High Times

Beyond THC and CBD: The science of cannabinoids and the brain

There are more than 100 cannabinoids in cannabis, and all of them can affect our brains and bodies. Here's what science does — and doesn't — know about cannabinoids and the brain.

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When we think cannabis, most of us think of the chemical THC — although CBD is quickly rising in popularity, too. Both cannabidiol and tetrahydrocannabinol, to give them their full names, are cannabinoids — chemical compounds found in marijuana. But while they are the most famous, they are far from the only cannabinoids.

In fact, scientists have discovered more than 100 other cannabinoids — and those are just the ones found in the cannabis plant. In total, there are more than 500 cannabinoids, all of which can have an affect on our bodies and brains. What is perhaps most exciting about these myriad chemicals are the potential therapeutic effects they could have — if the research holds up, cannabinoids could represent hundreds of new drugs for human benefit.

And that list is growing.

In a December 2019 study, scientists announced the discovery of two new cannabinoids — and both of them could pack some real psychoactive power, even compared to the well-known THC.

But despite how abundant they are and the affects they can have, most of the cannabinoids know to science remain a mystery: Scientists aren’t sure how exactly they change the brain and body. Legal restrictions in cannabis — it is a Schedule 1 drug in the United States — mean researchers are stymied by protocol and lack of available resources to do the work. But from what little research has snuck through the barriers, we do know that the body’s own natural endocannabinoid responds uniquely to phytocannabinoids — those that come from the cannabis plant. And some can have some unusual — and maybe even beneficial — effects.

"All cannabinoids are equally important."

Inverse spoke to the experts to find out exactly what scientists do — and don't — know about the different cannabinoids and what they do to our brains. We focused on five cannabinoids — they’re the big ones to watch as cannabis’ wide-ranging potential therapeutic uses become increasingly important in modern medicine.

Tetrahydrocannabinol

  • What does THC do in the brain?

Cannabinoids bind to two receptors in the brain, CB1 and CB2 — CB1 is linked to the nervous system, while CB2 is connected to the immune system. Tetrahydrocannabinol (THC) mainly targets the CB1 receptors, which means the chemical affects the brain.

In the brain, THC mimics something known as the “bliss molecule,” or anandamide, a chemical that naturally occurs in the body. Anandamide and other endogenous cannabinoids affect the brain areas that play a role in pleasure, memory, cognition, concentration, movement, coordination, sensory perception, and perception of time, according to the National Institute on Drug Abuse.

One of the most important brain areas THC alters is the hippocampus, which plays a critical role in learning and memory. When you take THC, it limits the brain’s capacity to learn new things and do complex tasks. At the same time, it stimulates your reward system to release more of the neurotransmitter dopamine, which all adds up to the feeling of being “high.”

The length of a cannabinoid's side chain determines its potency, at least in part, research shows. Shutterstock
  • How does THC change behavior?

THC is the chemical most commonly associated with smoking, vaping, or ingesting cannabis. It is the compound that causes all the stereotypical hallmarks of being stoned — including giggling, bumbling, silly "highdeas," and heightened appetite.

  • How is THC used in medicine or recreation?

In regions where cannabis is legal for recreational and/or medical use, you can buy THC isolate — that's the THC chemical by itself — to get the effects of the cannabinoid without any potential interference from the myriad other chemicals in weed.

In medicine, THC is often prescribed in tandem with CBD for a variety of conditions. One drug that contains THC is Sativex, which treats muscle spasms and stiffness from multiple sclerosis. Although it has shown promise in early clinical trials, it is not currently available for use in the United States.

In the US, people with AIDS and those undergoing chemotherapy can respectively take advantage of two Food and Drug Administration-approved drugs, Marinol and Cesamet. Both of these medications ease nausea and can improve appetite.

Cannabidiol

  • What does CBD do in the brain?

Cannabidiol (CBD) is a rather different beast to its sister compound THC. Instead of binding to specific brain receptors, CBD works by blocking your brain's receptors' from binding to cannabinoids. When it is consumed with THC, it actually blocks some of THC's effects.

Understanding how it works involves backing up to look at what makes cannabis work in the first place.

Cannabis’ key affect on the brain is called retrograde inhibition — the idea that brain signals can flow backward. For decades, scientists believed that when the brain receives an incoming piece of information, it processes it and sends a signal triggering a corresponding reaction. "we thought neurotransmissions only went one way," says David Bearman, a California-based physician who researches and writes about cannabis and other substances.

But with cannabinoids — and especially cannabinoids like CBD — things can get weird. When these cannabinoids bind to receptors in the brain, the resulting signal can travel from the part of your brain that normally receives these transmissions to the neurons that normally send them.

If that happens, it can create problems for neural signaling as a whole, Bearman says.

"This is like throwing sand in the machinery,” he says.

CBD's popularity has spiked recently as a cure-all supplement.Shutterstock
  • How does CBD change behavior?

Like THC, cannabidiol is psychoactive in that it changes your brain, but it doesn’t give you the same high as THC. In fact, CBD offsets some of THC’s effects, like the sense of euphoria it causes, and, in isolate, can actually make you feel less stoned. Taken alone, some say CBD produces a relaxing, chilled-out effect.

  • How is CBD used in medicine or recreation?

CBD's affect on brain signaling may sound unusual, but it could also have some health benefits, especially in conditions where neural signaling has gone otherwise awry. Thus far, CBD has shown promise in treating conditions like epilepsy, migraine, attention deficit hyperactive disorder, or chronic pain, Bearman says.

To date, CBD is approved by the Food and Drug Administration to treat seizures, with a medication called Epidiolex. But the compound is widely available as an isolate, and some claim it can help with everything from anxiety to chronic pain.

Cannabichromene and the brain

  • What does CBC do in the brain?

Unlike THC and CBD, Cannabichromene (CBC) binds poorly to CB1 receptors in the brain, so its main effects are related to those CB2 receptors, which are connected to the immune system.

  • How does it change behavior?

This cannabinoid does not produce a high, and may not produce any behavioral affects in humans at all. But the research is still preliminary. A 2010 study in mice suggests that CBC may affect motor activity, essentially suppressing movement in response to fear in mice. However, a 2005 study of brain activity in 22 people found that CBC did not produce any noticeable changes in the participants' behavior or activity.

Cannabichromene molecule.Shutterstock
  • How is it used in medicine or recreation?

CBC’s anti-inflammatory properties are among the reasons more experts are showing interest in cannabinoids as medical treatment. The compound can even limit growth of some cancer cells, reported Cannabis Science and Technology. And it might have antibacterial properties — as does CBD — making cannabis a potential player in combatting the ongoing antibiotic-resistance crisis.

Cannabigerol

  • What does CBG do in the brain?

Cannabigerol (CBG) seems to target both CB1 and CB2, research suggests. That means that strains of cannabis that are high in CBG may affect both the mind and the body.

Cannabigerolic acid or CBGA cannabinoid molecule.Shutterstock
  • How does it change behavior?

CBG isn’t itself psychoactive. It works in tandem with other cannabinoids to alter some of the psychoactive effects of cannabinoids like THC. It can reduce paranoia, according to cannabis company Cresco Labs.

  • How is it used in medicine or recreation?

Like CBC, CBG, also has some antibiotic qualities, as well as some mild anti-fungal ones. Scientists believe it could help treat skin conditions like psoriasis and acne by limiting keratin-producing skin cells. These anti-inflammatory mechanisms also mean that CBG may have promise in stunting the growth of certain cancers and in easing the features of conditions like inflammatory bowel disease and Crohn’s disease.

Despite this promise, there are no drugs now on the market using CBG as an active ingredient, but unlike its sister compound THC, CBG is not set at Schedule 1.

Cannabinol

  • What does CBN do in the brain?

Cannabinol (CBN) is mostly found in aged cannabis plants, because it is produced by the degradation of THC. It has a much lower affinity for the body's CB1 receptors, but a higher one for CB2 receptors. As a result, CBN doesn't have too much affect on our brains and has a more pronounced affect on the immune system, research suggests.

Cannabinol molecule.Shutterstock
  • How does CBN change behavior?

Research suggests that CBN increases the potency of THC — making people feel more “drugged, drunk, dizzy, and drowsy” than they did after consuming THC alone. CBN is found in small amounts in cannabis and typically not consumed in isolate, so it is hard to say if taking CBN by itself might not have a dramatic effect.

  • How is CBN used in medicine or recreation?

The legality of CBN is tricky: The substance itself isn’t as strictly regulated as other cannabinoids like THC. But it could also be considered an analogue to THC — after all, it’s derived from THC — under US federal laws. As of right now, there aren’t any drugs available that contain CBN, and it’s not a readily available isolate like CBD.

The future of cannabinoid research

There is a lot we still don’t know about cannabis, but a growing number of researchers are working to understand its many constituent chemical parts. Doing so, despite the barriers to research, could hold big benefits for our health.

One of the lesser-known kids on the block is cannabinodiol, which arises when CBN — a product of THC — is "photochemically rearranged." It is found in cannabis in small amounts and carries some psychotropic effects. Another is CBT, or cannabitriol, which has a structure similar to THC and, potentially, similar therapeutic properties.

"If you called it chicory, instead of cannabis, there would be less prejudice."

Two cannabinoids discovered in December 2019 may hold promise, too. Both of them are relatives of THC and CBD, although one of them may be much more potent than THC, the researchers speculate.

Dubbed tetrahydrocannabiphorol and cannabidiolic acid, or THCP, and CBDP, the two cannabinoids join the ever-expanding list of compounds in cannabis. The pair may help researchers identify the medical components of cannabis, says Giuseppe Cannazza, corresponding author and assistant professor at the University of Modena and Reggio Emilia in Italy.

"It is important to understand what a medicine contains," Cannazza tells Inverse. "Up to now nobody could imagine the existence of these new phytocannabinoids, thus their presence could explain some therapeutic activities observed with different strains of cannabis."

THCP has a structure identical to THC, but it is a longer molecule. It could be much more powerful than regular THC — it binds to the brain's receptors with a "30-fold affinity compared to THC," Cannazza says. "This explains the high THC-like activity observed in the in vivo experiments on mice."

But that doesn't necessarily translate to the intensity of your high, as Vice reported at the time. In fact, THCP might not even be psychoactive. Like most of the compounds found in the cannabis plant, researchers don't know precisely how it changes the brain.

Answering the question of which cannabinoids have therapeutic value is difficult, Cannazza says. The answer could be "none and all."

Each phytocannabinoid "has both therapeutic properties and side effects," he says. "It depends on the dose."

For that reason, getting too specific about individual cannabinoids and what each one does isn't always the most helpful for research, he says.

"I don’t think our attention should focus on a particular phytocannabinoid, but all cannabinoids are equally important."

Flowering cannabis plant of the strain Diamond Zkittlez. Humboldt countyShutterstock

To get a sense of the different effects however, it is important to remember that a particular strain of cannabis may have a higher concentration of a specific cannabinoid, which means there's a good chance that the effect of that strain can be attributed to that cannabinoid. Of course, Cannazza says, it may be that the effects of any given kind of cannabis arise from the different cannabinoids working in tandem, like the different instruments of an orchestra playing in sync to produce a melody.

Bearman agrees. “I think trying to isolate any one constituent of cannabis is a mistake,” he says. That goes even for the big ones, THC and CBD: "Are they useful? Yes. Are they as useful as the whole plant? No.”

Federal laws and logistical barriers can hinder progress, researchers say. Researchers have a history of pushing back against the Drug Enforcement Agency, saying that policies can delay projects for more than a year.

Moving cannabis from Schedule 1 — the highest drug class — to Schedule 2 would be a boon, Bearman says. “That would break the dam in terms of allowing researchers to do effective research,” he says.

Teaching clinicians about the endocannabinoid system may also increase their willingness to do cannabinoid research, Bearman says.

But the blocks on research aren't entirely the fault of federal laws: Part of what holds the science back is the perception of cannabis, Cannazza says.

"Unfortunately, there is a lot of prejudice on cannabis and its derivatives," he says. "It would be important to treat it as any other medicinal plant that provides important active principles for the treatment of different pathologies. If you called it chicory, instead of cannabis, there would be less prejudice."

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