Meet the New Phytocannabinoids

Meet the New Phytocannabinoids

FUNCTIONAL/INTEGRATIVE MEDICINE

Meet the New Phytocannabinoids

Go beyond CBD to explore other phytocannabinoids that can help you deal with anxiety, stress, inflammation, insomnia, PTSD, depression, and more.

By Mo Perry | Experience Life

February 29, 2024

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Several years ago, follow­ing the birth of her second child, ­Cindy Applebaum was struggling with anxiety and insomnia. A friend gave her a CBD edible to try, but she was wary — her experiments with cannabis as a teenager hadn’t been pleasant. She decided to try the gummy on a weekend when her husband would be home to help with the kids, in case she didn’t respond well.

The result was one of the best, most relaxed days she’d enjoyed in years. Eventually, Applebaum (not her real name) discovered that taking a CBD-rich sublingual tincture for periodic anxiety greatly improved her quality of life. Her sleep improved as well. She’s now a self-described cannabis advocate and considers the plant an invaluable support for managing everyday stress.

One key reason humans tend to ­respond so well to phytocannabinoids is because they closely mimic the cannabinoids produced by the human body. The endocannabinoid system, or ECS, was first identified in the late 1980s and early 1990s by researchers who were exploring the physiological effects of cannabis. They discovered that our body’s endocannabinoids ­interacted with the same receptor sites as the cannabis molecules.

“The ECS is located just about everywhere in our body,” explains Bonni Goldstein, MD, medical director of Canna-Centers Wellness & Education in California and author of Cannabis Is Medicine. “It’s a physiologic regulator, so when we have a stressor of some sort — an illness, a traumatic injury, inflammation, anything that tips us out of homeostasis — the ECS goes into action to help us get back into balance.”

Thanks to a changing legal landscape, most of us now have access to phytocannabinoids in some form. The illicit aura that so recently surrounded cannabidiol (better known as CBD) has largely vanished. Today it appears routinely on supplement shelves as a remedy for pain, insomnia, and anxiety.

Yet CBD is just one of the many phytocannabinoids found in cannabis plants — and it’s worth getting to know more of them.

What Are Phytocannabinoids?

Phytocannabinoids are found primarily in cannabis, though they also ­appear in some legumes, fungi, and rhododendrons. Cannabis also contains phytochemicals called flavonoids and terpenes. These molecules may give different cannabis strains their unique therapeutic properties, as well as any distinct aroma.

Cannabis refers to the drug-variety plant, which contains tetrahydrocannabinol, or THC, the principal psychoactive element. It also refers to industrial hemp, which is legally defined as cannabis containing less than 0.3 percent THC. THC and CBD are by far the most studied phytocannabinoids — and the most abundant.

Still, they’re not the only ones. ­Researchers have now identified more than 140 phytocannabinoids. Some, such as cannabigerol (CBG), cannabinol (CBN), cannabichromene (CBC), and cannabidiolic acid (CBDA) — known as the minor cannabinoids — are increasingly appearing alongside CBD in products geared toward specific aims. These include improved sleep, better focus, and pain relief.

“I liken cannabis to a bowl of chili,” says Goldstein. CBD and THC are the meat and beans, she says, and the minor cannabinoids, flavonoids, and terpenes are the vegetables and spices. “They have an influence on how the chili tastes — meaning its ­effect on humans — but they’re not the dominant compounds.”

Most commercially available CBD products are made from hemp, since cannabis plants with higher levels of THC remain illegal at the federal level. In Goldstein’s analogy, you can think of hemp as a Texas chili: mostly meat (CBD) and minimal beans (THC).

But as anyone who’s attended a chili cook-off knows, it’s the other ­ingredients that make a recipe sing. “It’s a mistake to focus on THC and CBD alone,” notes Robert Rountree, MD, a Boulder-based functional-medicine physician. “They are two chemicals out of hundreds in Cannabis sativa, and they all seem to work in concert with each other.”

What Is the Entourage Effect?

Combining phytocannabinoids follows traditional plant-medicine practices. “Our modern medical approach is to isolate cannabis compounds like we do with drugs, but there’s wisdom in how nature has put these things together,” notes ­integrative psychiatrist Henry Emmons, MD. “Plant-based, natural therapies are often more effective when you’re getting the whole plant.”

This theory is known as the entourage effect. It’s one reason choosing a full-spectrum product may be so important: It contains multiple extracts from the cannabis plant, including terpenes and flavonoids, and these appear to work together for greater benefit.

“It’s like these compounds are playing a complex symphony,” says Matt Storey, director of medical sales at Charlotte’s Web, a company that manufactures hemp-based CBD products. (Note: Charlotte’s Web products are sold at Life Time, which publishes Experience Life.) Rather than isolating the brass section, cannabis research is increasingly focused on how various elements are playing together — and which combinations of compounds tend to produce certain harmonious effects.

For example, some evidence suggests CBD can moderate the intoxicating effect of THC, while THC may augment the pain-relieving properties of CBD.

Terpenes play a role here too. The terpenes limonene and linalool have been found to enhance CBD’s capacity to soothe anxiety. And a combination of CBD, CBG, and the terpene beta-caryophyllene appears to calm inflammation more effectively than any one of the compounds alone.

Research into minor cannabinoids and terpenes is still preliminary, but it’s advancing quickly. In 2022, a group of federal health agencies reasserted their interest in minor cannabinoids and terpenes and how they may affect a range of conditions, including cancer treatment, pain, and substance-use disorders.

“We’re seeing more and more interest in the activities of these compounds,” says Storey. “I think we’re moving toward a point where people will base their preferences on products’ minor cannabinoid profiles or terpene action versus just their major phytocannabinoids.”

5 Phytocannabinoids and Their Benefits

These are some of the most potent phytocannabinoids. Here’s what researchers are learning about them.

1) CBD

Full name: Cannabidiol
Best used for: Sleep, anxiety, stress, inflammation, PTSD

A 2020 survey found that roughly a third of Americans had tried CBD to address pain, inflammation, anxiety, insomnia, headaches, arthritis, or depression. Some pet owners were even using it to help their animals with stress and inflammation. (The bacon-flavored tinctures are an easy sell.)

“I mainly use CBD with my patients for sleep, anxiety, and stress-related symptoms. It’s helpful with calming the nervous system, turning down the alarm bells, and telling your body it’s OK to stand down,” Emmons says. He’s found it particularly helpful for his patients with PTSD who struggle with insomnia.

A growing body of research, much of which has been conducted on animals, has found that CBD’s medicinal benefits are broad. They include antibacterial, anti-inflammatory, neuroprotective, and anticonvulsant effects, as well as nausea reduction, pain relief, and appetite restoration.

CBD blocks the reabsorption (or reuptake) of the body’s own endocannabinoids, allowing them to prolong their effect at the cannabinoid receptors. “This is one way that CBD helps to enhance the function of the endocannabinoid system,” Goldstein says.

Unlike THC, CBD is not intoxicating, though it can be mildly stimulating in lower doses and sedating in higher doses. It’s extremely safe, and side effects are rare. Because it’s metabolized by the liver, however, it can interact with other drugs, so be sure to talk to your medical provider before using it if you’re taking any prescriptions.

Meanwhile, even small amounts of THC appear to boost CBD’s efficacy. “Ideally, a whole-plant cannabis product would be CBD-dominant with a little bit of THC, but also include some of the raw cannabinoids like CBDA, CBGA, and THCA [the acid precursors to the minor cannabinoids],” Goldstein says. “I rarely recommend a purified cannabinoid, for the same reason it’s better to have a whole apple instead of taking a single vitamin.”

2) CBG

Full name: Cannabigerol
Best used for: Depression, anxiety, inflammation, psoriasis

Often referred to as the mother of all cannabinoids, CBG is another non-intoxicating phytocannabinoid that acts as a precursor for the others. “It’s the foundation for producing CBD, CBC, and THC,” Emmons explains.

It’s typically sourced from young plants because CBG levels diminish as plants mature.

“A lot of people report that CBG helps them feel calmer and more focused, but more research is needed to qualify those consumer reactions,” Storey says. It blocks the reabsorption of anandamide — also known as the “bliss molecule” because it contributes to feelings of pleasure and contentment — and this enhances anandamide’s effects.

In response to a recent survey of patients using CBG-dominant supplements to treat anxiety, pain, depression, or insomnia, a majority reported their conditions were “very much improved” or “much improved.”

Goldstein has seen the same results in her patients, alongside other benefits. “I’ve found that CBG helps with pain; it helps with anxiety and depression; and it’s been shown to help with some skin conditions, like psoriasis,” she says.

Researchers have discovered that the skin has its own endocannabinoid receptors (see “The Endocannabinoid System,” further down). The research is still in its infancy, but a study published in 2022 conducted on in vitro skin cells found that CBG can inhibit skin inflammation “more potently than CBD.”

Another case study, from 2019, with two participants, found that topical ­applications containing both CBG and CBD led to improvement in their psoriasis lesions, while the lesions that received a placebo oil showed no improvement.

“In some studies, it’s been shown to have anticancer effects similar to CBD and THC,” Goldstein adds.

3) CBN

Full name: Cannabinol
Best used for: Sleep, inflammation

CBN is widely promoted as a sleep aid, though there’s not yet much research that can explain how it might work. Studies of people taking isolated CBN haven’t reported sedation, though one small study found that CBN did enhance the sedating effects of THC.

“CBN has a higher affinity for the type 2 cannabinoid receptor, which is more involved in ­inflammation than with psychoactivity,” Goldstein notes. People who enjoy better sleep when using CBN may be benefiting from lower inflammation rather than a direct sedative effect.

Meanwhile, studies have found that CBN can ­enhance other phytocannabinoids. In a pre-­clinical drug-screening model, CBN increased the neuroprotective action of THC. And in an animal study, a combination of CBN and CBC offered more pain relief than either compound alone.

4) CBC

Full name: Cannabichromene
Best used for: Pain, gut inflammation

“CBC is really understudied,” Goldstein says. Still, like CBD, CBN, and CBG, CBC is non-intoxicating and appears to enhance the efficacy of other phytocannabinoids.

One study found a greater anti-inflammatory effect from CBC and THC in combination than either alone. And a paper published in 2013 showed that CBC improves the viability of neural stem progenitor cells, which are critical to brain health and healing.

Some research has focused on CBC’s impact on inflammatory pathways in the gut. A study published in 2012 found that CBC normalized gut motility in a mouse model of ­intestinal inflammation, though the mechanism remains unclear.

Researchers in 2020 revealed that both CBG and CBC display antitumor effects against gastro­intestinal cancer cells, inducing significantly higher rates of cancer-cell death compared with other cannabinoids.

5) CBDA

Full name: Cannabidiolic acid
Best used for: Pain, inflammation, epilepsy, nausea

Found in raw cannabis flowers, CBDA converts to CBD when heated. Animal studies have shown it to have antidepressant and antianxiety effects.

Like other phytocannabinoids, CBDA targets serotonin receptors as well as specific cellular sensors called transient receptor potential channels; these are involved in pain, inflammation, skin function, brain function, and cancer. “They’re like tunnels on the cell membrane that allow ions to go in and out of the cell, which regulates how the cell functions,” Goldstein explains.

CBDA can be especially ­potent for inflammatory conditions. “I have a 91-year-old in my practice who developed gout a couple of years ago,” she says. “We found that a daily dose of CBDA kept the gout away, but when he stopped taking it, it flared.”

Although Goldstein usually recommends formulas with some THC for pain relief, she views CBDA as a great option for those who wish to steer clear of THC’s potentially intoxicating effects.

What Is the Endocannabinoid System?

The body produces its own cannabinoids (known as endogenous cannabinoids, or endocannabinoids) to help modulate appetite, memory, immune response, and pain. We have receptors for endocannabinoids in the brain, gastrointestinal tract, reproductive system, heart, blood cells, muscles, and elsewhere. This is called the endocannabinoid system, or ECS, and it’s a big reason phytocannabinoids are such effective medicine.

Like other physiological systems, the ECS may function slightly differently in each of us as a result of genetics and lifestyle. For instance, chronic sleep deprivation can lead to what Goldstein calls endocannabinoid deficiency, in which the body isn’t making enough endocannabinoids.

An underactive ECS can also be congenital. People with conditions such as migraines, fibromyalgia, irritable bowel ­syndrome, epilepsy, and autism often suffer from endocannabinoid deficiency or dysregu­lation. “THC can and does ­correct this imbalance for many patients,” Goldstein says.

The two best-known endocannabinoids are anandamide and 2-arachidonoylglycerol. They help manage nerve-cell signaling in the brain in ways that relieve pain and regulate mood, among other things. When we’re deficient in these chemicals, those processes can suffer.

Our “endocannabinoid tone” reflects our levels of endocannabinoids, how they’re produced and metabolized, and the number and state of cannabinoid receptors — in essence, the overall functioning of our ECS. This used to be impossible to measure directly, and clinicians instead evaluated endocannabinoid tone simply by seeing if someone’s symptoms responded to phytocannabinoids.

That’s starting to change. Some ­research has shown statistically significantly lower levels of the endocannabinoid anandamide in the cerebrospinal fluid of people with migraines. And imaging studies have demonstrated diminished ECS function in people with PTSD.

It will likely be some time before this research informs clinical practices, since the legality of cannabis products still varies across state lines. But diminished ECS function is easily diagnosed through its effects.

The good news for people with an underactive ECS? “You can replace or enhance your own natural endocannabinoids with plant-derived phytocannabinoids,” Goldstein says. “By augmenting that system, you get back into balance.”

Exploring THC as a Medicinal Solution

Among the most abundant phytocannabinoids in the cannabis plant, THC is known for delivering the high that’s associated with marijuana. But research has revealed that it can also be a potent tool for healing.

“THC has amazing medicinal properties, and with proper and responsible use, many different symptoms can be managed,” Goldstein writes in her book.

“THC has amazing medicinal properties, and with proper and responsible use, many different symptoms can be managed.”

A key difference between therapeutic and recreational use of THC involves targeting your minimal effective dose, or the lowest dose that provides positive results without side effects, such as intoxication, a racing heart, or paranoia. This amount varies from person to person.

“I don’t judge the actual milligram dose,” Goldstein says. “You may take 10 mg and get the same medical benefits as your sister with the same condition, who’s taking 50 mg. ­Different people have different absorption, different metabolism, and different underlying endocannabinoid tone.” (See “The Endocannabinoid System” above.)

Some conditions that respond well to THC-rich medical cannabis include Alzheimer’s disease, HIV/AIDS, Crohn’s disease, glaucoma, chronic pain, multiple sclerosis, and nausea from cancer treatment.

“I’ve seen people tolerate cannabis products extremely well when they’re used with guidance such as you’d get at a medical cannabis dispensary,” says Emmons. He adds that people with a family history of psychotic illnesses, such as bipolar disorder or schizophrenia, are at higher risk for psychiatric problems from THC; they should proceed with caution.

Understanding Delta 8 and Delta 9

You may have seen products touting Delta 8 or Delta 9 THC on their labels — possibly even at the convenience store. What’s up with these compounds?

“Delta 8 and Delta 9 just refer to the chemical structure of the compound,” explains Goldstein. Every cannabis plant makes a tiny amount of Delta 8 and much higher amounts of Delta 9 THC.

Chemists figured out that CBD from industrial hemp, which is nonintoxicating, can be synthetically converted into Delta 8 THC. This makes it intoxicating in a way similar to the Delta 9 THC abundant in drug-variety cannabis plants — though it’s less potent, so more is required to produce the same effect.

“If you’re getting a cannabis product in a convenience store, it’s probably unregulated, and I don’t recommend taking anything unregulated because you risk some serious side effects.”

When hemp was legalized at the federal level in the 2018 Farm Bill, a loophole allowed manufacturers to sell synthetic Delta 8 THC — including in states where recreational cannabis is still illegal — because it’s derived from industrial hemp.

Yet it’s not clear if Delta 8 is safe. “The problem is that other compounds are also made in the process of converting CBD to Delta 8,” Goldstein says. “If you start with 100 percent CBD, about 80 percent of it converts to Delta 8 and 20 percent to other, synthetic cannabinoids. And these have never been studied in humans, so we don’t know if they’re safe.”

There are numerous reports of people ending up in the emergency room after using Delta 8 products, often with hallucinations, anxiety, and vomiting. “If you’re getting a cannabis product in a convenience store, it’s probably unregulated, and I don’t recommend taking anything unregulated because you risk some serious side effects,” Goldstein says.

Most Delta 9, on the other hand, whether extracted from hemp or drug-variety cannabis plants, is “made by Mother Nature,” she adds. Dosing still matters, but with proper use of a tested product, it doesn’t seem to carry the same risks as unregulated Delta 8 — which is likely to be contaminated — for most people.

Getting Started: A Safe and Informed Approach

Like any new terrain, the world of phytocannabinoids is best explored with a well-informed guide.

If you have a complex condition or set of symptoms, find a professional who can help you determine the most effective dose, delivery method, and combination of phytocannabinoids for your situation — particularly if you’re taking other medications that may interact. Many medical dispensaries offer online lists of local providers who can offer prescriptions and guidance. And the onsite pharmacists and staff at dispensaries are well-equipped to help you.

While it’s now possible to find CBD in anything from bubble bath to lip balm, experts agree that phytocannabinoids are best approached as serious medicine. Capsules, tinctures, and ­edibles with clearly labeled dosage levels from a reputable supplier are your best bet. Look for products from manufacturers (such as Charlotte’s Web and CV Sciences) that subject their label claims to third-party testing.

And before you start asking your friends for advice, know that individuals may respond differently to the same phytocannabinoids. For instance, more than a few ­milligrams of THC might send some people into an anxious spiral, while others appear largely immune to THC-induced paranoia.

“I could line up 10 people who are all using cannabis to successfully treat PTSD, and they might not all be taking the same thing,” Goldstein says. “Some may benefit from a full-spectrum product with a relatively higher amount of CBG or CBC, while others need a certain amount of THC.”

Finally, be patient. You may need to give cannabis three to six months to determine whether it’s beneficial. Finding the right combination and dose of phytocannabinoids is likely to be an exercise in trial and error. And your needs may change as you go along.

“Often, people end up taking less cannabis over time because their ECS becomes upregulated — it’s functioning better,” ­Goldstein says. “Botanical medicine tends to do that. It nudges you in the right direction.”

This article originally appeared as “Beyond CBD” in the March/April 2024 issue of Experience Life.

MO PERRY

Mo Perry is an Experience Life contributing editor.

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