The changes medical marijuana brings to Arkansas will likely be less widespread than advocates hope or opponents fear, at least at first, recent history and research suggest.

The voter-approved constitutional amendment allowing medical marijuana use will soon fall into place. The state plans to start taking license applications for shops to distribute marijuana products and cultivation facilities in July. The people who qualify to use and possess those products could be able to apply for the necessary state cards even sooner.

The amendment legalizes marijuana use in Arkansas for the first time in almost a century, though it's still against federal law. Supporters say the drug will mean comfort instead of misery and potentially less risk than other medications for some patients.

"It truly felt like a miracle," Fayetteville resident Emily Williams said last fall, describing marijuana's immediate soothing effect on her chemotherapy-induced pain and relentless nausea other medicines failed to alleviate.

But how many patients will want it, how many doctors will allow it and how many marijuana businesses will succeed remain open questions. Experts worry about unintended side effects of legalization, such as lessening the oversight of doctors over their patients' medications, or want more study into the drug.

"The situation's looking a little rough," said Storm Nolan, founder of the Arkansas Cannabis Industry Association, pointing to the inability of marijuana businesses to get many bank loans and other issues. "There are a lot of unknowns, and I know that's scaring away a good number of people."

The patients

Arkansas in some ways is playing catch-up. People have used marijuana's medicinal properties for about 5,000 years at least, according to a 2013 report in the scientific journal Pharmacotherapy. Twenty-nine states have legalized its medical use, starting with California 21 years ago.

Thousands of studies since 1999 have found examples of marijuana or individual compounds found in the plant providing relief from pain, muscle spasms associated with multiple sclerosis and nausea induced by chemotherapy, an analysis from the National Academies of Sciences, Engineering, and Medicine concluded this year.

Research also has found marijuana use can impair learning and attention and increase the risk of developing some mental health disorders and of being in a vehicle accident, according to the analysis.

Marijuana's active compounds, called cannabinoids, work much like other medicines or drugs, hitching onto specific molecular keyholes on the outer surface of the body's cells and changing the cells' behavior. The receptors that fit cannabinoids largely appear on nerve cells and cells that fight disease.

How long it takes for cannabinoids' effects to begin can depend on how the plant, its extracts or its synthetic equivalents are ingested.

They can be quick and powerful, based on accounts from some who have used it.

A Springdale resident and veteran with tremors from Parkinson's disease, chronic pain and post-traumatic stress said he smokes marijuana every few hours to hold the symptoms at bay. The substance helped him half his use of opioids, painkillers such as oxycodone that can become addictive and kill tens of thousands of Americans each year from overdoses, according to the U.S. Centers for Disease Control and Prevention.

No overdose deaths from marijuana have been recorded, according to the U.S. Drug Enforcement Administration.

Morphine and other medications caused serious nausea and "hateful" mood swings and left him curled up in a chair for hours, said the Springdale resident, who spoke on condition of anonymity because his marijuana use is still illegal and often stigmatized. Marijuana allows him to play sports with his child. He looks forward to being able to take the substance with him during longer trips away from home without fear of arrest.

"There's a lot more of us than you know," the man added, referring to ordinary people who use marijuana for medicinal reasons. He said he'll be the first one in line once the state starts taking applications for medical use. "I promise you that."

Traditional prescriptions for federally approved drugs treating a variety of illnesses have fallen in states allowing medical marijuana or its extracts, according to a study of recent Medicare Part D data published last year in the journal Health Affairs. Patients with pain medicine prescriptions in particular filled 1,800 fewer doses per physician per year.

A 2014 study found opioid overdose deaths went up regardless of a state's medical marijuana law, but those allowing marijuana's use saw a slower increase.

Nolan, the state cannabis association founder, said his mother was a successful attorney who died three years ago because of an opioid addiction and its side effects. He and his family watched "a very sad and slow decline" that included months in the hospital and a rehabilitation facility, where her life ended.

"We would have tried anything," Nolan said, calling marijuana "just so much more humane."

The doctors

Adult patients and caregivers can register for medical marijuana with the Department of Health only if their physicians certify the patients have one of 18 qualifying conditions and the benefit of marijuana outweighs its possible drawbacks.

The latter point might be a high hurdle to clear. Arkansas Children's Hospital and the state surgeon general opposed the marijuana amendment, and several area physicians and health systems declined or didn't respond to repeated requests for comment on their stance.

Mercy Northwest Arkansas said the decision would be between doctors and patients, as with any treatment.

Some health care providers said they have multiple concerns about using the drug. Dr. Juan Lombeida, a supportive care provider with Highlands Oncology Group, said he would treat medical marijuana with the same caution as any other medication, weighing side effects and whether another treatment would do the trick.

Highlands Oncology sometimes prescribes Marinol, a U.S. Food and Drug Administration-approved synthetic version of the cannabinoid THC that can help with nausea and appetite, Lombeida said. He called it a "back pocket" option if other medications aren't effective. Marijuana itself has helped a few patients, but made no worthwhile difference for others, in his experience.

"It may not work as well as you hope, just like any other treatment we have," he said. "It's going to have its benefits and its burdens, and you need to be aware of those and be willing to make a change if needed."

Every marijuana plant and dispensary can be different from the next, so dosages and other details typically determined long before a regular medication goes on the market remain hazy, Lombeida added. Even if the drug's workings were clear, a doctor won't be giving a prescription with exact instructions.

"I think we are doing this whole thing kind of backwards," Lombeida said, referring to the research that's catching up with wider marijuana use.

The Arkansas General Assembly passed a law requiring dispensaries to hire a licensed pharmacist as a consultant to bring more medical expertise to the process. Scott Pace, a pharmacist and CEO of the Arkansas Pharmacists Association, said the law will help make sure marijuana doesn't interact badly with other medications.

How marijuana's dozens of cannabinoids achieve their effects and how well they can work are still questions missing many of their answers, said Ziva Cooper, an associate professor of clinical neurobiology at Columbia University Medical Center in New York. She was an author of the national academies report.

Studies might look at use of the plant, specific cannabinoids or their synthetic versions, and findings in one category don't necessarily follow in another, Cooper said. Research that's designed to reveal the difference those separate categories make and what individual cannabinoids are doing are still relatively uncommon, she said.

She and other researchers partly blame marijuana's classification by the Drug Enforcement Administration for the shortage of information. It's held in the same category as heroin and LSD, and research into the drug requires repeatedly getting special licenses and approvals that can add difficulty and months of paperwork to a study.

Study nonetheless goes forward around the country. Dr. Greg Sharp of Arkansas Children's Hospital is doing three studies examining the cannabinoid called cannabidiol and its effect on several seizure disorders. The studies' results won't be known until they finish.

Cooper is working on two studies, including one also looking at cannabidiol. Some evidence suggests cannabidiol can soften THC's high, though "the jury's still out on that," she said.

"We do have a long way to go, but it is an exciting time because a lot more people are interested in pursuing the science," Cooper said. "I expect over the next decade there's going to be a lot of good data."

The businesses

Once people with the requisite medical conditions get their doctors' certifications and their state cards, they'll be able to buy from a marijuana dispensary, basically something between a pharmacy and a health supplement shop. The marijuana amendment allows up to 32 dispensaries supplied by five cultivation facilities around the state.

Other states' industries offer a preview of what could be for sale, commonly featuring dozens of varieties of plant material, oral solutions or pills, food products and cartridges for vaporizers such as e-cigarettes. Businesses often develop types heavier in THC or cannabidiol or try to balance the two, depending on the desired effect.

"We're constantly working with our patients to understand what works better for people with certain conditions, but it is very personalized," said Ari Hoffnung, CEO of Vireo Health of New York.

Hoffnung said the company uses research from the U.S. and other countries to tailor capsule and oral solution formulas that are all state-tested for quality. Customers usually meet with a licensed pharmacist when they first come in.

Other states also offer caveats for Arkansas' marijuana entrepreneurs. Bank loans and accounts are difficult if not impossible to secure across the country because of marijuana's federal classification as an illegal drug, and other vendors are sometimes reluctant to get involved. Health insurance and public programs such as Medicare generally won't cover patients' marijuana, which typically costs $200 or more per ounce or bottle of pills in other states.

Nolan wants to start a dispensary and cultivation operation in Fort Smith with his brother and stepfather. Good relationships with local banks after years selling real estate were fruitless when it came to marijuana, he said.

"As soon as they bring it up to the FDIC (Federal Deposit Insurance Corporation) regulators, they say, 'So sorry, we're not going to be able to help you,'" Nolan said. The family is financing the license application and potential business alone, including state fees and required bonds for dispensaries and cultivation facilities adding up to more than $2 million.

State regulations and other factors can also limit the marijuana customer base. New York, for example, didn't include chronic pain as a qualifying condition until recently, Hoffnung said. Reports from Colorado and other state governments show pain is often what qualifies the majority of medical marijuana users.

Vireo, its subsidiary Minnesota Medical Solutions and other marijuana companies have yet to turn a profit since legalization in those two states in 2014, according to Hoffnung and media reports. The states' registries for marijuana use include several thousand people out of a combined population of 25 million.

"Certainly many businesses are not profitable during the early phase of their existence," said Hoffnung, who's also president of the New York Medical Cannabis Association. "With that said, a business cannot exist indefinitely without turning a profit, and it is worrying."

Arkansas regulations compared to other states' are more strict in some ways and less in others. Arkansas allows fewer conditions to qualify than Minnesota and California, for example, but joins Delaware and Rhode Island in allowing residents of other states who are registered for marijuana at home to buy from dispensaries here if their illness qualifies.

Under the amendment, the Arkansas Medical Marijuana Commission sets other rules for businesses, and Alcoholic Beverage Control will inspect them.

Arkansas legislators this year took other steps to limit marijuana use in some ways. Smoking in public or by anyone younger than 21 is banned, and product packaging must be childproof and not be appealing to children.

"It's not going to be a slam dunk," Nolan said of the industry's success in Arkansas, but he thought the state's rules struck a reasonable balance. "Obviously we're motivated personally, but we also think there's a decent shot of it being financially feasible."

State Rep. Robin Lundstrum of Elm Springs pushed unsuccessfully to ban the smoking of medical marijuana. She said the state will have to wait and see if its rules are enough to keep Arkansans safe.

"This is going to be a process, and it's not going to be pretty at times," she said.

Some are more optimistic. Brian Faught, a telecommunications contractor in central Arkansas, is looking to move to Fayetteville and open a cultivation facility and dispensary and said he has the resources to power through the bumpy early years.

Fayetteville's City Council this month approved selling 5 acres to Faught for the businesses if his state applications go through.

"I don't even smoke the stuff, but it's a real product and it's a real industry," he said, citing marijuana's medicinal power and moneymaking potential as his reasons to jump in. "I can't wait to be a part of this industry."