Is CBD a Cure-All?

Panacea, elixir of health, a universal remedy that heals every disease. Pharmacy has been searching for it since time immemorial. Many candidates for the title “king of medicines” have come from the plant kingdom. All of them ended the same way: expectations were too high and were not confirmed in scientific studies. This soon led to a decline in public and scientific interest and a shift to other types of compounds. Who is today’s candidate?

Is CBD a Cure-All?

Panacea, elixir of health, a universal remedy that heals every disease. Pharmacy has been searching for it since ancient times. Many candidates for the title “king of medicines” have emerged from the plant world. So far, all ended up the same: expectations were too high and not confirmed by scientific studies. This soon led to a decline in public and scientific interest and a transition to other types of compounds. So who is today’s contender?

It could be said that after alkaloids and saponins (compounds similar to steroids found, for example, in ginseng), cannabinoids have taken the baton. And among them, the main favorite is none other than cannabidiol — CBD.

Non-Psychoactive and Accessible

There are two main reasons why the greatest hopes are placed in CBD rather than another cannabinoid.

First, cannabidiol is non-psychoactive and, as far as we know, has virtually no side effects. Therefore, it is legal in most countries around the world.

Second, unlike most other cannabinoids, CBD occurs in cannabis in significant amounts. In this regard, only CBG can compete with it alongside THC, but high-CBG strains have only appeared in recent years.

Thanks to these two factors, there are no major obstacles to clinical research on CBD or the sale of products containing it. While commercial claims are often sensational, scientific findings are much more cautious.

What’s striking about the conditions and indications where CBD has shown some efficacy is not just the number, but especially the diversity. How can the same molecule suppress epileptic seizures, exhibit anticancer activity, help with infections and depression, regulate blood pressure, and accelerate bone healing?

At first glance, it seems like nonsense and a marketing trick. Is such a thing even possible? The answer is: yes.

Endocannabinoid System

The reason may lie in the incredible complexity and importance of the endocannabinoid system. It consists of much more than just the two well-known receptors (CB1, CB2) and one signaling molecule (anandamide) that binds to them.

So far, five receptors directly part of this system are known, along with at least four more closely related ones. There are eight known endocannabinoids that bind to these receptors. Their production and breakdown are managed by at least four enzymes. And since endocannabinoids are not water-soluble, several transport proteins allow them to move through intercellular fluid, which is primarily water.

How Does CBD Fit In?

CBD acts at multiple sites within this system. Let’s take a closer look.

A receptor is a protein molecule with a complex 3D structure. If a smaller molecule of the right shape binds to a specific site, it fits like a key in a lock and either fully activates it (full agonist), partially (partial agonist), or not at all — simply blocking it (antagonist).

A special case is when it attaches at a different site — "from the side" — and makes it easier or harder for the key to fit in. This is called positive or negative allosteric modulation.

It is not yet fully certain which of these variants happens when CBD contacts CB1 and CB2 receptors. In the case of CB1, it likely acts as a negative allosteric modulator, enabling CBD to reduce the undesirable mental effects of THC.

The interaction of CBD with CB2 is still under debate. CBD was once considered a full activator of CB2, believed to be behind its strong anti-inflammatory effect. However, several in vitro studies have disproven this, often describing negative allosteric or even antagonist activity.

GPR Receptors

It is now known that the endocannabinoid system also includes receptors GPR18, GPR55, and GPR119. Until recently, they were called "orphan" receptors because it was unknown what substances bind to them.

Today we know that GPR18 is primarily activated by the endocannabinoid N-arachidonylglycine. However, CBD has the opposite effect — it blocks it. The exact function of GPR18 is still unknown, but it appears to play a key role in inflammation.

GPR55 was recently declared the long-sought CB3, the third receptor for anandamide. However, many experts believe it is too early for such a reclassification. Although still poorly studied, the receptor’s extraordinary importance is already evident.

CBD’s ability to block this receptor seems essential: it is believed to regulate blood pressure, act against tumors, and accelerate fracture healing. It is fairly well known that CBD’s interaction with GPR55 also plays an important role in its antiepileptic and anti-inflammatory effects.

Finally, GPR119 has so far been found only in the pancreas and is activated by the endocannabinoid 2-oleoylglycerol. It appears to play a key role in the development of diabetes. CBD’s interaction with this receptor has not yet been investigated.

TRPV Receptors

Closely related to the endocannabinoid system are TRPV-1 receptors. They respond to certain chemical stimuli such as capsaicin (from chili peppers) and also to high temperatures. Malfunction of these receptors plays a key role in epilepsy, seizure disorders, and chronic pain.

Surprisingly, CBD fully activates these receptors, just like capsaicin. When applied, capsaicin initially causes a painful response, but then reduces pain — which is why it’s used in warming patches and creams. It is still unclear why CBD does not cause a burning sensation despite acting similarly. Some studies even suggest that co-administration with CBD reduces capsaicin’s burning. Through TRPV-1 activation, CBD helps suppress epileptic seizures and chronic pain.

CBD also activates TRPV-2 receptors, which do not respond to capsaicin but are involved in epilepsy, cardiovascular disease, diabetes, and inflammation.

PPAR Receptors

Among other receptors activated by endocannabinoids are PPARs, especially the alpha and gamma subtypes. They are mainly responsible for regulating fat and sugar metabolism — burning or storing them.

Insufficient activation is typical for chronic inflammatory diseases such as diabetes or Alzheimer’s disease, and for some cancers. CBD, like other phytocannabinoids (especially in their acidic forms), is an agonist of these receptors.

Influencing Other Receptors

The endocannabinoid system is responsible for maintaining harmony within the entire organism. To do this, it must regulate all chemical pathways in the body. One mechanism it uses is forming receptor dimers — where a cannabinoid receptor binds to another type of receptor, such as serotonin, dopamine, or opioid receptors, and influences it indirectly.

In addition to this indirect activity, plant cannabinoids usually affect neurochemical subsystems directly. CBD is no exception. Like some modern antidepressants, it acts on the serotonin system in two ways.

First, it allosterically binds to the 5-HT1A receptor, making it easier for serotonin to bind. Second, it blocks serotonin reuptake, allowing longer action. CBD thus reduces anxiety and improves mood without strong sedative effects.

On opioid delta and mu receptors, CBD acts as a negative allosteric modulator, reducing their ability to bind to endorphins or opioid molecules. This likely explains CBD’s therapeutic success in treating addiction. Evidence also suggests CBD may partially activate dopamine D2 receptors, potentially contributing to its antipsychotic effects.

Interaction with Enzymes

The most important part of CBD’s complex effect may not lie in receptor interaction, but in its effect on enzymes. Enzymes, like receptors, are protein molecules with complex structures that bind to smaller, appropriately shaped molecules. Enzymes can join (synthases), break down (lyases), or modify these molecules (e.g., aminases, oxidases, etc.). CBD is one of the compounds that can influence enzyme activity — speeding it up, slowing it down, or completely stopping it.

The most important enzyme CBD interacts with is FAAH (fatty acid amide hydrolase). Its primary role is to break down the best-known endocannabinoid — anandamide.

If FAAH activity is inhibited — for example, by CBD — anandamide levels increase. Anandamide has strong anti-inflammatory, antipsychotic, mood-enhancing, and antimicrobial effects.

It’s no wonder pharmaceutical companies quickly tried to develop synthetic drugs to inhibit FAAH. However, this proved risky. In 2016, a clinical trial with BIA 10-2474 endangered five volunteers and led to one death. The likely cause was low selectivity for FAAH, meaning the compound also bound to other important enzymes.

Transport via Proteins

As mentioned earlier, transport proteins are responsible for moving endocannabinoids through a water-based environment in which they are not soluble. This is crucial for reaching enzymes that degrade them (e.g., FAAH).

Reduced activity of transport proteins slows down the degradation of endocannabinoids, particularly anandamide. It was only recently confirmed that one of the world’s most commonly used analgesics, paracetamol, works in this way. A similar effect has been described for CBD.

The Unique Role of CBD and THC

Some known mechanisms of CBD action (e.g., TRPA-1 and TRPA-8 receptor activation) are not included here, and many more are yet to be discovered. However, we can already say that very few compounds interact with the human body in such a complex and multifaceted way.

So is CBD a mythical panacea? No. But does it have a place in clinical medicine? Absolutely. Some conditions, however, require a stronger intervention in the endocannabinoid system, and only THC is capable of that among known compounds. CBD has the greatest medical value when combined with THC and other cannabinoids. Such treatment, however, is only possible in a society that values its citizens' health more than ideological nonsense.

This article was also published in the magazine KONOPÍ.