A Beginner’s Guide to Cannabidiol & Cannabis Therapeutics
Reprinted with permission from Project CBD.
In 2009, a handful of CBD-rich cannabis strains were discovered serendipitously in Northern California, America’s cannabis breadbasket, where certified patients could access medical marijuana legally. Thus began a great laboratory experiment in democracy involving CBD-rich cannabis therapeutics.
The advent of whole plant CBD-rich oil as a grassroots therapeutic option has changed the national conversation about cannabis. It’s no longer a question of whether medical marijuana works—today the key question is how to use cannabis for maximum therapeutic benefit.
But most health professionals have little experience in this area. So Project CBD has created a CBD User’s Manual for patients that addresses key questions about cannabidiol and cannabis therapeutics.
What is CBD?
Cannabidiol or CBD is a non-intoxicating component of the cannabis plant with enormous therapeutic potential. Although CBD doesn’t make people feel high like THC does, it’s causing quite a buzz among scientists, health professionals, and medical marijuana patients who are using CBD-rich products to treat a wide range of conditions—chronic pain, cancer, Crohn’s, diabetes, rheumatoid arthritis, PTSD, cardiovascular disease, anxiety, antibiotic-resistant infections, multiple sclerosis, schizophrenia, and more. Academic research centers in the United States and elsewhere are currently studying the effects of CBD on these and other ailments. Scientists refer to CBD as a “promiscuous” compound because it confers therapeutic benefits in many different ways while tapping into how we function physiologically and biologically on a deep level. Extensive preclinical research and some clinical studies have shown that CBD has strong antioxidant, anti-inflammatory, anticonvulsant, anti-depressant, antipsychotic, anti-tumoral, and neuroprotective qualities. Cannabidiol can change gene expression and remove beta amyloid plaque, the hallmark of Alzheimer’s, from brain cells.
Which is better CBD or THC?
Cannabidiol and THC (The High Causer) are the power couple of cannabis therapeutics; they work best together. CBD and THC interact synergistically to potentiate each other’s curative qualities. CBD enhances THC’s painkilling and anticancer properties, while lessening THC’s intoxicating effects. CBD can also mitigate adverse effects caused by too much THC, such as anxiety and rapid heartbeat. When both compounds are present in sufficient amounts in the same cannabis strain or product, CBD will lower the ceiling on the THC high while prolonging its duration. (“Relaxing but not intoxicating” is how one patient described CBD-rich cannabis.) CBD broadens the range of conditions treatable with cannabis, such as liver, cardiovascular and metabolic disorders, which may be less responsive to THC-dominant remedies. CBD and THC both stimulate neurogenesis, the creation of new brain cells, in adult mammals.
What’s the best way to take CBD?
The most appropriate delivery system for CBD-rich cannabis is one that provides an optimal dose for a desired duration with few unwanted side effects. CBD-rich cannabis flower varietals for smoking or vaping are available in many medical marijuana dispensaries, but most CBD patients prefer non-inhalable products made with cannabis oil concentrates. Although banned by federal law, measurable doses of potent CBD-rich cannabis remedies are available in many non-smokable forms and can be utilized in various ways. The time of onset and duration of effect vary depending on the method of administration. CBD-rich cannabis oil products can be taken sublingually, orally (as edibles, lozenges, beverages, tinctures, and gel caps), or applied topically. Concentrated cannabis oil extracts can also be heated and inhaled with a vape pen. Inhalation is good for treating acute symptoms that require immediate attention; the effects can be felt within a minute or two and typically last for a couple of hours. The effects of orally administered CBD-rich cannabis oil can last for four hours or more, but the onset of effects is much slower (30-90 minutes) than inhalation.
Can CBD cure epilepsy?
Marijuana has a rich history as a medicine for quelling seizures and convulsions going back thousands of years. In the mid-19th century, the U.S. Pharmacopeia listed cannabis tincture as a treatment for pediatric epilepsy, and subsequent scientific studies have documented the anticonvulsant effects of CBD, THC, and whole plant cannabis. CBD-dominant/low- THC cannabis strains and oil extracts can facilitate dramatic improvement in some children with intractable seizure disorders. Between 10-15 percent of severe childhood epileptics who are given CBD oil products experience a near complete cessation of seizures; most improve (with a decrease but not total elimination of seizures); and some children have worse seizures when they take CBD. Many parents of epileptic children have learned through trial and error that augmenting CBD-rich oil by adding some THC—or better yet, THCA, the unheated, non-psychoactive form of THC that’s present in raw cannabis flowers and leaves—helps with seizure control. The take-home message: Low-THC cannabis oil products don’t work for everyone. Patients of all ages need access to a wide spectrum of whole plant cannabis remedies, not just high CBD oil.
What is the right CBD:THC ratio for me?
Cannabis therapeutics is personalized medicine. There is no single ratio or strain or product that’s right for everyone. Optimize your therapeutic use of cannabis by finding the proper combination of CBD and THC that works best for you. A person’s sensitivity to THC is a key factor in determining the appropriate ratio and dosage of CBD-rich medicine. Many people enjoy the cannabis high and can consume reasonable amounts of any cannabis product without feeling too high or dysphoric. Others find THC unpleasant. CBD can lessen or neutralize the intoxicating effects of THC. So a greater ratio of CBD-to- THC means less of a high. In some states with medical marijuana laws, cannabis oil concentrates and other products with varying ratios of CBD:THC are available so users can adjust or minimize psychoactive effects to suit their needs and sensitivities. Those who don’t like THC have the option of healing without the high by using a CBD-rich remedy with only a small amount of THC. But a low THC remedy, while not intoxicating, is not always the most effective treatment option. 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.
Are specific CBD:THC ratios better for different conditions?
Some patterns are beginning to emerge. For anxiety, depression, spasms, psychosis, and seizure disorders, many people report they do well starting with a small dose of a CBD-rich remedy with little THC. For cancer, autism, and many other diseases, some say they benefit more from a balanced ratio of CBD and THC. Extensive clinical trials conducted outside the United States have shown that a 1:1 CBD:THC ratio can be effective for neuropathic pain. Some people use cannabis products with different CBD:THC ratios at different times of the day (more CBD for sunlight hours, more THC at night). Almost any cannabis strain or product theoretically could benefit a wide range of autoimmune and inflammatory disorders because THC and other cannabis components activate the CB2 cannabinoid receptor, which regulates immune function. Note: The CBD:THC ratio in not an indication of how much CBD or THC is present in a given cannabis product or strain.
What is the optimal dosage of CBD?
An effective dosage can range from as little as a few milligrams of CBD-enriched cannabis oil to a gram or more. Begin with a small dose of high CBD/low THC oil, especially if you have little or no experience with cannabis. Take a few small doses over the course of the day rather than one big dose. Use the same dose and ratio for several days. Observe the effects and if necessary adjust the ratio or amount. Don’t overdo it. Cannabis compounds have biphasic properties, which means that low and high doses of the same substance can produce opposite effects. Small doses of cannabis tend to stimulate; large doses sedate. Too much THC, while not lethal, can amplify anxiety and mood disorders. CBD has no known adverse side effects, but an excessive amount of CBD could be less effective therapeutically than a moderate dose. “Less is more” is often the case with respect to cannabis therapy.
What should one look for when choosing a CBD-rich product?
Look for products with clear labels showing the quantity and ratio of CBD and THC per dose, a manufacturing date, and a batch number (for quality control). Select products with quality ingredients: No corn syrup, trans fats, GMOs, artificial additives, thinning agents or preservatives. CBD-rich products should be lab tested for consistency and verified as being free of mold, bacteria, pesticides, solvent residues, and other contaminants. Best to avoid products extracted with toxic solvents like BHO, propane, hexane or other hydrocarbons. Opt for products that utilize safer extraction methods such as supercritical CO2 or food-grade ethanol.
If CBD is so good, won’t pure CBD be even better?
Single-molecule CBD will inevitably become a federally approved Big Pharma medicine. Products infused with a crystalline CBD isolate, derived and extensively refined from industrial hemp, are already being marketed by unregulated internet storefronts. But single-molecule CBD is less effective therapeutically than whole plant CBD-rich oil extract. Scientific studies have established that synthetic, single-molecule CBD has a very narrow therapeutic window and requires precise, high doses for efficacy, whereas lower dose, whole-plant, CBD-rich treatment regimens are already showing efficacy for many conditions among patients in medical marijuana states. Whether synthesized in a Big Pharma lab or derived from industrial hemp, single-molecule CBD lacks critical secondary cannabinoids and other medicinal compounds found in high-resin cannabis strains. These compounds interact with CBD and THC to enhance their therapeutic benefits. Scientists call this the “entourage effect.” Numerous cannabis compounds have medicinal attributes, but the therapeutic impact of whole plant cannabis is greater than the sum of its parts.
Is there a difference between CBD derived from hemp and CBD derived from marijuana?
If you live in a state where medical marijuana is legal and available, look for CBD products made from high-resin cannabis (rather than low resin industrial hemp) that are sold in medical marijuana dispensaries. Hemp-derived CBD-infused products of varying quality are also available via dozens of internet storefronts. Compared to whole plant CBD-rich cannabis, industrial hemp is typically low in cannabinoid content. A huge amount of hemp is required to extract a small amount of CBD, thereby raising the risk of contaminants because hemp, a bioaccumulator, draws toxins from the soil. That’s a great feature for restoring a poisoned ecosystem, but it’s not recommended for extracting medicinal oil. Heavily refined CBD paste or terpene-free CBD powder is poor starter material for formulating CBD-rich oil products. The FDA has tested dozens of so-called CBD “hemp oil” products and found that in many cases these products contained little or no CBD. CBD-infused nutraceuticals have not been approved by the FDA as food supplements; nor are these products legal in all 50 U.S. states. By and large, however, interstate CBD commerce is tolerated by federal authorities.
Is it safe to inhale hemp CBD oil fumes from a vape pen?
Many cannabis- and hemp-derived CBD vape oil products include a thinning agent, which dilutes the oil that is heated and inhaled by vape pen users. Beware of vape pen oil that contains propylene glycol. When overheated, this chemical additive produces formaldehyde, a carcinogen, as a byproduct, according to a 2015 report in the New England Journal of Medicine. Why do so many vape oil products contain this thinning agent? It’s because of the dubious quality of the extracted material from which these unregulated cannabis oil products are made.
Does CBD have any adverse side effects? What about drug interactions?
CBD is a very safe substance, but patients taking other medications should check with their doctor about drug interactions, which are more likely when consuming high doses of single-molecule CBD products. At sufficient dosages, CBD will temporarily deactivate cytochrome P450 enzymes, thereby altering how we metabolize a wide range of compounds, including THC. Cytochrome P450 enzymes metabolize more than 60 percent of Big Pharma meds. CBD is a more potent inhibitor of cytochrome P450 than the grapefruit compound Bergapten, so ask your doctor if grapefruit interacts with your medication. If grapefruit does, then CBD probably does, too. Patients on a CBD-rich treatment regimen should monitor changes in blood levels of prescription medications and, if need be, adjust dosage.
Will big pharmaceutical companies control the CBD market when cannabis is legalized for adult use?
Only if we let them. Cannabis is a medicinal herb and it should be regulated as an herb, not as a pharmaceutical or a street drug.
How CBD Works
Cannabidiol (CBD), a non-intoxicating component of the marijuana plant, has generated significant interest among scientists and physicians in recent years—but how CBD exerts its therapeutic impact on a molecular level is still being sorted out by scientists. Cannabidiol is a pleiotropic drug in that it produces many effects through multiple molecular pathways.
Although CBD has little binding affinity for either of the two cannabinoid receptors (CB1 and CB2), cannabidiol activates several non-cannabinoid receptors and ion channels. CBD also acts through various receptor-independent channels—for example, by delaying the “reuptake” of endogenous neurotransmitters (such as anandamide and adenosine) and by enhancing or inhibiting the binding action of certain G-coupled protein receptors.
Here are some of the ways that CBD confers its manifold therapeutic effects.
Serotonin Receptors
Jose Alexandre Crippa and his colleagues at the University of San Paulo in Brazil and King’s College in London have conducted pioneering research into CBD and the neural correlates of anxiety. At high concentrations, CBD directly activates the 5-HT1A (hydroxytryptamine) serotonin receptor, thereby conferring an anti-anxiety effect. This G-coupled protein receptor is implicated in a range of biological and neurological processes, including (but not limited to) anxiety, addiction, appetite, sleep, pain perception, nausea and vomiting.
5-HT1A is a member of the family of 5-HT receptors, which are activated by the neurotransmitter serotonin. Found in both the central and peripheral nervous systems, 5-HT receptors trigger various intracellular cascades of chemical messages to produce either an excitatory or inhibitory response, depending on the chemical context of the message.
CBDA [Cannabidiolic acid], the raw, unheated version of CBD that is present in the cannabis plant, also has a strong affinity for the 5-HT1A receptor (even more so than CBD). Preclinical studies indicate that CBDA is a potent anti-emetic, stronger than either CBD or THC, which also have anti-nausea properties.
Vanilloid Receptors
CBD directly interacts with various ion channels to confer a therapeutic effect. CBD, for example, binds to TRPV1 receptors, which also function as ion channels. TRPV1 is known to mediate pain perception, inflammation and body temperature.
TRPV is the technical abbreviation for “transient receptor potential cation channel subfamily V.” TRPV1 is one of several dozen TRP (pronounced “trip”) receptor variants or subfamilies that mediate the effects of a wide range of medicinal herbs. Scientists also refer to TRPV1 as a “vanilloid receptor,” named after the flavorful vanilla bean. Vanilla contains eugenol, an essential oil that has antiseptic and analgesic properties; it also helps to unclog blood vessels. Historically, the vanilla bean has been used as a folk cure for headaches. CBD binds to TRPV1, which can influence pain perception.
Capsaicin—the pungent compound in hot chili peppers—activates the TRVP1 receptor. Anandamide, the endogenous cannabinoid, is also a TRPV1 agonist.
GPR55—orphan receptors
Whereas cannabidiol directly activates the 5-HT1A serotonin receptor and several TRPV ion channels, some studies indicate that CBD functions as an antagonist that blocks, or deactivates, another G protein-coupled receptor known as GPR55.
GPR55 has been dubbed an “orphan receptor” because scientists are still not sure if it belongs to a larger family of receptors. GPR55 is widely expressed in the brain, especially in the cerebellum. It is involved in modulating blood pressure and bone density, among other physiological processes. GPR55 promotes osteoclast cell function, which facilitates bone reabsorption. Overactive GPR55 receptor signaling is associated with osteoporosis. GPR55, when activated, also promotes cancer cell proliferation, according to a 2010 study by researchers at the Chinese Academy of Sciences in Shanghai. This receptor is expressed in various types of cancer. CBD is a GPR55 antagonist, as University of Aberdeen scientist Ruth Ross disclosed at the 2010 conference of the International Cannabinoid Research Society in Lund, Sweden. By blocking GPR55 signaling, CBD may act to decrease both bone reabsorption and cancer cell proliferation.
PPARs – nuclear receptors
CBD also exerts an anti-cancer effect by activating PPARs [peroxisome proliferator activated receptors] that are situated on the surface of the cell’s nucleus. Activation of the receptor known as PPAR-gamma has an anti-proliferative effect as well as an ability to induce tumor regression in human lung cancer cell lines. PPAR-gamma activation degrades amyloid-beta plaque, a key molecule linked to the development of Alzheimer’s disease. This is one of the reasons why cannabidiol, a PPAR-gamma agonist, may be a useful remedy for Alzheimer’s patients.
PPAR receptors also regulate genes that are involved in energy homeostasis, lipid uptake, insulin sensitivity, and other metabolic functions. Diabetics, accordingly, may benefit from a CBD-rich treatment regimen.
CBD as a reuptake inhibitor
How does CBD, an exogenous plant compound, get inside a human cell to bind to a nuclear receptor? First it has to pass through the cell membrane by hitching a ride with a fatty acid binding protein (FABP), which chaperones various lipid molecules into the cell’s interior. These intracellular transport molecules also escort tetrahydrocannabinol (THC) and the brain’s own marijuana-like molecules, the endocannabinoids anandamide and 2AG, across the membrane to several targets within the cell. CBD and THC both modulate receptors on the surface of the nucleus, which regulate gene expression and mitochondrial activity.
CBD also exerts an anti-cancer effect by activating PPARs on the surface of the cell’s nucleus.
Cannabidiol, it turns out, has a strong affinity for three kinds of FABPs, and CBD competes with our endocannabinoids, which are fatty acids, for the same transport molecules. Once it is inside the cell, anandamide is broken down by FAAH [fatty acid amide hydrolase], a metabolic enzyme, as part of its natural molecular life cycle. But CBD interferes with this process by reducing anandamide’s access to FABP transport molecules and delaying endocannabinoid passage into the cell’s interior.
According to a team of Stony Brook University scientists, CBD functions as an anandamide reuptake and breakdown inhibitor, thereby raising endocannabinoid levels in the brain’s synapses. Enhancing endocannabinod tone via reuptake inhibition may be a key mechanism whereby CBD confers neuroprotective effects against seizures, as well as many other health benefits.
CBD’s anti-inflammatory and anti-anxiety effects are in part attributable to its inhibition of adenosine reuptake. By delaying the reuptake of this neurotransmitter, CBD boosts adenosine levels in the brain, which regulates adenosine receptor activity. A1A and A2A adenosine receptors play significant roles in cardiovascular function, regulating myocardial oxygen consumption and coronary blood flow. These receptors have broad anti-inflammatory effects throughout the body.
CBD as an allosteric modulator
CBD also functions as an allosteric receptor modulator, which means that it can either enhance or inhibit how a receptor transmits a signal by changing the shape of the receptor.
Australian scientists report that CBD acts as a “positive allosteric modulator” of the GABA-A receptor. In other words, CBD interacts with the GABA-A receptor in a way that enhances the receptor’s binding affinity for its principal endogenous agonist, gamma-Aminobutyric acid (GABA), which is the main inhibitory neurotransmitter in the mammalian central nervous system. The sedating effects of Valium and other Benzos are mediated by GABA receptor transmission. CBD reduces anxiety by changing the shape of the GABA-A receptor in a way that amplifies the natural calming effect of GABA.
Canadian scientists have identified CBD as a “negative allosteric modulator” of the cannabinoid CB1 receptor, which is concentrated in the brain and central nervous system. While cannabidiol doesn’t bind to the CB1 receptor directly like THC does, CBDinteracts allosterically with CB1 and changes the shape of the receptor in a way that weakens CB1’s ability to bind with THC.
As a negative allosteric modulator of the CB1receptor, CBD lowers the ceiling on THC’s intoxicating effects—which is why people don’t feel as “high” when using CBD-rich cannabis compared to when they consume THC-dominant medicine. A CBD-rich product with little THC can convey therapeutic benefits without having a euphoric or dysphoric effect.
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