February 07

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CBD: Believe the Hype?

CBD_PosterI first stumbled upon CBD at a farmers market in Solana Beach, CA. A couple of enthusiastic salesmen were promoting their CBD-infused cold brew. Once I heard the claims of how it could reduce anxiety, improve sleep, and increase energy, I mentally put it into the same category as those pads you put on the bottom of your feet to ‘suck out all the toxins’ and snake oil. Instead of staying on the fringes, however, CBD-infused products ranging from lotions to dog treats have started to appear everywhere with little sign of going away. Since it does seem to be sticking around, I wanted to find out what CBD really is and which, if any, of the touted benefits hold any water.

For starters, CBD is short for cannabidiol (pronunciation here) and is one of over 100 cannabinoids which can be extracted from the cannabis plant [1-2]. It is similar in structure to the most famous cannabinoid, THC, but does not exhibit the characteristic high associated with the devil’s lettuce. These compounds interact directly with the body’s built-in system for producing and recognizing cannabinoids (the endocannabinoid system) which has been implicated in regulating appetite, memory, and pain and is mediated by two main receptors: CB1 and CB2 [2-4]. One of the reasons that elucidating the effects of cannabinoids has proven difficult is that the CB1 receptor seems to be found essentially everywhere in the central nervous system (the CB2 receptor is mostly found in immune cells).

CBD_Cartoon

Neurons typically communicate with one another in a “feedforward” manner by sending neurotransmitters across narrows gaps from Neuron A to Neuron B . Importantly, this signal can only travel in one direction; Neuron B typically has to just sit there and listen to whatever Neuron A is saying without responding. Except, that is, in cells equipped with endocannabinoid receptors such as CB1. These allow retrograde (backward) signaling , essentially enabling Neuron B to tell Neuron A  to “shut up.”

CBD_Schematic

While the body makes its own molecules that bind with the CB1 cannabinoid receptor, THC binds to this receptor as well and has a similar effect, i.e. to “shush” the neurons sending it signals. CBD’s function, however, is more mysterious because it  does not bind to or even block CB1. Instead, CBD seems to reduce the effectiveness of the molecules that do bind to CB1 (like THC) through a yet-unknown indirect pathway. Behaviorally, CBD taken before THC has been shown to preempt many of the psychoactive effects of THC including anxiety [5,6]. The jury is still out on the effectiveness of taking CBD after the fact, so if you end up eating an entire tray of special brownies like this couple, and are hoping to take CBD as an antidote, you’re likely out of luck.

Epidiolex

The truth is, we know very little about the effects of cannabinoids, and even less about the action of CBD than we do THC. So why the explosion in popularity of CBD in the homeopathic sector? This can likely be traced to a rare form of pediatric epilepsy known as Dravet syndrome. A small community of parents in 2013 found that oil extracted from marijuana plants low in THC had miraculous effects on children otherwise unresponsive to medication and doomed to 10s to 100s of seizures a week [7]. While the evidence was at first anecdotal, in 2017 a phase III clinical trial measuring the effectiveness of CBD in treating Dravet syndrome was successful, leading to the first FDA-approved cannabis-derived drug, Epidiolex [8].

The Rub

While CBD has gained medical legitimacy with the success of Epidiolex, legally all other CBD products are a bit of a mess. From the Drug Enforcement Agency’s (DEA) perspective, almost all CBD products are classified as schedule I drugs, meaning they have the highest potential for abuse. This means they have no currently accepted medical use. In theory, this implies they are as dangerous as heroin and more dangerous than meth and fentanyl (both schedule II drugs). Only CBD products derived from the leaves or stems of the hemp plant (not the flowers) and without the smallest trace of THC are federally legal. While the federal government has mostly turned a blind eye to what is done within states, interstate transport of the cannabinoid is illegal, potentially making access difficult for those in remote areas. Equally pressing is the fact that CBD’s federal status restricts research using federal funds, meaning that it will be much longer before we have a basic scientific understanding of how CBD acts on the body.  

Partially as a consequence of this restriction, CBD research has been slow. A quick poll of the scientific literature turned up 17,000 studies featuring CBD in 2018. While that might seem like a lot, there were more than 4 times as many studies featuring coffee over the same time period. This dearth of research has left a vacuum which has been happily filled with YouTube doctors who joyfully tout CBD as the panacea. While CBD has clearly shown promise with certain forms of epilepsy, how does it pan out in treating other ailments like pain, anxiety, and cancer?

Chronic Pain

There have been a few large trials in Europe utilizing a THC/CBD oral spray for managing cancer-related and peripheral nerve pain [9,10] . These studies found significant improvements in reported pain and quality of life metrics relative to a placebo group. Notably, a mixture of THC and CBD was found to be more effective than THC alone.

Anxiety/Paranoia

As we saw earlier, CBD can preempt THC-induced paranoia [5,6]. It would follow that CBD might also work for other types of anxiety such as that associated with public speaking or general social situations. While some preliminary work shows positive results, these studies were exploratory, had low sample sizes, and in one case (for some unknown reason) only surveyed 10 right-handed men [11,12]. Larger studies more indicative of the general population are needed before any real inferences can be made here.

Cancer

While CBD and marijuana in general have an established history in reducing the symptoms tied to cancer treatment, such as loss of appetite, there is much less known about the actual effects of the molecule on tumors themselves. Some have suggested that CBD might be a good candidate as an anti-cancer drug [13], with in vitro studies (those conducted in a petri dish) showing it may fight the spread of lung cancer [14]. However, as has been seen time and time again, early success in vitro rarely translates to in vivo success (studies conducted in living organisms), and there is no reason to assume that CBD will fare differently from other potential cancer drugs that made it to this point.

Wrapping Up

Looking forward, CBD has potential to be a useful therapeutic for pain and possibly a host of other ailments. For now, due to the limited research into CBD, we have far more questions than answers. The absence of scientific evidence to support (or refute) their claims has allowed CBD manufacturers to tell their own narrative to a receptive audience. For instance, a YouTube search for “CBD” returns this video as the #1 result. Unfortunately, biology is not as simple as the speaker’s caption would have you think.

CBD_YouTube

On the bright side, CBD does not show any signs of being dangerous [4-12] as long as what you consume is actually CBD. Several recent studies have found that many or most CBD products misreport their CBD content (by an average of over 10%) and are often found to contain high levels of THC [15]. For those who can’t wait for science to catch up with the hype, it would be a good idea to at least verify the CBD product you are taking (or giving to your dog) is what it says it is. Consumer reports suggests verifying a supplier has a certificate of analysis indicating the content of the final product and ensuring the product you buy has the CBD and THC content you desire [16].

While there is a lot of excitement and potential for CBD as a therapeutic, this largely stems from its youth in the collective consciousness. With time, scientific inquiry will uncover what is true and what is hype. Notably, the chief source of evidence for many of the reports seen in online forums or at farmers markets is anecdotal. While personal accounts are important, without an understanding of variability across individuals, as well as the effects of expectation itself, no individual can act as a deciding data point. In the clinical trial for Epidiolex [8] for example, 27% of patients receiving placebo (oil without CBD) had their seizures reduced by over 50% during the trial! While this was significantly less than the 43% of patients seeing a 50% reduction in the CBD group, if you happened to be friends with someone from this 27% and they were taking wheatgrass shots instead, you might be tempted to slug the utterly impalpable juice yourself when good ol’ water would probably have the same effect. When it comes to any health craze, it is probably best to let the science catch up to the hype.

Works Cited

[1] Aizpurua-Olaizola, O., Soydaner, U., Öztürk, E., Schibano, D., Simsir, Y., Navarro, P., … & Usobiaga, A. (2016). Evolution of the cannabinoid and terpene content during the growth of Cannabis sativa plants from different chemotypes. Journal of natural products, 79(2), 324-331.

[2] Pertwee, R. G. (2008). The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9‐tetrahydrocannabinol, cannabidiol and Δ9‐tetrahydrocannabivarin. British journal of pharmacology, 153(2), 199-215.

[3] Wilson, R. I., & Nicoll, R. A. (2002). Endocannabinoid signaling in the brain. Science, 296(5568), 678-682.

[4] Silvestri, C., & Di Marzo, V. (2013). The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders. Cell metabolism, 17(4), 475-490.

[5] Englund, A., Morrison, P. D., Nottage, J., Hague, D., Kane, F., Bonaccorso, S., … & Feilding, A. (2013). Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. Journal of Psychopharmacology, 27(1), 19-27.

[6] Bhattacharyya, S., Morrison, P. D., Fusar-Poli, P., Martin-Santos, R., Borgwardt, S., Winton-Brown, T., … & Mehta, M. A. (2010). Opposite effects of Δ-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology, 35(3), 764.

[7] CBS Denver (November 18, 2013), Epilepsy Patients Flock To Colorado After Medical Pot Gives Them Hope, CBS Denver, retrieved January 1, 2014

[8] Devinsky, O., Cross, J. H., Laux, L., Marsh, E., Miller, I., Nabbout, R., … & Wright, S. (2017). Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. New England Journal of Medicine, 376(21), 2011-2020.

[9] Johnson, J. R., Burnell-Nugent, M., Lossignol, D., Ganae-Motan, E. D., Potts, R., & Fallon, M. T. (2010). Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC: CBD extract and THC extract in patients with intractable cancer-related pain. Journal of pain and symptom management, 39(2), 167-179.

[10] Serpell, M., Ratcliffe, S., Hovorka, J., Schofield, M., Taylor, L., Lauder, H., & Ehler, E. (2014). A double‐blind, randomized, placebo‐controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment. European journal of pain, 18(7), 999-1012.

[11] Zuardi, A. W., Cosme, R. A., Graeff, F. G., & Guimarães, F. S. (1993). Effects of ipsapirone and cannabidiol on human experimental anxiety. Journal of psychopharmacology, 7(1_suppl), 82-88.

[12] Crippa, J. A. S., Derenusson, G. N., Ferrari, T. B., Wichert-Ana, L., Duran, F. L., Martin-Santos, R., … & Filho, A. S. (2011). Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. Journal of Psychopharmacology, 25(1), 121-130.

[13] Massi, P., Solinas, M., Cinquina, V., & Parolaro, D. (2013). Cannabidiol as potential anticancer drug. British journal of clinical pharmacology, 75(2), 303-312.

[14] Ramer, R., Bublitz, K., Freimuth, N., Merkord, J., Rohde, H., Haustein, M., … & Hinz, B. (2012). Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1. The FASEB Journal, 26(4), 1535-1548.

[15] Bonn-Miller, M. O., Loflin, M. J., Thomas, B. F., Marcu, J. P., Hyke, T., & Vandrey, R. (2017). Labeling accuracy of cannabidiol extracts sold online. Jama, 318(17), 1708-1709.

[16] Gill, L. L. (2018, September 27). How to Shop for CBD. Retrieved February 6, 2019, from https://www.consumerreports.org/marijuana/how-to-shop-for-cbd/

Image Sources

[1] Personal

[2] Adapted from [2]

[3] Adapted from [3]

[4] https://www.epidiolex.com/

[4] https://youtu.be/3bZb10ZxpBk?t=23

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