Lopez HL, Cesareo KR, Raub B, et al. Effects of hemp extract on markers of wellness, stress resilience, recovery and clinical biomarkers of safety in overweight, but otherwise healthy subjects. J Diet Suppl. 2020;17(5):561-586.
The objective of this study was to examine the effects of a hemp extract with cannabidiol (CBD) on liver and kidney safety biomarkers, perceived mood, body composition, and stress resilience in healthy, overweight/obese participants.
Randomized, placebo-controlled, double-blind trial
Researchers recruited overweight and obese (body mass index [BMI] between 25–34.99 kg/m2), but otherwise healthy (normotensive and normal resting heart rate) women and men (N=65). Participants were excluded if they reported regular exercise of more than 3 days per week; used weight-loss medications, thyroid medications, anticoagulants, antiplatelet medications, or fish oil supplements; used tobacco; or were diagnosed with any metabolic disorder or chronic inflammatory disease.
Participants received either 60 mg of a hemp extract containing 15 mg of CBD or a placebo every day for 6 weeks.
Study Parameters Assessed
Researchers randomly divided participants into 2 groups: HEMP group (n=33) received 60 mg of a hemp extract containing 15 mg of CBD (PlusCBD, manufactured by CV Sciences, San Diego, California), and the placebo or PLA group (n=32) received a matching placebo softgel containing olive oil. Participants adhered to their normal diet and were instructed to perform a routine of low-intensity physical activity (30 minutes of walking exercise 5 days per week). Data were collected before and after 6 weeks of supplementation.
Outcome variables included changes in stress resilience, a panel of various psychometric parameters, heart-rate variability, plasma chromogranin A, and body composition (lean mass, fat mass, bone mineral content, visceral adipose tissue via dual-energy X-ray absorptiometry [DEXA]) as well as general wellness markers including heart rate, blood pressure, and clinical chemistry panels. Data were analyzed via ANOVA (analysis of variance), t-tests, and effect sizes.
High-density lipoprotein (HDL) cholesterol levels significantly improved in the HEMP group compared to the PLA group (P=0.004). No other statistically significant changes were observed between groups; however, statistically significant changes were observed from baseline to 6 weeks within the HEMP group. These included subjective psychometric improvements in sleep quality (P=0.005) and sleep quantity (P=0.01). While not significant, there were trends between HEMP and PLA group differences found for “I Get Pleasure from Life” (P=0.06) and “Ability to Cope with Stress” (P=0.07). All values for plasma and serum chemistry, including hepatorenal function, remained within normal clinical ranges with no between-group differences.
The popularity of hemp-derived and CBD-containing consumer products has dramatically outpaced research on the ingredient. Despite a long human history of Cannabis cultivation and use, within the United States legislators only recently removed the hemp plant from the Controlled Substances Act as a result of the 2018 Farm Bill. Hemp, defined as Cannabis sativa (Linnaeus) containing no more than 0.3% tetrahydrocannabinol (THC) by dry weight, is used as a source for the nonintoxicating cannabinoid CBD, which is being marketed as a dietary supplement. The US Food and Drug Administration (FDA) views CBD as a drug ingredient, as it is the active ingredient in the prescription drug Epidiolex®. Epidiolex is prescribed for treatment-resistant seizures associated with Dravet and Lennox-Gastaut syndromes and tuberous sclerosis complex.1-3 Epidiolex was researched as an Investigational New Drug (IND) before the passage of the 2018 Farm Bill, thus limiting the FDA from recognizing CBD as a supplement ingredient. However, the FDA’s policy that prohibits an ingredient from being included in supplements if it has been previously researched as a drug under an IND uniquely affects hemp. Unlike fish oil or niacin, both of which were already supplements before they became prescription drugs, hemp-derived CBD never had a chance to be added to dietary supplements because it was illegal. This has created a legal gray area for a natural compound found in one of the oldest commercially traded botanical medicines: Cannabis.4
Peer-reviewed research may help clarify this complicated regulatory landscape. To craft policy pertaining to cannabinoids in supplements, the FDA has stated that more safety data are needed on human health following long-term CBD consumption. This randomized controlled trial (RCT) examining the human safety and efficacy of a commonly available CBD-containing commercial hemp supplement adds to the growing body of evidence that can help the FDA establish guidelines that balance consumer access with safety. Data illustrating that there are no clinically significant alterations in hepatorenal function between HEMP and PLA groups is an important finding, given that significantly higher doses of CBD, as found in Epidiolex, are associated with risk of elevated liver enzyme levels. Furthermore, the safety of the hemp extract used in this RCT has been corroborated with in vivo toxicology studies and adverse-event reporting data.5,6
CBD and the ECS have also recently been linked to the health of the gut microbiome, the status of which has been shown to alter lipid chemistry and overall metabolism.
In the general populace, CBD is used as a wellness supplement. Surveys indicate that the 3 most popular uses for which responders report that CBD is either “very” or “moderately” effective include chronic pain, arthritis/joint pain, and anxiety.7 The present RCT examined a mostly healthy population with some underlying metabolic challenges, but otherwise those with diagnoses were excluded from the study. The only significant change between HEMP and PLA groups was an improvement in HDL cholesterol. Within-group changes from baseline to week 6 of hemp-CBD supplementation did see significant improvements in sleep quality and quantity. It is possible that researchers may have observed a greater statistical or clinical significance with this dose of CBD if the cohort did have some underlying medical condition, such as arthritis or anxiety. Previous case reports have indicated that a similar dose and preparation of CBD did support improvements in anxiety; however, this was not a placebo-controlled study.8,9
CBD may interact through multiple biochemical pathways; however, the endocannabinoid system (ECS) is most widely suggested.10 ECS is composed of eicosanoid-like lipid mediators that act as neurotransmitters and immunomodulators that bind to G-protein-coupled cannabinoid receptors, and enzymes that anabolize or catabolize these ligands.11 Researchers have investigated whether CBD improves the tone of the ECS by inhibiting the major metabolizing enzyme fatty acid amide hydrolase (FAAH), although allosteric effects at cannabinoid receptors have also been observed. Imbalances in ECS tone/activity have been found in multiple pathophysiological states, including fibromyalgia, PTSD, glaucoma, metabolic syndrome, irritable bowel syndrome (IBS), and inflammatory bowel disease (IBD), with CBD sometimes suggested as a potential treatment.12 Whereas the ECS is described as a biochemical mediator of homeostasis, its dysregulation suggests that it is also an allostatic system. Because of this, it is possible that CBD supplementation would produce a greater significant effect in participants with an established pathophysiological state, if in fact ECS dysregulation is involved.
Why would hemp-derived CBD supplementation affect HDL cholesterol? Cannabinoid receptors are expressed in multiple tissue and cell types, including various gastrointestinal cell types, hepatocytes, and adipocytes.13 The role of ECS extends to modulating adiposity, food-seeking behavior, lipogenesis, and lipid metabolism. Cannabinoid receptor 1 (CB1) antagonism is shown to ameliorate dyslipidemia and increase HDL.14 Unlike the psychoactive phytocannabinoid THC, a partial cannabinoid receptor 1 agonist, CBD is a negative allosteric modulator at CB1, possibly explaining the pharmacology of HDL improvement in the present study.15 CBD and the ECS have also recently been linked to the health of the gut microbiome, the status of which has been shown to alter lipid chemistry and overall metabolism.16-18 Further research should be conducted on the impact of hemp and cannabinoids on the gut microbiome, as this is an attractive and relevant field of study via its wide-ranging effects on other physiologic processes (eg, the gut-brain axis).
Although high-potency isolated CBD has been studied in multiple double-blind and placebo-controlled human trials for treatment of rare seizure disorders, the present RCT is one of the first attempts at assessing the effects in healthy humans of supplementation with a full-spectrum hemp extract containing CBD. Although a larger cohort, different doses of CBD, and more parameters may yield additional findings, this work offers new safety data and evidence to support the benefits of hemp extracts as a general wellness supplement at 15 mg of CBD within a 60-mg hemp extract. As we move away from the research limitations that resulted from hemp being classified as a controlled substance, we can look forward to additional research that will increase the scientific understanding of hemp extracts with CBD as a new botanical tool.
- Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376(21):2011–2020.
- Devinsky O, Patel AD, Cross JH, et al. Effect of cannabidiol on drop seizures in the Lennox–Gastaut syndrome. N Engl J Med. 2018;378(20):1888–1897.
- Thiele E, Bebin EM, Filloux F, et al. Long-term safety and efficacy of cannabidiol (CBD) for the treatment of seizures in patients with tuberous sclerosis complex (TSC) in an open-label extension (OLE) trial (GWPCARE6) (677). Neurology. 2020;94(15 Supplement):677.
- Marinotti O, Sarill M. Differentiating full-spectrum hemp extracts from CBD isolates: implications for policy, safety and science. J Diet Suppl. 2020;17(5):517-526. .
- Marx TK, Reddeman R, Clewell AE, et al. An assessment of the genotoxicity and subchronic toxicity of a supercritical fluid extract of the aerial parts of hemp. J Toxicol. 2018;2018:8143582.
- Schmitz SM, Lopez HL, Marinotti O. Post marketing safety of Plus CBDTM products, a full spectrum hemp extract: a 2-year experience. J Diet Suppl. 2020;17(5):587-598.
- Corroon J, Phillips JA. A cross-sectional study of cannabidiol users. Cannabis Cannabinoid Res. 2018;3(1):152-161.
- Shannon S, Lewis N, Lee H, Hughes S. Cannabidiol in anxiety and sleep: a large case series. Perm J. 2019;23:18-41.
- Shannon S, Opila-Lehman J. Effectiveness of cannabidiol oil for pediatric anxiety and insomnia as part of posttraumatic stress disorder: a case report. Perm J. 2016;20(4):108-111.
- Di Marzo V, Piscitelli F. The endocannabinoid system and its modulation by phytocannabinoids. Neurotherapeutics. 2015;12(4):692-698.
- Leuti A, Fazio D, Fava M, Piccoli A, Oddi S, Maccarrone M. Bioactive lipids, inflammation and chronic diseases. Adv Drug Deliv Rev. 2020; S0169-409X(20)30074-0. https://doi.org/10.1016/j.addr.2020.06.028 [Epub ahead of print on July 3, 2020].
- Russo EB. Clinical endocannabinoid deficiency reconsidered: current research supports the theory in migraine, fibromyalgia, irritable bowel, and other treatment-resistant syndromes. Cannabis cannabinoid Res. 2016;1(1):154-165.
- Engeli S. Peripheral metabolic effects of endocannabinoids and cannabinoid receptor blockade. Obes Facts. 2008;1(1):8-15.
- Després JP, Ross R, Boka G, Alméras N, Lemieux I. Effect of rimonabant on the high-triglyceride/low-HDL-cholesterol dyslipidemia, intraabdominal adiposity, and liver fat the ADAGIO-lipids trial. Arterioscler Thromb Vasc Biol. 2009;29(3):416-423.
- Laprairie RB, Bagher AM, Kelly MEM, Denovan-Wright EM. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol. 2015;172(20):4790-4805.
- Al-Ghezi ZZ, Busbee PB, Alghetaa H, Nagarkatti PS, Nagarkatti M. Combination of cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), mitigates experimental autoimmune encephalomyelitis (EAE) by altering the gut microbiome. Brain Behav Immun. 2019;82:25-35.
- Cani PD, Plovier H, Van Hul M, et al. Endocannabinoids—at the crossroads between the gut microbiota and host metabolism. Nat Rev Endocrinol. 2016;12(3):133-143.
- Fu J, Bonder MJ, Cenit MC, et al. The gut microbiome contributes to a substantial proportion of the variation in blood lipids. Circ Res. 2015;117(9):817-824.