In a secluded lab in Pullman, furry vermin are providing startling revelations about marijuana and its effects on the sexes.
Rebecca Craft, a researcher at Washington State University, has been studying the creatures, male and female rats, to see if they react differently to the drug.
And it looks like she's on to something, especially when it comes to THC, the chemical in marijuana that creates a sense of euphoria for recreational users. It's a finding that women who use the plant may want to consider, she said.
There are a wide variety of potential uses for marijuana that advocates say need further study. Among them:
• Nerve disorders.
• Pain relief.
• Multiple sclerosis symptom relief.
• Slowing or prevention of memory loss in Alzheimer’s disease.
• Reduction of some cancer tumors.
• Nausea relief.
• Appetite enhancement.
• Rheumatoid arthritis pain.
• Reduction of muscle spasticity.
• Reduction of post-traumatic stress disorder symptoms.
• Reduction of migraine headaches.
"Female (rats) show a spike in THC (sensitivity) right around the time they're ovulating," she said. "I suspect that's true in humans too, but there are no studies on that yet."
The discovery means that women who are ovulating may have a much stronger reaction to the THC, possibly because it gets amplified when it interacts with estrogen, she said.
And as the legalization and sales process moves along and marijuana becomes more readily available in Washington and Colorado, that sort of knowledge could certainly be useful.
But while the research suggests a possible dosage problem for women, it could be a long time before studies are done on humans.
That's because of the extremely complex bureaucratic process required for clinical trials of marijuana in the United States — a process that has made many researchers give up on the idea of researching it.
As pot stores begin to open in Vancouver and around the state, there's a lot more we don't know about the active ingredients in marijuana, a consequence of strict anti-drug laws and a federal classification that says the plant has no benefits and is unsafe to use.
Even animal studies, while not as strict as human trials, require "a lot of hoops to jump through" for researchers that want to learn more, Craft said.
"It's unfortunate, but you can count on one hand the number of human studies done in this country," she said. "It's possible to get approval, but people are just very leery, I think for political reasons."
And those that make it through the process can face a whole other set of issues.
There was another WSU animal marijuana researcher, psychology professor Michael Morgan, who had a federally funded and approved study to look at the drug's potential as pain medicine in 2009 at WSU Vancouver. At the time he was awarded $148,438 in federal stimulus funds from the National Institutes of Health.
But Morgan ended up in Republican Dino Rossi's cross hairs during Rossi's 2010 campaign for a U.S. Senate seat. Rossi, who lost the campaign, publicly said several disparaging things about Morgan's efforts to study the plant.
"Washington state taxpayers are tired of their money going up in smoke," Rossi's office said in a press release at the time. "This bill isn't going to stimulate anything other than sales of Cheetos."
Because of the political backlash, Morgan ended his project. He also declined to be interviewed for this story because of the negative press that surrounded his project, officials at the university said.
Still, there are signs things might be changing.
Medical marijuana is legal in 20 states and the District of Columbia, and 13 other states have legislation for medical use pending.
Recreational marijuana is legal in two states. And about 58 percent of the country supports legalization of the drug nationwide, according to a Gallup poll released last fall.
Those changing attitudes about marijuana could change the atmosphere toward studying the plant. But a lot still has to change if the country wants to ease restrictions on the scientific process, and it's not clear yet if legalization of marijuana in Washington will help those who to study the plant locally.
Marijuana is listed as a Schedule I drug in the United States as part of the Controlled Substances Act. The classification, which it's held since 1970, defines it as having no medical benefits, no safe use and a high potential for abuse.
But that's not what many researchers think. Worldwide studies have shown it to be useful for treating pain, reducing nausea and increasing appetite, among a growing list of other things.
It also doesn't seem to be what many voters think, at least in the states that have legalized medical marijuana.
The federal government, for that matter, doesn't seem to agree with its own classification. It has approved at least one pharmaceutical derived from THC, Marinol, since 1999. And the Food and Drug Administration also has a handful of other marijuana-derived drugs in the pipeline awaiting the go-ahead for clinical trials.
And yet, pot is actually more restricted than some of the other Schedule I drugs, including heroin, LSD and Ecstasy.
To study marijuana, research must be approved by four federal agencies: FDA, the National Institute on Drug Abuse, the Drug Enforcement Agency, and Health and Human Services.
If a study is approved, researchers must get their marijuana from a special farm at the University of Mississippi, the only federally sanctioned source in the United States.
One of the biggest roadblocks in that complicated process, critics say, is that Health and Human Services has been reluctant to approve any studies looking at possible medical or beneficial uses for the marijuana.
"This process (with the four agencies) was started in 1999," said Brad Burge, a spokesman for the Multidisciplinary Association for Psychedelic Studies, a research group that is pushing for more scientific study of the plant. "There wasn't any research at all looking at the benefits in the United States before that. There were plenty of studies looking at the risks."
Even if states with legal marijuana create a research pipeline and local source of the plant, it may not help the situation much for those who want to publish papers for the larger scientific community, said Paul Armentano, deputy director of National Organization for the Reform of Marijuana Laws.
"Any cannabis used in (a clinical) trial must come from NIDA," Armentano said. "Changes in the state status of cannabis does not change this fact. Historically, these federal agencies have been reticent to approve protocols, including FDA-approved protocols, seeking potential nonadverse effects of cannabis."
Since 1999, only about 15 studies looking at positive medical uses have been approved by the agencies, Burge said.
"With PTSD there is major room for study," Burge said. "Also acute anxiety, epilepsy, MS, anti-cancer, slowing Alzheimer's. Those are all really important areas of research to open up."
Oddly enough, it's much easier to get LSD and other psychedelic drugs for study than it is to get marijuana, he added.
"With LSD there are multiple independent suppliers, and you can get DEA approval to do a drug study," Burge said.
In fact, the group has already done some successful studies looking at Ecstasy as a psychotherapeutic treatment for post-traumatic stress disorder — in part because it's easier to study than marijuana, he said.
"We've had great success there," Burge said. "And you have to consider that those drugs are higher risk."
Drug trials with LSD and Ecstasy don't have to go through parts of the marijuana review process, but they're still reviewed by the FDA and the Industrial Review Board to make sure they're ethically appropriate.
"For drug approval you need federally approved research, and for that you need federally approved marijuana," Burge said. "People often forget that the federal government is still locking down on it."
Making it through
Despite the criticisms, a few human studies have made it through the approval process.
Dr. J. Hampton Atkinson, co-director of the University of California San Diego Center for Medical Cannabis Research, has coordinated six studies with the agencies since his group was created by the state of California 10 years ago.
"(Health and Human Services), their focus has been on drug abuse, but I don't know that we experienced them dragging their heels," Atkinson said. "There's a process and you have to be credible. We didn't experience it as a reluctance toward approval."
Still, he favors reclassification of the drug, he said.
"A great benefit would be if the drug were reclassified to Schedule II, which might ease some of the regulatory process," Atkinson said.
Schedule II drugs are those with a high potential for abuse but that have some medical uses. Those drugs include cocaine, methamphetamine, methadone, oxycodone and Ritalin.
It took Atkinson's group about two years to get approval for its first marijuana study, which dropped down to about 18 months for the subsequent ones, he said.
The group's six studies looked at marijuana as a pain medication for diseases such as HIV, diabetes and shingles, he said.
"Overall we found a benefit in various neuropathic pain states," Atkinson said. "The benefits were basically at lower doses. You didn't need to be stoned or high to get relief."
In fact, getting high in some cases made symptoms worse, he said.
"Roughly 50 percent of people got 50 percent or greater pain relief," he said. "This was in different studies at different sites by different investigators. We saw it repeat in all six studies."
What the group would like to do now is a larger set of studies and a longer duration of use, but approval may take a while, he admitted.
"We determined that there might be call for longer-duration studies, that's what we're hoping will happen," Atkinson said. "But it's not something that's going to happen overnight."
In her rat studies at WSU, Craft was also able to get a DEA license and prove that she had the facilities to store the Schedule I drug safely.
She's had that license since 2000, and is the only researcher studying marijuana in Washington state, at least that she's aware of, she said.
She also gets her marijuana for the research from the NIDA lab.
"They recently upped their regulatory control, and the DEA also audited all regional researchers last year," Craft said.
And even though the drug is now legal in Washington, it doesn't change the process for her studies.
A plant with potential
So what are some of the potential uses for marijuana?
There are quite a few, researchers say.
"There's so much potential," said Sunil Aggarwal, a senior resident at the New York University Medical Center, "and it's not just THC. There are cannabinoids, hundreds of compounds in these plants. They have so many uses."
Aggarwal is a physician who also has a doctorate in geography and a bachelor's degree in chemistry. He graduated from the University of Washington's medical school and previously practiced medicine in the state before getting a job in New York.
"There's evidence that THC can in some cases reduce the size of brain tumors," Aggarwal said. "That's one study that needs to be replicated. Some patients also use extracts to help fight blood cancers and it may reduce other tumors. This has a huge potential for cancer reducing processes."
Also neurological conditions, seizure reductions, a shield for brain damage and recovery from brain trauma, a memory aid for Alzheimer's that may slow progression of the disease.
It also has several uses for psychiatric disorders such as PTSD and anxiety.
"Going back to ancient times cannabis had been used for mood disorders," Aggarwal said. "The Chinese even used it for people who were forgetful."
While marijuana is associated with short-term memory interruption, it can also help the brain filter content, can sometimes bring lost memories back or can help filter a traumatic memory so it can be experienced without the associated stress, he said.
"It's known to have general mood-boosting properties as an antidepressant and anti-anxiety drug," he said. "There's a huge potential in psychiatric disorders that we can look at."
And people have been using the plant all over the world for thousands of years — without any particularly severe side effects, Aggarwal said.
Plant remnants have been found at sites dating back at least 10,000 years Taiwan.
Marijuana was used as a therapeutic agent and painkiller during surgical procedures in China for at least 2,000 years.
In India, also for thousands of years, marijuana was used to make a beerlike drink called bhang, which is still sold in some places today. The drink and the plant are also used for religious purposes there.
The ancient Romans also used cannabis juice as a topical treatment for earaches — knowledge that spread throughout Europe, where it was used through the Middle Ages.
There are more than 4,000 peer-reviewed papers worldwide on studies of marijuana and cannabis, but most of those were not done in the United States because of the restrictions, said Douglas Hiatt, a lawyer and director of the pro-marijuana group Sensible Washington in Seattle.
"You have all this research going on all over the world, except here," Hiatt said. "This is one of the stupidest things in this country, to not study marijuana as medicine."
And despite the criticism, there are a few signs that the restrictive approval process is easing some.
Health and Human Services in March approved a study by University of Arizona Professor Suzanne Sisley to study marijuana and PTSD. She still needs approval from the Drug Enforcement Administration, but that should go more smoothly, said Burge, whose group, MAPS, is funding the research.
"It's taken us four years for this particular study," Burge said. "We still have a few hurdles left but that was the biggest barrier."
And the approval may be a crack in what once was an almost impenetrable barrier, Burge said.
"We really want to change the conversation about marijuana and psychedelic drugs," Burge said. "We're trying to use marijuana research as a wedge to force these roadblocks open."
Legalization in Washington and Colorado may encourage more scientists to do marijuana research, at least on the health impacts compared with alcohol and other drugs, Craft said, especially if more federal restrictions were loosened.
"We're probably going to learn more about long-term use of marijuana now," she said. "Is marijuana absolutely benign? No. Marijuana is addictive, but the withdrawal is much milder than something like alcohol withdrawal, which can be life-threatening."
There are many other things Craft also wants to investigate about the plant, especially about how women react to it differently than men.
Females, because their biology is more complex than males', have been dramatically understudied by many animal researchers — whose projects often eventually lead to human studies, Craft said.
"Almost all the animal research is done in males," Craft said. "That's been done historically because during the female cycle, hormones change and that complicates things. But that doesn't make it any less important to study. And it's important in pain research because the variety of pain disorders, they're much more common in women than in men."
Women tend to get migraines and other pain disorders such as irritable bowel syndrome more frequently than men, she said.
"It's something we need to be talking about, and not in a knee-jerk way," Craft said. "It does have some reasonable uses."
I-502, the initiative that legalized recreational marijuana in Washington, could create a new avenue for researchers, said Alison Holcomb, criminal justice director for the American Civil Liberties Union of Washington and author of the initiative.
In the law, 1 percent of the total excise taxes from sales will be split between the University of Washington and Washington State University for marijuana-related research. As a rough estimate, she said she expects about $4 million a year to be divided between the two after the first year of licensed sales begins.
"Those funds will go to study short-term and long-term effects of marijuana use, intoxication and impairment and methods of measuring that, but also other things related to marijuana use," Holcomb said. "It could be also used for medical studies, or nonmedical studies, with either positive or negative expected results."
The idea, in part at least, is to create a pathway for researchers to study marijuana grown in Washington state.
"Of course there may not be many researchers that want to do that without federal blessing," Holcomb said. "It can be hard to get papers published without going through that process. But maybe we'll get some researchers willing to engage through a state process."
WSU seems somewhat open to considering the idea.
On April 2, Washington State University President Elson S. Floyd's office released a statement saying that the university "recognizes the need for education and research around the many complex issues raised by implementation of the initiatives pertaining to industrial hemp and recreational and medicinal cannabis."
WSU would like to study the economics, industry, agriculture, product development, health effects and public policy of the drug. But the university would still like to have federal approval for the source of its cannabis, the statement said.
"Issues remain that must be resolved prior to embarking on any research that involves the production of industrial hemp or recreational and medicinal cannabis. … In the months to come, WSU will continue to monitor emerging opportunities to assist the state in addressing issues resulting from the legalization of industrial hemp and marijuana production," it said.
Either locally or federally, the hope is that as attitudes shift, more avenues will open for study of the drug, Holcomb said.
"There's certainly a great need for research," Holcomb said.