharmaceuticals, gets a green light from the FDA, cannabidiol will join single-molecule THC (Marinol) as a legally available prescription medication. But the cannabis plant itself will remain federally illegal for the foreseeable future. Go figure.

Project CBD recognizes that single molecule CBD is not the same as whole plant CBD-rich cannabis, which includes hundreds of medicinally active components. Whether synthesized in a lab or heavily refined from industrial hemp paste, “pure CBD” products lack the full array of medicinal terpenes and minor phytocannabinoids found in marijuana. These compounds interact with CBD and THC to create what scientists refer to as an “entourage” or “ensemble” effect, so that the therapeutic impact of the whole plant is greater than the sum of its parts.

It’s not that single-molecule CBD won’t work—pure CBD might be helpful in certain cases, but whole plant CBD has a much wider therapeutic window than CBD as an isolate. This was underscored in a 2015 experiment by Israeli scientists who found that single-molecule CBD required a much higher dose to be effective as compared to whole plant CBD-rich oil. Moreover, if one missed the mark slightly, either too low or too high, then single-molecule CBD had little impact on pain and inflammation—unlike whole plant CBD-rich oil, which was effective at a much lower, and broader, dosage range. Problematic interactions with other drugs are also more likely with high doses of single molecule CBD. “The therapeutic synergy observed with plant extracts results in the requirement for a lower amount of active components, with consequent reduced adverse effects,” the Israeli researchers concluded. Other scientists have reported similar findings.

CBD is a mighty molecule, to be sure, but the whole plant is mightier.

Martin A. Lee is the director of Project CBD and the author of several books, including Smoke Signals: A Social History of Marijuana—Medical, Recreational and Scientific and Acid Dreams: The Complete Social History of LSD—the CIA, the Sixties and Beyond.