endocannabinoid receptors

Resveratrol A Phytocannabinoid Cousin to CBD

There are many naturally occurring plant cannabinoids, also known as phytocannabinoids (i.e. phyto = plant). The two most well-known of these are CBD and THC, which are derived from hemp or marijuana, both varietal plants of the Cannabis sativa species. In past years, cannabinoids were defined as “terpene phenolic constituents” of Cannabis known to directly interact with cannabinoid receptors in the body, which are part of the endocannabinoid system (eCBs). However, in more recent years the scientific community has recognized there are several plant compounds that are not from Cannabis but are capable of either directly interacting with cannabinoid receptors or sharing chemical similarity with cannabinoids or both. Consequently, the term phytocannabinoids is now inclusive of these other plant compounds as well as those from Cannabis.¹

The first part of this article will review the phytocannabinoid properties of resveratrol, a natural antioxidant compound found in grapes, peanuts² and Japanese Knotweed (Polygonum cuspidatum),³ providing antioxidant protection to the plants— as well as to humans that consume them.⁴ The second part of the article will compare resveratrol to CBD in terms of human health benefits.

Resveratrol 101
Resveratrol originally made its introduction splash into the dietary supplement marketplace based upon the consideration that intake of it and other polyphenol compounds from red wine may contribute to the “French paradox”—the unexpectedly low rate of death from cardiovascular disease in the Mediterranean population despite the relatively higher intake of saturated fats.⁵ Then, the excitement increased with the understanding that resveratrol helped activate the SIRT 1 gene, associated with longevity.⁶ Since that time, interest in resveratrol has continued to expand due to human research demonstrating its effectiveness for reducing inflammation and other health benefits.

Resveratrol and the eCBs
As research continued, it became evident that resveratrol also affects signaling with endocannabinoid receptors. In turn, this exerts modulatory effects in the survival signaling pathways, neural plasticity (i.e. the ability of the brain to change continuously throughout an individual’s life), as well as a variety of neuroinflammatory and neurodegenerative processes. The therapeutic effects of this ubiquitous signaling system in Alzheimer’s disease, epilepsy, multiple sclerosis, mood and movement disorders, spinal cord injury, and stroke have been well-documented,⁷ and helps to explain why it is that resveratrol has a broad range of activities.

Resveratrol, eCBs, cognition and mood
Recently, resveratrol is implicated in the biology of nerve growth factor (NGF), a critical player in the maintenance of neuronal growth and function. Likewise, resveratrol has also shown antidepressant-like effects in behavioral studies. The interaction between the nerve growth factor (NGF) and eCBs and their contribution to the antidepressant/emotional activity prompted researchers to further evaluate the mechanism of action of resveratrol. Results were that four-week treatment with resveratrol led to significant and sustained enhancement of NGF and eCB contents in dose-dependent and brain region-specific manner. Essentially, resveratrol like the classical antidepressant, amitriptyline, affects brain NGF and eCB signaling under the regulatory drive of CB1 receptors in the eCBs.⁸

A practical application of resveratrol effects in this regard were demonstrated in a study⁹ in which 80 post-menopausal women aged 45–85 years received resveratrol (75 mg, twice daily) or placebo for 14 weeks to examine the effect on cognitive performance and other parameters. Results were that, compared to placebo, significant improvements were observed in the performance of cognitive tasks in the domain of verbal memory (p = 0.041) and in overall cognitive performance (p = 0.020). Mood also tended to improve in multiple measures. In another study, 200 mg of resveratrol daily improved memory performance in association with improved glucose metabolism in older adults.¹⁰

Resveratrol, eCBs and inflammation
Resveratrol has been shown to have anti-inflammatory effects with as little as 40 mg/day in normal human subjects.¹¹ This included the reduction of inflammatory markers such as TNFalpha, IL-6, and C-reactive protein, with no changes in the placebo group. Similarly, in postmenopausal women with osteoarthritis pain, 75 mg of resveratrol twice daily significantly reduced pain and improved total well-being.¹² Other research has also shown similar results, including research^13,14 in patients with ulcerative colitis (a chronic inflammatory bowel disease) receiving 500 mg/day of resveratrol, and research¹⁵ in receiving 100 mg/day resveratrol.

	Resveratrol	CBD
Pain/Inflammation	40 mg, 100 mg, 150 mg, 500 mg	100 mg, 150 mg, 300 mg
Cognition/mood	150 mg	n/a
Arterial Function^24,25	100 mg	n/a
Exercise-related muscle fatigue*	500 mg	n/a
Fat metabolism/weight loss ²⁷	100 mg, 150 mg, 1500 mg	n/a
Appetite Control	n/a	15 mg
Stress/Anxiety	n/a	25 mg
Sleep	n/a	15 mg, 25 mg

But what is resveratrol’s mechanism of action for these anti-inflammatory effects? This was examined in a 6-week resveratrol study¹⁶ on rats who were fed a high-fat diet (HFD), which in turn resulted in non-alcoholic steatohepatitis (NASH)—a condition of liver inflammation and damage caused by a buildup of fat in the liver. The HFD caused an increase in body weight, liver index, hepatic lipid accumulation, and inflammation, which was inhibited by resveratrol. Resveratrol also attenuated gut microbial dysbiosis (i.e. imbalance of microorganisms in the gut). Moreover, resveratrol led to a reduction in metabolic endotoxemia and colon inflammation. These benefits appear to have been mediated by resveratrol’s effect on the CB1 and CB2 receptors in the gut eCBs. In short, these data indicate that the eCBs, particularly the expressions of CB1 and CB2, appears to play a crucial role in the resveratrol induced anti-NASH effect by maintaining the gut barrier integrity and inhibiting gut inflammation. Other research¹⁷ has also suggested that resveratrol induces peripheral blocking of pain through ì-opioid receptor and CB1 receptor activation by endogenous opioid and endocannabinoid releasing.

CBD 101
Much has been written about CBD elsewhere, so I won’t spend much time in a lengthy reiteration. Rather, here is a short overview. As previously mentioned, cannabidiol, or CBD, is a naturally-occurring phytocannabinoid from hemp. Human clinical research on CBD has revealed that it is effective in helping to reduce stress/anxiety and sleep complaints with daily doses of 25 mg.^18,19,20 In a more recent study,²¹ 15 mg of hemp-derived CBD for six weeks led to significant decreases in appetite, along with improvements in sleep quality and duration, and enhancements in “quality of life” scores in healthy humans. An emerging area of CBD research is inflammation and pain. However, considerably higher doses of CBD were used in these studies,^22,23 ranging between 100–300 mg/day. Other research on CBD also exists, but those studies center around more serious health issues and require medical intervention.

Conclusion
Comparing resveratrol to CBD (See table above) Although they are both phytocannabinoids, resveratrol and CBD’s applications are not precisely the same. This table demonstrating the specific applications of each, including daily doses used in human research:

In reviewing the areas in which resveratrol and CBD offer benefits, it is clear that there are some distinct differences as well as some overlap. Both offer benefits for pain/inflammation. That being said, there are significant differences in cost. The minimum effective dose of CBD shown to have efficacy for this purpose is exponentially higher than that of the highest dose of resveratrol shown to have efficacy. So for purposes of pain/inflammation, resveratrol is the better choice—although it could certainly be combined with lower, more affordable doses of CBD.

Resveratrol is also the clear winner with regard to cognition/mood, while CBD has the advantage for stress/anxiety. In addition, resveratrol also offers benefits for arterial function and exercise-related muscle fatigue that CBD does not have. Conversely, CBD offers benefits for promoting sleep, while resveratrol does not.

Both resveratrol and CBD have different but complementary effects with regard to weight management. CBD appears to help reduce appetite, while resveratrol has a more direct effect on fat metabolism/weight loss. Hence, both phytocannabinoids could be used together to help achieve a greater overall effect.

References

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