Building a better edible

Lo Friesen reaches for a plastic bag the size of a pillowcase filled with dark green plant matter. “Here we have some more material for our edibles clients,” she says. “Just giant bags of weed.”

Behind her, something is making a soft, regular chirping noise, like a little bird. Friesen turns and gestures at a silver contraption made of pipes and cylinders. “These are our machines,” she says. “This is where the material goes in.”

Friesen is a cannabis extractor in Seattle. Her company, Heylo Cannabis, is part of a whole ecosystem of suppliers, processors and distributors that has sprouted up since Washington state legalized marijuana in 2012. In this food chain, Friesen is somewhere between the plant growers and the retailers that sell to consumers. With the help of the chirping machines, her team separates and distills the various compounds found in the raw cannabis plant — the essence of weed. The result is a kind of oily, maple syrup–colored liquid that gently sloshes in glass flasks and jars in her lab.

Some of that oil is for vaping. But a hefty portion of Friesen’s extract will go into chocolates, mints, gummy candies and even beverages — consumables that are broadly referred to as cannabis edibles.

This shopping aisle’s worth of pickings — from sweets such as brownies and gummies to savory treats such as beef jerky and mac and cheese — have become big business. Recreational cannabis is currently legal in 16 states and Washington, DC, and several more are considering legalization. The global market for edibles — spurred in part by people being both housebound and lung-health wary during the pandemic — was nearly $3 billion in 2020; it’s predicted to top $11.5 billion by 2025. Major brands including Molson Coors and Carl’s Jr. are staking claims in the edibles landscape.

Many people still prefer inhaling cannabis — edibles make up roughly 11 percent of the cannabis market — but a growing number are eating their greens, so to speak. Edibles are more lung-friendly than smoking and more discreet — they don’t generate stinky secondhand smoke and can be consumed both in and out of the home. And edibles can be a vehicle for a more sustained high.

But therein lies a problem for both product makers and consumers. The potency, duration and timing of an edible experience can’t always be counted on. They are notoriously variable in their effects.

Two edibles, both with the same quantity of THC (tetrahydrocannabinol, the main intoxicating ingredient in cannabis), can feel very different to a consumer. One may have milquetoast results, while the other hits like a truck and lasts for hours.

And it’s very difficult to investigate exactly what’s behind that variability, both on the product side and the consumer side. The federal government still lists cannabis as a Schedule 1 drug, a classification that severely restricts access to the plant and its compounds for research purposes.

“In more than half of the United States right now, these products are available for retail purchase and millions of people are taking them,” says Ryan Vandrey, a psychiatrist at Johns Hopkins School of Medicine who has studied the effects of cannabis edibles in the body. And yet, he says, there are still many fundamental things about edibles that we don’t understand, leaving gaps in the knowledge needed to make rules to protect consumers.

Nonetheless, chemistry and nutrition science do offer clues to how edibles are absorbed by the body and how that might influence their effects. The aim is to design precision products to provide finely tailored experiences while protecting consumers — despite the uncertainty baked into edibles by the diversity of ingredients and quirks of human physiology.

The trip in

The cannabis plant contains hundreds of compounds that interact with the human body. Most well-studied — and arguably most important — are the cannabinoids, which include both the psychoactive THC and cannabidiol (CBD). These chemicals mimic ones made in the brain and other organs and can have diverse effects — from appetite stimulation to pain relief to altering mood and more.

When smoked, the path cannabinoids travel is relatively straightforward — they are inhaled into the lungs and pass into the bloodstream. Via this route, data suggest, blood levels of THC peak within about 10 minutes of exposure, and then dive, returning to baseline within three to six hours.

But cannabinoids that are eaten take a longer, more circuitous route to the bloodstream. The little research available suggests that the effects of many edibles peak two to three hours after consumption and may persist for as long as six to 20 hours. If this initial delay is unexpected, it may prompt people to dose again and end up with a far more intense experience than desired. For some, it prompts a visit to the emergency room.

Even if the delayed onset is anticipated, there’s still a lot of variation in the timing and potency of the effect, thanks in part to the food — whether brownie or beverage — that delivers the cannabinoids.

“From a consumer perspective, if I’m a cannabis user and I go to a dispensary and the product says it’s got 10 milligrams of THC in it, and then there’s another product that says 10 milligrams — and another product, it says 10 milligrams — my assumption is that, well, they’ll all be the same,” Vandrey says.

But not necessarily. If one product is a vitamin-like capsule, another’s a buttery brownie and the third is a drink, the different fats in the vitamin capsule versus the brownie can skew how quickly and how much the body absorbs. And the drink? Vandrey says compounds in drinks will sometimes separate out of the solution and get stuck to the lid or glass.

“So even though 10 milligrams may have gone into the bottle, only three might come out. And the high-fat–containing brownie’s going to have three times the absorption than the capsule.” So three products all labeled as containing 10 milligrams can produce a huge range of effects.

Some of those differing effects result from basic chemistry. Cannabinoids are hydrophobic — meaning they don’t dissolve in water. But they do in fats and oils. That’s why the home chef’s classic recipe for pot brownies calls for slowly and patiently cooking the cannabis with butter to leach out the compounds from the herb. Once dissolved in butter or oil, cannabinoids can be absorbed during digestion much more easily.

Skip this buttery step and just throw the raw plant matter into the batter and you’ll probably get a batch with no kick. The cannabinoids will either be absorbed so slowly that you don’t notice, digested by the bacteria that live in the gut, or end up flushed down the toilet.

A key step in the dissolving process is the formation of little bubbles of fat or oil called micelles. During digestion, the body makes soaplike chemicals called surfactants that break down large blobs of fat or oil, creating smaller micelles that can be taken up by cells lining the gut.

The size, quantity and chemical structure of these micelles may be important factors in when cannabinoids hit the rest of the body, dictating in part the timing, potency and duration of their effects.

Most edible fats and oils are made of chainlike molecules called triglycerides, which can be saturated (often solid at room temperature, like butter) or unsaturated (typically liquid at room temperature, as with many vegetable oils). The amount of saturation and length of triglyceride molecules can affect the shape and properties of the micelles that form in the gut.

Carotenoids — fat-soluble molecules such as beta-carotene — are more absorbable in the body when packaged in micelles with oils containing long triglycerides, like sunflower oil, research suggests. Coconut oil, on the other hand, has shorter triglycerides and yields smaller micelles. Such small micelles may not be able to carry larger molecules, like cannabinoids, to the gut wall at all, says David Julian McClements, a food nanotechnologist at the University of Massachusetts Amherst.

“Say you had a cannabinoid. It’s like an elephant and you want to get it transported somewhere,” says McClements, who wrote about cannabinoid delivery in the 2020 Annual Review of Food Science and Technology. “You couldn’t get it into a MINI Cooper. But if you put the elephant into a big truck, then you could carry it around somewhere.”

So using sunflower oil instead of coconut oil in a pot brownie could, theoretically, increase how much and how soon the effects kick in. That information could inform both consumer expectations and product-maker recommendations.

A 2020 study in rats, for example, investigated delivering cannabinoids via different formulations of tiny, oil-based globules. The globules formulated from cocoa butter (long-chain molecules and mostly saturated) were more available for absorption than those delivered via a medium-chain fat called tricaprin.

But the data aren’t clear-cut. The same study compared drug delivery in globules based on the long-chain, mostly unsaturated sesame oil with a medium-chain oil derived from saturated coconut and palm kernel. The two formulations basically performed the same, the researchers reported in International Journal of Pharmaceutics.

Various factors influence the effects of cannabis beverages as well. These drinks are emulsions — blends of two liquids that don’t like to mix, akin to a balsamic vinaigrette dressing — so surfactants are added to stabilize things and slow separation. Adding surfactants, such as the milk protein casein, into a recipe could potentially accelerate micelle formation and promote uptake in the gut. Surfactants added to a THC-rich emulsion sped up pain relief in mice, for example.

Variable outcomes

The perplexing complexity of edibles science may actually present an opportunity for designing specific outcomes: a fast-acting edible to stimulate appetite, for example, or an extended-release one for pain management. But such efforts are hindered by the lack of regulations and quality control standards at the federal level. Currently, there’s a patchwork of different rules and methods developed by various labs, associations and states.

“It’s very clear that we need some sort of standard,” says Friesen, the extracts processor.

Such regulations exist for pharmaceutical cannabinoids. The drug Epidiolex, for example, contains the cannabinoid CBD and was approved by the US Food and Drug Administration in 2018 for epilepsy. Its CBD is always delivered via a sesame oil carrier that should keep the effective dose consistent, and the product is regularly analyzed and monitored, says Tyler Gaston, a neurologist at the University of Alabama at Birmingham who has studied the use of cannabinoids for treatment-resistant epilepsy.

But with artisanal products, lack of regulation leads to uncertainty, Gaston says.

Regulations and monitoring could also protect consumers from erroneous claims. The labeling for THC and CBD content on commercial products is often inaccurate, research by Vandrey and colleagues has shown.

The Schedule 1 status of cannabis continues to pose obstacles for researchers who would like to better understand the nuances of edibles physiology. Approval to work with cannabis can mean a long and arduous series of review processes, including multiple applications to the FDA, the Drug Enforcement Administration and state agencies. There are also burdensome protocols, such as requiring vaults or safes for storage and on-site security inspections of the lab by the DEA.

What’s more, funding for the research and supplies of the plant itself have historically been very limited. For years, researchers have had to purchase cannabis for research through a specific agency, the National Institute on Drug Abuse, which typically offered only a handful of products and potencies.

This situation may be changing. In December 2020, the DEA finalized regulations that would increase the number of approved marijuana growers and the variety of products available to researchers. And federal bills to deschedule the drug have been proposed, though not passed. If legislation changes things, then researchers could really dive in and investigate the complexity in people and animals, says McClements. “Then we can ask, you know, what is the difference between coconut oil and palm oil or fish oil?”

Researchers have a good idea about such differences from previous work with vitamins and nutraceuticals, he says, “but I think we need to confirm it, because every system’s a little bit different.”

For now, much of edibles science remains shrouded. So many consumers, especially those new to edibles, can’t predict how strong or how delayed the effects may be, which can lead to people inadvertently taking too much. It also means people who might benefit from edibles might be missing out, says Friesen.

She’s seen one bad experience turn people away from what might be a promising way to help manage their anxiety or pain. Was it an ingredient that caused that? Can we make it better? Perhaps one day we will know.