CORVALLIS, Oregon, January 11, 2021 - PRESS RELEASE – Hemp compounds identified by Oregon State University (OSU) research via a chemical screening technique invented at the university shows the ability to prevent the virus that causes COVID-19 from entering human cells.

Findings of the study, led by Richard van Breemen, a researcher with Oregon State’s Global Hemp Innovation Center, College of Pharmacy, and Linus Pauling Institute, were published today in the Journal of Natural Products.

Hemp, known scientifically as Cannabis sativa, is a source of fiber, food, and animal feed. Multiple hemp extracts and compounds are added to cosmetics, body lotions, dietary supplements, and food, van Breemen said.

Van Breemen and collaborators, including scientists at Oregon Health & Science University (OHSU), found that a pair of cannabinoid acids bind to the SARS-CoV-2 spike protein, blocking a critical step in the process the virus uses to infect people.

The compounds are cannabigerolic acid (CBGA) and cannabidiolic acid (CBDA), and the spike protein is the same drug target used in COVID-19 vaccines and antibody therapy. A drug target is any molecule critical to the process a disease follows, meaning its disruption can thwart infection or disease progression.

“These cannabinoid acids are abundant in hemp and in many hemp extracts,” van Breemen said. “They are not controlled substances like THC, the psychoactive ingredient in marijuana, and have a good safety profile in humans. And our research showed the hemp compounds were equally effective against variants of SARS-CoV-2, including variant B.1.1.7, which was first detected in the United Kingdom, and variant B.1.351, first detected in South Africa.”

Those two variants are also known as the alpha and beta variants, respectively.

Characterized by crown-like protrusions on its outer surface, SARS-CoV-2 features RNA strands that encode its four main structural proteins: spike, envelope, membrane, and nucleocapsid, as well as 16 nonstructural proteins and several “accessory” proteins, van Breemen said.

“Any part of the infection and replication cycle is a potential target for antiviral intervention, and the connection of the spike protein’s receptor-binding domain to the human cell surface receptor ACE2 is a critical step in that cycle,” he said. “That means cell entry inhibitors, like the acids from hemp, could be used to prevent SARS-CoV-2 infection and also to shorten infections by preventing virus particles from infecting human cells. They bind to the spike proteins, so those proteins can’t bind to the ACE2 enzyme, which is abundant on the outer membrane of endothelial cells in the lungs and other organs.”

He notes that using compounds that block virus-receptor interaction has been helpful for patients with other viral infections, including HIV-1 and hepatitis.

Van Breemen, Ruth Muchiro of the College of Pharmacy and Linus Pauling Institute, and five scientists from OHSU identified the two cannabinoid acids via a mass spectrometry-based screening technique invented in van Breemen’s laboratory. Van Breemen’s team screened a range of botanicals used as dietary supplements, including red clover, wild yam, hops, and three species of licorice.

An earlier paper in the Journal of the American Society for Mass Spectrometry described tailoring the novel method, affinity selection mass spectrometry, to finding drugs that would target the SARS-CoV-2 spike protein.

In the later research, lab tests showed that CBGA and CBDA prevented infection of human epithelial cells by the coronavirus spike protein and prevented the entry of SARS-CoV-2 into cells.

“These compounds can be taken orally and have a long history of safe use in humans,” van Breemen said. “They have the potential to prevent as well as treat infection by SARS-CoV-2. CBDA and CBGA are produced by the hemp plant as precursors to CBD and CBG, which are familiar to many consumers. However, they are different from the acids and are not contained in hemp products.”

Van Breemen explains that affinity selection mass spectrometry, which he abbreviates to AS-MS, involves incubating a drug target like the SARS-CoV-2 spike protein with a mixture of possible ligands--things that might bind to it--such as a botanical extract, in this case, hemp extract.

The ligand-receptor complexes are then filtered from the non-binding molecules using one of several methods.

“We identified several cannabinoid ligands and ranked them by affinity to the spike protein,” van Breemen said. “The two cannabinoids with the highest affinities for the spike protein were CBDA and CGBA, and they were confirmed to block infection.”

“One of the primary concerns in the pandemic is the spread of variants, of which there are many, and B.1.1.7 and B.1.351 are among the most widespread and concerning,” he added. “These variants are well known for evading antibodies against early lineage SARS-CoV-2, which is obviously concerning given that current vaccination strategies rely on the early lineage spike protein as an antigen. Our data show CBDA and CBGA are effective against the two variants we looked at, and we hope that trend will extend to other existing and future variants.”

Van Breemen said resistant variants could still arise amid widespread use of cannabinoids, but that the combination of vaccination and CBDA/CBGA treatment should make for a much more challenging environment for SARS-CoV-2.

“Our earlier research reported on the discovery of another compound, one from licorice, that binds to the spike protein too,” he said. “However, we did not test that compound, licochalcone A, for activity against the live virus yet. We need new funding for that.”

Timothy Bates, Jules Weinstein, Hans Leier, Scotland Farley, and Fikadu Tafesse of OHSU also contributed to the cannabinoid study.

Her 17-year-old son looked like he was dying.

Angie Calhoun could hardly bear to watch her only child, Austin Calhoun, go from active and happy to bedridden and miserable, as he began experiencing focal seizures, severe joint pain, and chronic nausea and vomiting.

The debilitating medical conditions took their toll, as Austin, unable to keep any food down, rapidly lost 40 pounds from his adolescent frame. As the pain progressed, weakening his body and spirit, Austin’s health deteriorated to the point where he no longer wanted to move.

“He had stopped playing tennis,” Angie said. “He didn’t feel like going out with friends anymore. That was one thing where my husband and I were like, ‘Something is really wrong with Austin.’ He is not going out, and he was one of those who enjoyed going out. He’s a social butterfly. But it just stopped, and he just felt so bad that he laid on the couch or in the bed and slept, and slept, and slept.”

In addition to sports and friends, Austin, who turns 26 this month, also enjoyed being outdoors hunting and fishing. But those activities came to a halt too, as did his schooling.

During his senior year of high school, Austin said he attended maybe four days of classes.

“It was kind of heartbreaking just having to lay there in the bed and call friends on the phone, because that was the most interaction I could have,” he said. “You know, they would come see me from time to time, but it’s not like I could get out and we’d go do stuff like we used to. It’s just kind of one of those situations where it was like being alive but not alive at the same time, where you just kind of lived in existence.”

Search for a Solution

During the next 18 months, Angie and Brad Calhoun drove their son to Texas, to Louisiana and all over their home state of Mississippi to visit more than 20 doctors in hopes of an accurate diagnosis and medicine that would help. With Austin often too weak to walk, Angie said she sometimes had to push him into the doctors’ offices in a wheelchair.

Eventually, a doctor in Dallas led the Calhouns to have Austin tested for Lyme disease, the most common vector-borne disease in the U.S., according to the Centers for Disease Control and Prevention. It is transmitted to humans through the bite of infected blacklegged ticks. If left untreated, infection can spread to joints, the heart, and the nervous system.

Austin’s official diagnosis was that he contracted Lyme disease, which the Calhouns said became chronic Lyme disease.

In addition to his other conditions, Austin began having accelerated heart-rate issues and it felt like everything in his body was malfunctioning, he said.

“I was a pretty active kid,” Austin said. “I wanted to go out with my friends. But when you’re basically bedridden because the Lyme disease is attacking your nervous system, and then all the pharmaceutical medications they put you on have you so out of it to the point where you can’t leave your bed for 20 hours on end, I mean, it’s one of those situations [where you ask], ‘Should a child ever have to do this?’ And the answer is absolutely not—not that many medications at one time.”

After a healthy first 16 years of his life, Austin was prescribed 17 pharmaceutical medications in an attempt to turn his world right-side up again. Those prescriptions ranged from Reglan, which can treat gastroesophageal reflux disease (GERD), nausea, and vomiting caused by chemotherapy, to Pulmicort, which can help control and prevent symptoms caused by asthma. The Lyme disease had attacked Austin’s autonomic nervous system, affecting his breathing.

In addition, Austin was put on three anti-seizure medications simultaneously, yet he would still experience break-through seizures, Angie said.

“So, every time we went to see a doctor, or he went to the hospital, and I’m sitting there, like, ‘Aren’t these too many medicines? He’s on 17 prescriptions,’” Angie said. “And they’re like, ‘Well, it is a lot. But we need to take this, and we need to take those.’ And I can’t imagine anybody in this world saying that it’s OK for a 17-year-old to take 17 prescriptions at one time, and multiple times daily. We were just not comfortable with that. And he wasn’t either.”

Angie said she recalled walking into Austin’s bedroom one morning to give him his medicines, and, as she paused at his bedside, she looked at him lying there and thought to herself, “My son looks like a skeleton with a sheet over his body.”

Angie wanted to take away her son’s pain and suffering. She said she was willing to do anything to get his health back. She asked God to take away Austin’s agony and put it onto herself.

A New Beginning

After doing some research, the Calhouns decided to try cannabis as an avenue to treat Austin’s medical conditions.

“We knew it had helped with seizures, we knew that it had helped chemo patients with nausea and vomiting, and, most medications, they were not working for Austin,” Angie said. “And the side effects were frightening for my husband and me both. So, Austin, he was willing to try anything because he was miserable.

“And after cannabis got into his system, Austin hasn’t had to take any of those medications. He’s [pharmaceutical] medication-free. Is that amazing?”

Roughly seven years after finding relief, medical cannabis remains Austin’s one and only avenue to treat his lifelong disease.

While he’s not 100% well 100% of the time, as he still has flare-ups from his Lyme disease, Austin is no longer glued to his bed. He’s no longer throwing up a dozen times a day. His chronic pain is no longer unmanageable. And his seizures are under control.

“None of the medications had worked,” Austin said of the 17 pharmaceuticals. “And when I finally got to try cannabis, I mean, it was almost an instant relief, feeling like myself again. As the days just kept going and I kept on [using cannabis], I ended up feeling like my previous self. I would still get some aches and pains, but I wasn’t forced to lay in the bed for 20 hours because of all the pharmaceutical medications.”

The problem?

It’s 2022, and medical cannabis still isn’t legal in the state of Mississippi, even after voters passed Initiative 65 to legalize it with a more than two-thirds majority in the November 2020 election. In May 2021, the Mississippi Supreme Court struck down the voter-approved ballot measure, ruling it unconstitutional on an outdated signature-gathering technicality.

RELATED: Mississippi Supreme Court Overturns Voter-Approved Ballot Initiative for Medical Cannabis

While fewer than 20 states had legalized medical cannabis when Austin first got sick in 2013, Mississippi is now just one of 11 states remaining without commercial medical cannabis use and where personal cultivation is outlawed.

16 Hours Away

With the lack of access to medical cannabis in Mississippi, Austin made the decision to move to Colorado, a state with a legal and regulated medical cannabis program, in 2015. He was 19 at the time.

Google Maps

While Puckett, Miss., a village of roughly 350 people about 30 miles southeast of Jackson, was where Austin called home, the teenager relocated to a “homey little town” near Pueblo, Colo., a city of over 100,000 people that was a 16-hour-plus car ride away.

Austin said the move was one of the hardest things he’s ever had to do.

“The people in Colorado are great, but for a southerner to go over to that right there, it’s kind of a culture shock,” he said. “My mom and dad would come and see me whenever they could. But it was definitely extremely tough to be that far away. If I have a medical emergency, my folks would have to buy a plane ticket just to come out there and check on me. I mean, I felt extremely guilty over all that.”

The previous year—in January 2014—Colorado became the first U.S. state to launch adult-use cannabis sales. Before Austin went through the process of becoming a resident and obtaining his medical cannabis card, his mom said she visited an adult-use dispensary for him.

“It was really an eye-opener, and it just made my heart leap with joy to see that Austin seemed to be like his happy self again,” Angie said. “Like, we could go out to dinner, and he could keep it down. And that just had not happened in so long. And I’m kind of getting emotional, but when your child vomits, sometimes 12 times a day, everything he eats, he was so malnourished.”

Austin figured attending college would be a good pathway to meet people, but when he started feeling well again, he ultimately began working at Yeti Farms, a Colorado-based, sun-grown cannabis farm. There, Austin learned the extraction side of the business, as well as the harvesting and growing side of the trade. He said learning under founder and owner Shawn Honaker was basically his college experience.

But Austin still remained eager for Mississippi to legalize medical cannabis so he could move back home and be with his family and friends, he said.

Initiative 65

In 2017, Mississippi state Sen. Kevin Blackwell, a Republican from the northwest corner of the state, connected with a constituent who had just lost his wife to cancer.

Mississippi State Senate

“She had difficulty eating and stuff, and so he ended up going to another state to find cannabis and bringing it back for his wife, so she could eat and get through her normal days,” said Blackwell, who responded by introducing a medical cannabis bill in the Mississippi Legislature.

“There was not much discussion,” he said of his 2017 proposal. “In fact, there was no discussion. I recall no appetite from the Legislature to take up anything [on medical cannabis].”

It wasn’t until Mississippians for Compassionate Care submitted roughly 106,000 signatures to place Initiative 65 on the November 2020 ballot—and had those signatures certified by the secretary of state’s office—that medical cannabis talks heated up, Blackwell said. In fact, state legislators introduced a competing measure, Alternative 65A, to appear on the same ballot.

Mississippians ultimately passed Initiative 65 with more than two-thirds of voters in support of requiring the state’s Department of Health to adopt rules and regulations for a medical cannabis program by July 1, 2021, and begin issuing medical patient cards and treatment center licenses by Aug. 15, 2021.

“Austin was here, and I just broke down in tears I was so thankful,” Angie said of the 2020 election results. “And he was too. He was in tears. He said, ‘Momma, I’m going to get to come home to a state that has the medicine that I need.’”

Stumbling Reform

Six months later, six of nine justices on the Mississippi Supreme Court ruled Initiative 65 was void because the state never updated its initiative process after the 2000 Census.

Chad Robertson | Adobe Stock

The high court’s decision was based on a ballot procedure that requires signatures from each congressional district in Mississippi to not exceed one-fifth of the total number of signatures required for an initiative to be placed on the ballot. But after the 2000 Census, Mississippi dropped from five districts to four districts, putting the one-fifth requirement mathematically at odds with the political structure of the state’s electorate.

With other voter-approved ballot measures since the 2000 Census going unchallenged, Austin said it was like a “kick in the stomach” when the Supreme Court struck down medical cannabis legalization.

In 2011, for example, Mississippians voted in favor of Initiative 27, which requires residents to show government-issued photo identification before voting, and in favor of Initiative 31, which limits the use of eminent domain—the right of a government to expropriate private property for public use. Neither measure was challenged.

Legislative Reform

In the eight months since the Supreme Court’s decision, state lawmakers have worked to restore the will of their constituents through drafting medical cannabis legislation, specifically Blackwell, who chairs the Senate Medicaid Committee, and Republican Rep. Lee Yancey, chairman of the House Drug Policy Committee.

Earlier this year, Blackwell sponsored Senate Bill 2765, the Mississippi Medical Cannabis Act, which included “trigger language,” meaning it could only be enacted if Initiative 65 was struck down. While the Senate passed that bill, the House killed it and the legislation died when Mississippi’s 2021 legislative session ended April 1.

But Blackwell didn’t stop working on legislation after the Legislature adjourned.

“I felt it was upon us to try to get a program in place as soon as we could, as best we could match the intent of what [Initiative] 65 was,” Blackwell said. “So, we began work on that in May [2021], and I think in September had reached an agreement with the House, let the governor know, who had said once we reach an agreement, he would call a special session.”

While Republican Gov. Tate Reeves said he’d call a 2021 special session upon Senate and House leaders reaching an agreement with enough votes to pass medical cannabis legislation, he never did.

After Mississippi lawmakers reached a deal, Blackwell said Reeves came back with nine requests.

“We accommodated seven of them,” Blackwell said of the governor’s requests. “Then he came back with about five or seven more. We accommodated [all but two]. And then he came back with some more.”

With the back-and-forth between legislative and executive branches, time ran out for a special session.

Pushing on in 2022

When Cannabis Business Times reached out to Reeves’ office in mid-October, asking what proposals the governor wanted legislative leaders to address in the bill, Press Secretary Bailey Martin declined an interview opportunity for the governor.

But one component Reeves has been more vocal about is reducing the proposed possession limit of 4 ounces of smokable cannabis per month for medical patients. That’s an ounce less than the possession limit approved by voters in Initiative 65, but Reeves still voiced his reservations.

governorreeves.ms.gov

“The bill allows any individual to get 3.5 grams of marijuana per day,” Reeves wrote on social media in late December. “A simple Google search shows that the average joint has 0.32 grams of marijuana. Therefore, any one individual can get enough weed to smoke 11 joints a day. Every day.”

Just last week, Blackwell met with Reeves and brought the governor a 4-ounce sample of hemp to demonstrate the possession limit, to convey a sense of scale.

“I think he was surprised,” Blackwell said. “I’m not sure he’s actually seen product before. He was certainly appreciative of the information, and I think of the direction we offered [him].

“He’s going to need to get with his people and truly digest what we’ve offered and if he can support that. So, we’re going to go ahead and go forward. I hope to hear from him before we move forward with debate in committee and on the floor, but we’re prepared to move forward.”

Blackwell said it’s not his intention to put the Legislature in a position to override an executive veto, but he expects a quick committee process on medical cannabis legislation leading to a Senate floor debate as soon as this week.

A Patient Alliance

Amidst the hiccups in providing access to medical cannabis for Mississippians who need it, Angie founded the Mississippi Cannabis Patients Alliance (MCPA), a non-profit organization, in October 2021.

Previously, she chaired the board of the Mississippi Medical Marijuana Association (3MA), which launched in December 2020 as a group of associate members gearing to operate cultivation, testing, transportation, manufacturing, extraction and retail businesses in what was the state’s forthcoming cannabis program.

But Angie left 3MA, more of a trade association, to form MCPA and focus solely on advocating for and representing patients in need of medical cannabis.

“Most of my patients cannot get access,” Angie said of those she advocates for under MCPA. “And some are on medications that are $5,000 and $10,000 a month, which is ridiculous, you know, pharmaceutical medications that cost that much.

“They want options for a safe, natural alternative to pharmaceutical drugs. And when you’ve gotten to the point that it is putting you into bankruptcy … we certainly need to give those patients options.”

One of MCPA’s founding board members is Kent McDaniel, who began his career of public service with the Mississippi Bureau of Narcotics as one of the original agents in 1972. He also served 24 years as an appointed judge on the Rankin County Court, before retiring in September 2021.

Despite never trying cannabis, McDaniel said he supports legalization for medical patients.

courts.ms.gov

“It just makes so much sense from a medical research perspective; there’s just too much information out there now about the medical benefits of marijuana,” he told Cannabis Business Times. “The arguments against it, I know them all by heart. I’ve dealt with them for years.”

McDaniel was first sworn in as a narcotics agent 50 years ago this month. Back then, his perception of cannabis was a bit different, as “the folks who were real into it were just worthless. They let it take control of their lives,” he said about his opinion as an undercover narcotics agent.

“Since then, I’ve learned that’s very much just an overstatement as to marijuana, particularly when you line it up against what has proven to be medical benefits from people who need the relief it provides.”

The very first cannabis sale case McDaniel made undercover in the early 1970s resulted in an offender getting four years in the penitentiary for an ounce, he said.

Since then, public perceptions and criminal penalties have changed. As Mississippi cannabis laws stand today, possession of 30 grams (a little more than an ounce) or less is decriminalized, with first-time offenders receiving no penalty, no possibility of incarceration and a max fine of $250.

“If you track the history of this, as we as a society have become more enlightened, we’ve realized that this is not something to make felons out of or even to put people in jail for,” McDaniel said, reflecting on his 24 years behind the bench.

Governor Holdup

Despite the changing public perception, Reeves’ gubernatorial stance doesn’t offer much optimism for medical legalization advocates in 2022.

In addition to calling for a reduction in proposed possession limits, from 4 ounces to 2 ounces per month, the governor said what lawmakers have crafted in the Legislature equates to a recreational cannabis program and implied that approving the compromise bill Blackwell and Yancey came up with this past fall would allow medical patients to flood the streets with cannabis.

“As a dad of three daughters that I love dearly—I cannot put my name on a bill that puts that much marijuana on the streets of Mississippi,” Reeves wrote in late December.

As someone with Lyme disease who relies on cannabis to cope in his daily life, Austin called the governor’s comments disappointing.

“Out of all the states I visited that have medical and even recreational marijuana, people are not out on the street just smoking,” Austin said. “I’d say 99.9% of people who have common sense are not out there doing it on the roads or in the streets. They’re doing it in their homes because nine times out of 10 they don’t feel well.”

Advocating for potential medical cannabis patients in Mississippi, Austin’s mother Angie said she has concerns about 2 ounces per month not being sufficient for some patients, which would mean they would go back to suffering or pursuing the illicit market, where testing and certificates of analysis aren’t available, meaning patients don’t know exactly what they’re getting.

She also questioned what Reeves would do if it were one of his three daughters who fell ill and only found relief through cannabis.

“What would you do?” Angie said. “I know I would walk out in the middle of the road and go in front of an 18-wheeler if it meant saving my son’s life. There’s nothing I wouldn’t do for him. But I want all patients to be able to get medical cannabis here in Mississippi.