There are few nutraceuticals that have generated such confusion as hemp oil/CBD (cannabidiol). There are two major sources for that confusion. The first is the plethora of claims being made about the health benefits of hemp oil/CBD. Which of the claims actually have any supportive research substantiation them? The second, and even murkier, source of confusion is the actual regulatory status of hemp oil/CBD. In this article, I will attempt to provide evidence that, hopefully, will shed some light on the confusion. Let’s start with a little background.
Hemp vs. Marijuana
The prevailing wisdom is that hemp and marijuana are both derived from the same plant, Cannabis sativa, and that years of plant breeding and manipulation has resulted in two primary varieties. The “marijuana variety” contains significant amounts of a psychoactive compound called Δ9-tetrahydrocannabinol, or THC for short. The properties of marijuana make this plant the most widely used illicit drug in Western societies—although 29 states and the District of Columbia currently have laws broadly legalizing it in some form. As a psychoactive plant, cannabis is also one with the longest recorded history of human use, with evidence found as early as 5,000 years ago in an herbarium published during the reign of the Chinese Emperor Chen Nung.1
In addition to THC, marijuana contains other cannabinoid compounds, which are not psychoactive. Some of these same, non-psychoactive compounds, such as CBD are found in hemp. These other cannabinoids provide a variety of medicinal effects unrelated to getting high. In fact, this was recognized as early as the third millennium BCE when Chinese texts described the usefulness of cannabis extracts in the relief of pain and cramps, and more than 3,000 years ago when its anxiety relieving effects were recorded in ancient Indian texts.2 Currently, specific hemp oil extracts, lacking significant THC content, but providing other cannabinoids, are used for similar purposes.3
But is it true that marijuana and hemp really come from the same plant? Maybe not! There are two species or gene pools, Cannabis sativa and Cannabis indica that are widely used in describing the pedigree or appearance of cultivated cannabis plants. According to recently published research by Sawler et al., the genotyping (i.e. genetic analysis) of 81 marijuana and 43 hemp samples revealed that marijuana and hemp are significantly differentiated at a genetic level. This demonstrated that the distinction between marijuana and hemp is not limited to genes underlying THC production. Researchers found evidence that hemp is genetically more similar to C. indica type marijuana than to C. sativa strains. Consequently, it may turn out that marijuana and hemp are not actually from the same plant after all.
Cannabinoid Receptors and More
The fact that cannabinoids provided medicinal effects indicated that there must be cannabinoid receptors in the body. This was verified in 1988 when a synthetic cannabinoid was developed and found to bind to a receptor located in nerve cell membranes. This process led to the identification of an “orphan G protein-coupled receptor” (GPCR) as the brain receptor for cannabinoids. Thereafter, an understanding developed that there was an entire endocannabinoid (eCB) system in the body, including its receptors, endogenous (produced in the body) ligands with cannabinoid properties, and ligand metabolic enzymes.
Cannabinoid receptor 1 (CB1) is the most abundant G protein-coupled receptor expressed in the brain, and also expressed in non-neuronal cells, such as adipocytes and hepatocytes, and in musculoskeletal tissues. Cannabinoid receptor 2 (CB2) is principally associated with cells governing immune function, although it may also be expressed in the central nervous. eCB ligands of primary importance are N-arachidonylethanolamide (anandamide, AEA) and sn-2-arachidonoylglycerol (2-AG). It is interesting to note that arachidonoylethanolamide was named as anandamide based on the Sanskrit word ananda meaning bringer of inner bliss.8,9
This eCB system has expanded with the discovery of secondary receptors, ligands and ligand metabolic enzymes. In fact, the effects of AEA and 2-AG can be enhanced by so-called “entourage compounds” that inhibit their hydrolysis via substrate competition, prolonging their action. It has been suggested that these entourage compounds, which include N-palmitylethanolamide (PEA), N-oleoylethanolamide (SEA) and cis-9-octadecenoamide (OEA, oleamide), may represent a good case for the advantage of hemp oil, which provides a variety of naturally-occurring cannabinoids. Other research10 has likewise demonstrated the entourage effect of cannabinoids, showing that they do not bind to cannabinoid receptors, but they do potentiate the binding of ligands to cannabinoid receptors.
More on the Endocannabinoid System
One researcher summarized the endocannabinoid system in this way: “Metaphorically, the eCB system represents a microcosm of psychoneuroimmunology or mind-body medicine.”11 Considering that 1) cannabinoids and their receptors are found throughout the body (including the brain, organs, connective tissues, glands and immune cells); and 2) though performing different tasks, the goal of the eCB is consistently the maintenance of a stable internal environment despite fluctuations in the external environment, aka, homeostasis—this is an apt summary.
Emerging research indicates that ‘‘eCB deficiency syndrome’’ contributes to migraine, fibromyalgia, irritable bowel syndrome, psychological disorders, as well as other conditions.12 Conversely, enhancing endocannabinoid activity has broad therapeutic potential. This may include the treatment of patients with somatic dysfunction, movement disorders such as Parkinson’s and Huntington’s diseases, chronic pain, neurodegenerative diseases, mood and anxiety disorders, as well as inflammatory conditions, bowel dysfunctions, psychological disorders, multiple sclerosis and spinal cord injury, cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome and osteoporosis.13,14
Omega-3 Fatty Acids and the eCB System
Emerging research on the eCB system indicates that the health benefits of omega-3 fatty acids (O3FA) are mediated, in part, through metabolic conversion to bioactive epoxides. This is significant since naturally occurring O3FA-derived endocannabinoid epoxides are formed via enzymatic oxidation of O3FA by cytochrome P450s. These dual functional O3FA endocannabinoid epoxides are anti-inflammatory and vasodilatory and reciprocally modulate platelet aggregation. By virtue of their physiological properties, they are expected to play important roles in neuroinflammation and in cerebrovascular diseases such as stroke.15 Consequently, the powerful health benefits of O3FA would not be possible without the eCB.
Endocannabinoids and Phytocannabinoids
Both endocannabinoids and phytocannabinoids can stimulate eCB receptors. Endocannabinoids are the compounds our bodies produce naturally to stimulate eCB receptors. The two most well understood of these AEA and 2-AG, previously described. They are synthesized on-demand, and have a local effect and short half-life before being degraded by enzymes.
Phytocannabinoids are plant-derived compounds that stimulate eCB receptors. Though THC is the most psychoactive and well-known of these compounds, other cannabinoids such as CBD and cannabinol (CBN) also stimulate eCB receptors, and have been shown in research to provide various healing properties. These include benefits for heart health, cancer, Alzheimer’s, stress and anxiety, diabetes, stroke, COPD, influenza and pneumonia.
According to the Centers for Disease Control and Prevention, heart disease is the No. 1 leading cause of death.16 Specific medical issues affecting heart disease include arrhythmia, hypertension and inflammation. Endocannabinoids and the naturally occurring phytocannabinoids from hemp oil have been shown to have benefits for these issues.
Research in rats demonstrated that hemp-derived CBD effectively reduce arrhythmias17,18 (abnormal heartbeat or palpitations).
A randomized, placebo-controlled, double-blind, crossover study19 in nine healthy male volunteers demonstrated that supplementation with hemp-derived CBD reduced resting blood pressure and reduced blood pressure increase associated with a type of stress.
Inflammation is now understood to play a significant role in the development of heart disease.20 In animal research, hemp-derived CBD was shown to effectively reduce inflammatory markers in a variety of situations.21-25
Second only to heart disease, cancers represent a primary cause of death in the United States.26 The “United States Cancer Statistics: 1999–2014 Incidence and Mortality Web-based Report” (USCS) combines cancer registry data from CDC’s “National Program of Cancer Registries” and the National Cancer Institute’s “Surveillance, Epidemiology, and End Results Program” to reveal that each year of data includes more than 1.5 million cases of invasive cancer, including approximately 15,000 cases among children younger than 20 years, and more than 590,000 deaths from cancer.27
Research has also shown that cannabinoids have been successfully used for various purposes in the treatment of cancers. This includes anti-tumor properties, drug resistance problems during cancer treatments, diminishing cancer treatment side effects, and helping to reduce cigarette consumption in tobacco smokers.
CBD, CBG, CBC and CBDA (non-psychoactive phytocannabinoids) have been shown to exert anti-proliferative/pro-apoptotic effects for a variety of tumor cell lines. These include human breast carcinoma, human prostate carcinoma, lung human colorectal carcinoma, human gastric adenocarcinoma, C6 rat glioma, rat basophilic leukemia and transformed thyroid cells.28-29
Drug Resistance Problems:
Hemp-derived CBD might have a very important role in reduction of multi-drug resistance of tumor cells. For example, CBD showed high inhibition activities for P-glycoprotein (ABCB1) multi-drug resistance related protein 1 (ABCC1/MRP1) and breast cancer resistance protein.30-32
Diminishing Side Effects:
Chemotherapy drugs leads to the physiological side effects such as intensive vomiting. Recently, experimental evidence from animal experiments showed that cannabinoids help suppress related vomiting and nausea.33
Reduce Cigarette Smoking:
The role of chronic tobacco use in the development of various types of cancers is well established. A randomized double-blind placebo controlled pilot study34 in smokers demonstrated that hemp-derived CBD significantly reduced the number of cigarettes smoked by approximately 40 percent during treatment.
Alzheimer’s disease (AD) is a devastating form of nonreversible dementia (loss or major impairment of mental powers) affecting an estimated 5.5 million Americans in 2017. An estimated 5.3 million are age 65 and older and approximately 200,000 individuals are under age 65 and have younger-onset Alzheimer’s.35 Cannabinoids such as CBD may also help play a mitigating role in the development and outcomes of AD.
Amyloid beta (Aβ) plaques are a main neuropathological hallmark of AD. Research suggests that hemp-derived CBD may beneficially interfere with several Aβ-triggered neurodegenerative pathways.36
Stem Cell Treatment:
Mesenchymal stem cells (MSCs) have emerged as a promising tool for the treatment of neurodegenerative disorders such as AD. Research suggests that pre-treatment with hemp-derived CBD improve their therapeutic potential.37
Hemp-derived CBD has been shown to reverse cognitive deficits of AD mice and to exert neuroprotective, anti-oxidative, and anti-inflammatory properties in vitro and in vivo. This includes preventing a social recognition deficit,38 and reversing some cognitive deficits.39
Stress and Anxiety
According to the American Psychological Association’s annual Stress in America survey,40 more than three-quarters of Americans report experiencing one or more symptoms of stress, while 24 percent of Americans report experiencing extreme stress (a rating of 8, 9 or 10 on a 10-point scale)—and it doesn’t seem to get better. More than one-third report that their stress increased over the past year. As with AD, cannabinoids such as CBD may also help play a mitigating role in stress and anxiety.
Hemp-derived CBD oil resulted in a maintained decrease in anxiety and a steady improvement in the quality and quantity of the sleep in a child with post-traumatic stress disorder.41 In a large retrospective case series42 with 103 adult patients, hemp-derived CBD oil was associated with a rapid and sustained drop in anxiety scores.
As of 2015, 30.3 million Americans, or 9.4 percent of the population, had diabetes.43 When high blood glucose levels remain high and largely uncontrolled for a long period of time, the result can be a variety of serious complications. These complications include, but are not limited to, neuropathy (pain in the hands and feet), high blood pressure, cholesterol and triglyceride levels, peripheral vascular disease (including pain when walking and foot ulcers), retinopathy (the leading cause of blindness worldwide), and weight gain and/or obesity. Recent studies provided compelling evidence that modulation of the endocannabinoid system may hold tremendous therapeutic potential for diabetes and diabetic complications.44
Hemp-derived CBD was able to ameliorate diabetes when given at the time of the development of initial symptoms of diabetes in nonobese diabetic mice.45
In experimental diabetic retinopathy, hemp-derived CBD was able to reduce oxidative stress, inflammation, retinal cell death, and vascular hyperpermeability associated with diabetes.46
Diabetic Neuropathic Pain:
About 60 to 70 percent of all diabetic patients have some form peripheral neuropathic pain (PNP), characterized by pain and numbness, particularly in the hands and feet.47 In a 38-week open-label extension study48 with 234 patients, a combination THC/CBD oromucosal spray was shown to improve neuropathic pain.
Most people with diabetes have increased risk for cardiovascular disease, which can result in death. In fact, more than 65 percent of people with diabetes die from heart disease or stroke.49 In a study with diabetic mice and human cardiomyocyte cells, hemp-derived CBD attenuated myocardial dysfunction, cardiac fibrosis, oxidative/nitrative stress, inflammation, cell death, interrelated signaling pathways, high glucose-induced increased reactive oxygen species generation, nuclear factor-κB activation and cell death.50
Each year, approximately 795,000 people suffer a stroke, and it is the leading cause of serious, long-term disability in the United States. More than 140,000 people die each year from stroke in the United States, making it the third leading cause of death nationally. in vivo and in vitro studies have demonstrated a protective effect of hemp-derived CBD in reducing infarct size in stroke models and against epithelial barrier damage in numerous disease models.51-53
Chronic Obstructive Pulmonary Disease, or COPD, refers to a group of diseases that cause airflow blockage and breathing-related problems. It includes emphysema, chronic bronchitis, and in some cases, asthma. Chronic lower respiratory disease, primarily COPD, was the third leading cause of death in the United States in 2014.54 Almost 15.7 million Americans (6.4 percent) reported that they have been diagnosed with COPD.55 In a double blind, randomized, placebo-controlled crossover study,56 subjects with and without COPD received a combination of THC and CBD. The results showed that cannabinoids may ameliorate the unpleasantness of breathlessness without a change in conventional breathlessness ratings (VAS).
Influenza and Pneumonia
While the impact of influenza varies from season to season, it places a substantial burden on the health of people in the United States: millions of people become ill, hundreds of thousands are hospitalized and thousands or tens of thousands of people die from flu every year. Likewise, in the United States, approximately three million cases of pneumonia are reported each year and about 60,000 people die as a result of the condition. Combined, pneumonia and influenza are the eighth leading cause of death in the U.S.
One approach where CBD has relevance to the treatment of pneumonia and influenza, is reducing lung inflammation. This has been shown in two studies where hemp-derived CBD had anti-inflammatory effects’ in the lungs in an animal model.57-58
Ultra Low-dose THC
It should be noted that, even though the amount of THC present in hemp is so low as to lack any psychotropic effect, that does not necessarily mean that there is not enough present to offer health benefits. Mechoulam reported59 that researchers at Tel Aviv University found that a single ultralow dose of THC (0.002 mg/kg, several orders of magnitude lower than the conventional doses in mice) protects the brain from different insults, including inflammation, that cause cognitive deficits. THC protected the mice from the long-lasting cognitive deficits caused by an inflammatory-promoting agent. The authors of the study indicated that, despite the lack of psychotropic effect, an ultralow dose of THC protected the brain of mice from neuroinflammation-induced cognitive damage.
The Regulatory Status of Hemp/CBD
Now that we’ve examined the potential health benefits associated with hemp-derived CBD, let’s consider Federal and state laws in the U.S. that are in conflict regarding the medical use of cannabis and cannabinoids. This has led to confusion among patients, caregivers and health care providers. According to an article recently published in the journal Epilepsy & Behavior, cannabis is currently legal for medical purposes in 50 percent of the states, and another seventeen states allow products that are high in CBD and low in THC for medical use.
But what about CBD as a dietary supplement? The same journal article also indicates that, unlike THC, CBD is not listed separately in the Code of Federal Regulations (CFR) as controlled in Schedule I. So does that make it a candidate as a dietary supplement? On its website, the FDA (U.S. Food and Drug Administration) addresses this question:
No. Based on available evidence, FDA has concluded that THC and CBD products are excluded from the dietary supplement definition under sections 201(ff)(3)(B)(i) and (ii) of the FD&C Act, respectively. Under those provisions, if a substance (such as THC or CBD) is an active ingredient in a drug product that has been approved under 21 U.S.C. § 355 (section 505 of the FD&C Act), or has been authorized for investigation as a new drug for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public, then products containing that substance are outside the definition of a dietary supplement.60
Now while that seems to be the official position regarding CBD as a dietary supplement, it is not the end of the story. There is still the issue of industrial hemp—a plant typically grown for its fiber or seeds, and generally low in cannabinoid content. The aforementioned journal article indicates that the federal Controlled Substances Act (CSA) does not define hemp, but rather exempts the stalk, fiber, and sterilized seeds of the cannabis plant (and preparation made from them) from the definition of marijuana. However, CBD expression is typically limited to flowering buds and not stalk, fiber or sterilized seeds. So does that mean that CBD containing hemp oil doesn’t meet the definition of industrial hemp? Not necessarily.
According to Josh Hendrix, director of business development with California-based CV Sciences, Inc., a company researching hemp oil/CBD pharmaceuticals and consumer products:
“Industrial hemp goods, including those derived from the fiber and all of the aerial plant parts, including stems, seeds and tops have been sold for decades online and in retail stores across the country. It is our opinion that the interstate sale of such products with only traces of naturally-occurring cannabinoids such as THC and CBD is permitted by federal law and judicial precedent—assuming the products never contain more than 0.3 percent of THC on a dry weight basis.
“Furthermore, in the federal Agricultural Act Of 2014, P.L. No. 113-79 (the ‘2014 Farm Bill’), Congress specifically exempted from the CSA cultivation of industrial hemp under agricultural pilot programs authorized by state law. The Farm Bill defines “industrial hemp” as all parts of the Cannabis sativa L. plant containing less than 0.3 percent THC on a dry weight basis—which could include flowering buds where CBD is found.”
Hendrix goes on to state that, despite recent pronouncements by the DEA (Drug Enforcement Administration) concerning the sale of CBD-infused products, the DEA does not have the authority to rewrite federal law. That’s Congress’ job. In his opinion, non-psychoactive, naturally occurring hemp products remain excluded from that agency’s jurisdiction.
To illustrate his point, Hendrix discussed the results of a 2004 case with the U.S. Court of Appeals for the Ninth Circuit: Hemp Industries Assn v. Drug Enforcement Administration, 357 F.2d 1012 (9th Cir. 2004). The court affirmed that non-psychoactive hemp products do not contain any controlled substance as defined by the CSA. The court’s holdings included:
• “THC naturally occurring within non-psychoactive hemp products did not fall under the DEA’ s regulation;”
• “We conclude that Congress did not regulate non-psychoactive hemp in Schedule I;”
• “Congress knew what it was doing, and its intent to exclude non-psychoactive hemp from regulation is entirely clear,” and
• The DEA “cannot regulate naturally-occurring THC not contained within or derived from marijuana—i.e., non-psychoactive hemp products—because non-psychoactive hemp is not included in Schedule I. The DEA has no authority to regulate drugs that are not scheduled, and it has not followed procedures required to schedule a substance.”
So, at the end of the day, do I have a clear-cut answer on the regulatory status of Hemp oil/CBD? I’m sorry to say that I do not. However, I do have an opinion. Keeping in mind that I’m a scientist and academician, not a lawyer, my opinion is that non-psychoactive hemp oil products that naturally contain CBD (and contain less than 0.3 percent THC on a dry weight basis) are not in violation of the congressional definitions of hemp, are not in violation of the “2014 Farm Bill,” and are not listed in the Code of Federal Regulations (CFR) as a controlled substance in Schedule I. Furthermore, given the definition of a dietary supplement and the history of hemp products in interstate sales (not to mention that marijuana and hemp may not actually from the same plant after all, as discussed previously), such products should have status as a dietary supplement. Although the FDA clearly does not agree that non-psychoactive hemp oil-derived CBD products should be dietary supplements, it is my hope that industry pundits and other experts will have the opportunity to influence opinion and change the FDA’s position on this issue, so that millions of Americans will gain easier access to this important nutraceutical.
The eCB system, as well as the endocannabinoids and phytocannabinoids that stimulate eCB receptors, play important roles in homeostasis of human health and well-being. Cannabinoids derived from hemp oil, such as CBD, have been shown in research to provide various healing properties. These include benefits for heart health, cancer, Alzheimer’s, stress and anxiety, diabetes, stroke, COPD, influenza and pneumonia. However, the legal status of hemp oil-derived CBD remains murky. While hemp oil-derived CBD does not appear to be in violation of congressional and federal definitions of hemp, not is it listed in the Code of Federal Regulations (CFR) as a controlled substance in Schedule I, the FDA still contents that it does not meet the definition of a dietary supplement. In this author’s opinion, the FDA is doing a disservice to the American public by maintaining this position. VR References:
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