These days it seems like everyone is talking about hemp, from legislators to athletes to your neighbor. Not everyone is on the same page either, mixed messages are all around. For all the people singing its praise, it seems like there are just as many dolling out cautionary tales and warnings. You have probably heard of CBD (cannabidiol), the “active ingredient” in hemp. You might be aware that CBD can also be found in marijuana. You may have even heard that hemp is really just another name for marijuana without THC (tetrahydrocannabinol). But if marijuana “gets you high”, why doesn’t CBD?
To answer this question, we have to understand why marijuana is intoxicating. Marijuana contains a group of molecules known as “phytocannabinoids”, a group that includes both CBD and THC. Phytocannabinoids are molecules that mimic compounds produced by your own body known as “endocannabinoids”1. Both of these types of molecules are considered “cannabinoids”. Cannabinoids interact with special proteins on the surface of cells known as “cannabinoid receptors” (CB receptors), of which there are two varieties, CB1 and CB2. CB2 receptors are primarily found on immune cells, while CB1 receptors are primarily found on neurons (also known as brain cells)2.
Cannabinoids interact with CB receptors in two basic ways. The primary way is through a process known as orthosteric interaction4, 3. You can think of cannabinoid receptors as being sort of like a car’s ignition mechanism. The receptor has a “keyhole” that is shaped in such a way as to only allow certain molecules in. This is called the orthosteric binding site. When a cannabinoid comes along that is shaped just right, it fits into this “key hole” and activates the receptor in a way that is very similar to turning the key to start a car. This is how THC works. It fits into CB1 receptors in the brain just right, “turning them on”. This causes changes in the activity patterns in the brain, resulting in intoxication and “feeling high”4.
The second way cannabinoids can interact with CB receptors is through a process called allosteric modulation3. In this case, think again about starting a car. If you simply insert the key and twist, the car doesn’t start. However, if you put your foot on the break and then twist, the car can start. This is essentially how allosteric modulation works. An allosteric modulator is shaped just right to fit onto a different part of the cannabinoid receptor than its “keyhole” or orthosteric binding site. This other part of the receptor, called an allosteric binding site, changes what happens when a molecule fits into the “keyhole”. In the car analogy, the brake pedal is the allosteric binding site, and your foot is a “positive allosteric modulator”. It improves the activation of the “keyhole”, or orthosteric binding site.
CBD acts a lot like a foam block under the brake pedal. It is shaped just right to fit underneath the pedal, preventing it from being pressed down all the way. When the driver tries to press down on the brake pedal and turn the THC key, the car still won’t start because the ignition mechanism can’t fully engage. The THC key still fits in the CB1 keyhole, and pressing down on the break lets you twist the key a little bit. You might even hear some clicks from some of the machinery trying to engage, but the CBD foam block prevents the ignition from fully activating and actually starting the car. To sum it up, CBD acts as a “negative allosteric modulator” of CB1 receptors5, and can actually reduce (but not eliminate) some aspects of the “high” that comes from THC6 by interfering with its interaction at the orthosteric site of CB1 receptors.
CBD has a number of valuable properties, and does act on the brain. However, because of the special way that it interacts with cannabinoid receptors, it does not “get you high”. In fact, it can even help to reduce the “high” that comes from THC. This property means that nearly everyone can benefit from CBD and CBD oil, without it negatively affecting their lifestyle or job performance.
- Di Marzo, V., Piscitelli, F. The Endocannabinoid System and its Modulation by Phytocannabinoids. Neurotherapeutics 12, 692–698 (2015). https://doi.org/10.1007/s13311-015-0374-6
- Howlett, A. C., & Abood, M. E. (2017). CB1 and CB2 Receptor Pharmacology. Advances in pharmacology (San Diego, Calif.), 80, 169–206. https://doi.org/10.1016/bs.apha.2017.03.007
- Nussinov, R., & Tsai, C. J. (2012). The different ways through which specificity works in orthosteric and allosteric drugs. Current pharmaceutical design, 18(9), 1311–1316. https://doi.org/10.2174/138161212799436377
- Pertwee R. G. (2008). The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. British journal of pharmacology, 153(2), 199–215. https://doi.org/10.1038/sj.bjp.0707442
- Paula Morales, Pilar Goya, Nadine Jagerovic, and Laura Hernandez-Folgado.Cannabis and Cannabinoid Research.Dec 2016.22-30.http://doi.org/10.1089/can.2015.0005
- Abigail M. Freeman, Katherine Petrilli, Rachel Lees, Chandni Hindocha, Claire Mokrysz, H. Valerie Curran, Rob Saunders, Tom P. Freeman, How does cannabidiol (CBD) influence the acute effects of delta-9-tetrahydrocannabinol (THC) in humans? A systematic review, Neuroscience & Biobehavioral Reviews, Volume 107, 2019, Pages 696-712, ISSN 0149-7634, https://doi.org/10.1016/j.neubiorev.2019.09.036. (http://www.sciencedirect.com/science/article/pii/S0149763419305615)