Burgeoning

cannabis market

brings new opportunities

By Malorye A. Branca, C&EN Brandlab Contributing Writer

Demand for chemists and specialized instruments grows as range of products expands

It was an incurable tumor on her baby daughter’s optic nerve that led Tracy Ryan to cannabis.

Ryan and her husband were told that chemotherapy might slow the tumor’s growth but that was the most they could hope for, and the effect might be short-lived. After recovering from their shock, the Ryans did some research that led them to cannabis oil. Little Sophie Ryan received the oil in addition to chemotherapy. Her tumor shrank dramatically. Several years have passed since her diagnosis. Sophie turns five years old this year and is starting school. She is on track with her developmental milestones, “thriving, healthy, and happy,” her mother says.

Tracy Ryan, meanwhile, has founded CannaKids, a company that offers cannabis oil-based products for people of any age but with a focus on pediatric conditions. That business, she says, is “booming.”

Ryan’s is just one of many young businesses operating in the new world of medical marijuana, where products may have to be tested for purity and potency but do not have to go through the approval process of the U.S. Food & Drug Administration (FDA). In other words, this is a new “gray area” of medical products, unlike the approval processes for typical prescription medications or over-the-counter treatments. The Grand View Research market-research and consulting company estimated the market for medical marijuana to reach $55 billion by 2025.

The range and number of marijuana products is also growing. Producers have branched out from the highly popular dried flowers, extracts, and vape pens to include a wider range of products. CannaKids, for example, has expanded its product line from syringes of oil delivered by mouth to tinctures, topicals, and nasal spray. Testing these products is fueling demand for chemists and analytical instruments specifically for this market.

This new market was born of several trends: The public is increasingly accepting marijuana as a recreational drug, many of the medical conditions it is used for are otherwise untreatable, and anecdotes abound about its efficacy. “Why not?” seems to be the reasoning. As the market expands and evolves, “What’s next?” seems to be the looming question.

FDA-APPROVED PRODUCTS

"We found that the best product was 90% accurate with the labeled claim and the worst had 0% THC.” Neil Spingarn, Chief Science Officer of NebulaManagement

Besides the gray-area dispensaries, there are businesses aiming at the traditional drug market. Axim Biotechnologies CEO George Anastassov and his business partner got involved with cannabis while looking for novel analgesics to treat chronic pain. “We could see the opioid epidemic evolving,” he explains, “and being surgeons, we knew there was a critical need for new, powerful pain relievers that could be used on a long-term basis without the side effects that opioids have.”

Axim has nine cannabis-based products in development, including chewing gums, suppositories, ophthalmic formulations, and skin creams. These treatments target conditions including smoking, glaucoma, dry eye, psoriasis, eczema, vitiligo, restless legs syndrome, loss of appetite, chemotherapy-induced vomiting, and postherpetic neuralgia. One of the company’s flagship products is MedChew Rx, which is in preclinical trials for pain and spasticity associated with multiple sclerosis. A trial of CanChew, meanwhile, was just completed in people with irritable bowel syndrome.

Several other companies are also working on pharmaceutical-grade cannabis-based products, all of which will follow the stringent FDA-review path to approval. Those companies include Corbus Pharmaceuticals, GW Pharmaceuticals, Insys Therapeutics, and Zynerba Pharmaceuticals. “There are some wonderful products headed to the market from us and our competitors,” Anastassov says.

The progress is happening despite the massive legal and regulatory hurdles that have long hamstrung developers of cannabis-based products. The U.S. federal government has listed cannabis as a Schedule 1 drug (that is, it is deemed to have the highest level risk of abuse and so is among the most tightly regulated substances). As a result, simply being able to do research on cannabis is a major undertaking. It can take years to get approval, and transporting the plant, its extract, or even seeds across state lines to get it into a laboratory is another headache.

MORE OF EVERYTHING

Researchers and entrepreneurs are keeping up with surging demand for medical marijuana by expanding their operations and finding new uses for the cannabis plant, its extracts, and the hundreds of compounds it contains. Thanks to advances in instrumentation, it is now fairly easy to extract those compounds and identify them. The real challenge is figuring out which ones have medicinal effects and what those are. The barriers to research on the plant have resulted in a paucity of peer-reviewed data and a plethora of anecdotal accounts.

The two star compounds in cannabis that have been well studied so far are tetrahydrocannabinol (THC) and cannabidiol (CBD). THC has intense psychogenic effects; CBD does not. Some people have claimed that CBD has analgesic, anti-inflammatory, antianxiety, and other properties, so manufacturers are using CBD to make medicinal marijuana-based products that are nonpsychogenic. Some researchers in this field also believe the terpenes and other cannabinoids in the plant have healing properties. “Identifying safe ingredients that synergize with the cannabinoids is really important,” says Christian Sweeney, director of science and technology at Cannabistry Labs, which provides services from production through marketing to marijuana producers. But such synergy is hard to confirm both because the plant itself is so complex and because of the rules for its use and study.

The only cannabis-related pharmaceutical-grade products currently on the U.S. market—Marinol, Syndros and Cesamet—all contain synthetic THC. Detractors claim it is not as effective as the botanical version. GW’s Sativex for multiple sclerosis spasticity has been approved in at least a dozen countries, though not the U.S. yet. It contains botanically derived THC and CBD as well other cannabinoids and cannabis-related compounds.

Axim intends to be next to market, and with a slew of products. It has been a tough slog, to say the least. Anastassov points out that only one company in the world, Bedrocan, is allowed to produce flowers for pharmaceutical-grade cannabis extract, a crucial ingredient for these products. “It took 30 years for Bedrocan to get that approval,” he says. Axim uses such flowers to make its FDA-approvable products. Those flowers come from the Netherlands, and the Dutch ministry of health controls production. The strict regulations for transporting cannabis-related ingredients add to the challenges. Further, “THC is very volatile and oxidizes easily,” Anastassov says. Even the extraction process for FDA-approvable cannabis-based products is complex. Axim has proprietary intellectual property on its entire extraction process.

A key challenge is that there are many different cultivars of cannabis, and they all have different mixtures of the many compounds found in the plant, says Mark Scialdone, principal consultant at BetterChem Consulting. “There is now inexpensive [polymerase chain reaction] technology that makes it possible to do rapid testing to determine whether a cultivar is enriched with CBD or THC,” he says. Companies are also moving toward purification by short-path distillation to isolate pure cannabinoids from solvent extracts for accurate doses in products such as vape pens. The processing of the plant material into cannabinoid isolates, such as THC distillate or crystalline CBD, requires high volumes of starting material and extraction solvent.

That’s one of the reasons Heidolph North America has developed the automated Distimatic module for continuous, unattended solvent recovery. Distimatic pairs with the Heidolph rotary evaporator to remove bulk solvents that are added to the cannabis oil during earlier processing steps, thereby turning it into a higher purity extract.

The free form of the medical marijuana market has also led to a lot of variation in the quality of product. “We went out and grabbed some products from dispensaries. We found that the best product was 90% accurate with the labeled claim and the worst had 0% THC,” says Neil Spingarn, chief science officer of Nebula Management, which operates manufacturing facilities for cannabis-based products. “How could you even do a clinical study with products like that?”

Many states require that companies perform third-party testing to validate dose level and detect unwanted contaminants. Spingarn and others recommend that producers do rigorous testing on their own. “If someone questions your product, you want to have your own documented results,” he explains.

To do this type of analysis, most labs use high-performance liquid chromatography with an ultraviolet detector, says Bob Clifford, general manager of marketing at Shimadzu Scientific Instruments. But he adds, “If you want to know the molecular structure of the compounds you are seeing, you will go to a mass spectrometer.” Scialdone of BetterChem recommends that his clients who need to know the purity of their extracts and isolates obtain their own HPLC and gas chromatography/mass spectrometry instruments as well as “a real chemist who has expertise” to run the instruments and troubleshoot.

The analysis process has gotten easier as companies such as Shimadzu have developed cannabis-analysis-specific instruments.

Shimadzu’s systems include everything clients need, including a software overlay “to get up and running in a single day,” Clifford says. “Shimadzu and others are stepping up to the plate,” Scialdone says.

Although a lesser-used technique for routine quality assurance and quality control, nuclear magnetic resonance spectroscopy is also useful for analyzing organic components of cannabis extracts. Benchtop NMR spectrometers, such as the Nanalysis NMReady-60, improves efficiency for routine cannibinoid detection and quantification in extracts. “The NMReady provides high resolution spectroscopy in a compact, affordable instruments,” says Susanne Riegel, NMR Product Manager at Nanalysis. “Given the inherent quantitative nature of NMR and our simplified software packages, a wide range of professionals can use NMR spectroscopy to quickly and easily extract quantitative data, including parameters such as THC and CBD content” in cannabis extracts.

GOING FORWARD

Today’s cannabis product developers often say that the medical marijuana business started in people’s garages and that there was not much attention to chemistry or evidence-based medicine at that time. But that’s over. “Most customers want lab-tested medicines they can trust. “None of us would be here without those guys who started it,” CannaKids’ Ryan says. “But today there are lots of serious people in this business, including very big players. Some even have quality control, marketing departments, and expert scientists on their advisory boards.” Those companies seeking FDA approval for their products are tied to much tighter regulatory standards.

Companies such as Heidolph North America are trying to advance the science. Heidolph North America recently sponsored a scholarship in conjunction with the ACS Cannabis Chemistry Subdivision in the Division of Chemical Health & Safety. Heidolph North America has committed $50,000 over five years to support the participation at national ACS meetings of chemists doing research on cannabis. (C&EN is published by ACS.) “People working in this field have limited opportunity to present their findings to their peers,” says Michael Bishop, director of applied markets at Heidolph North America. “The scholarship is a great opportunity for cannabis chemists around the world to come together annually to recognize excellence and advance the field.”

Regulations will continue to be a challenge. The rules and qualifying conditions vary from state to state. Ohio, for example, allows the use of medical marijuana for more than 20 conditions, including hepatitis C and HIV-positive status. Mississippi allows only the use of CBD oil, and only for debilitating seizure disorder. Even within a single state, regulations can vary. “In California, the laws depend on the municipality,” Spingarn says. “You literally face different regulations from town to town.”

Despite some warning from the current U.S. Administration about possible crackdowns, the range and number of these products continue to grow at a dizzying rate. It now appears that medical marijuana is here to stay.