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Denver • Piper rolls back and forth across a large blanket on the living room floor, windmilling her arms and kicking her legs.

"Who's a happy girl?" asks her mom, Annie Koozer, kneeling over the 2-year-old with a small, oil-filled syringe. Piper fusses as Annie squirts a tiny amount into the side of her mouth.

"What do you think about that? That's not too bad, especially if it makes you feel better," says Annie.

It could take days or weeks before Annie and her husband, Justin Koozer, know whether the medicine controls Piper's debilitating seizures. But waiting is familiar ground for the young Tennessee family that has tried virtually every pharmaceutical fix available, traveled 1,300 miles to get here and waited more than two months for what may be their best and final hope: cannabis.

The Koozers are part of a migration of families uprooting their lives and moving to Colorado, where the medicinal use of marijuana is permitted. More than medical tourists, they are medical refugees, forced to flee states where cannabis is off limits.

"This is just the first wave," said Margaret Gedde, a Colorado Springs physician with a doctorate from Stanford who prescribes marijuana and has compiled case studies of children using cannabis-infused oil. "These families are going to keep coming as awareness spreads because the results are real."

Gedde has been monitoring 11 children with seizure disorders who are taking the same cannabis extract Piper is receiving, and she will present her findings at the annual meeting of the American Epilepsy Association in December.

Nine of the children have had a 90 to 100 percent reduction in their seizures, she said. The parents of one child aren't sure the oil has helped, but it hasn't hurt. And the other had a 50 percent reduction.

"It's absolutely remarkable," she said.

Medical marijuana is currently legal in 20 states, plus D.C. and Portland, Maine. But Colorado has become the go-to place for an extract from a plant that's high in cannabidiol (CBD) but low in tetrahydrocannabinol (THC), the psychoactive chemical component of marijuana that creates a high in users.

Marijuana entrepreneurs and cultivators Joel, Jesse, Jonathan, Jordan, Jared and Josh Stanley call it Charlotte's Web, named for the Colorado Springs girl who tried it first and went from having 300 seizures a week to about two a month. Videos showing a once-catatonic Charlotte Figi now talking, running on a beach and horseback riding have lured families from far and wide.

The number of children younger than 14 with marijuana "red cards" tripled in the last five months from seven in March to 21 in August, according to the Colorado Department of Health and Environment.

A waiting list the Stanleys keep for their CBD extract numbers about 200 and growing, said Josh Stanley, the oldest of the six brothers running the non-profit Realm of Caring Foundation.

The list includes about 30 kids in Utah whose parents, instead of relocating, are lobbying for permission to import the "herbal" remedy, which they've dubbed Alepsia. Since it's so low in THC, they argue, it meets U.S. agricultural standards for hemp, which is used in products such as clothing and lotions.

Next week they hope to receive the blessing of Utah's Controlled Substance Advisory Committee, which makes recommendations on the scheduling, or classification, of drugs.

'My heart is heavy' • The Koozers believe Piper is the first child with Aicardi syndrome to try Charlotte's Web.

Aicardi is a rare chromosomal disorder characterized by infantile spasms, or seizures, and the partial or complete absence of a structure in the brain called the corpus callosum.

Doctors discovered Piper was missing the thick band of nerve fibers that divides her cerebrum into left and right hemispheres when she was in the womb, during a 20-week ultrasound.

"We went to find out if we were having a girl or boy ... Ten minutes later we learned there was something wrong with how her brain was developing," Annie wrote on a blog she keeps to update friends and family.

Almost all the cases have been girls. There is no cure; most children die either before the age of 1 or in their early teens.

For months after she was born Piper seemed to develop normally, cooing, making eye contact and flashing dimpled grins right on cue.

"She is already trying to roll over," Annie blogged on Sept. 12, 2011. "We are amazed at what she can do already, and she is just 3.5 weeks old!"

The doctor suggested that, unless she suffered delays, to wait until she turned 2 to put her through the stress of testing.

A month later she had her first seizures and her first long stint in a hospital.

"My heart is heavy and my mind, body and spirit are tired ... I am trying to give my worry to God but it is easier said than done. I'm not sure I will ever feel like myself again," Annie wrote on November 11, 2011.

'So helpless and frustrated' • That year was a blur of doctor visits and brain scans as the Koozers searched for a drug to calm the seizures.

To date, they have tried nine therapies, including phenobarbital. It left Piper like a zombie, said Annie.  "She was sedated and lost muscle tone. She stopped smiling for nine months."

While weaning her from the barbituate the family sought approval to use vigabatrin, then an investigational treatment known as a "wonder drug" in the Aicardi community.

One of the side effects, however, is permanent vision loss. Already Piper's retinas are dotted with small holes, one of the markers of her disease. She has good vision but probably sees the world as if she's looking through Swiss cheese, Annie surmises.

"Last night we had a particularly bad night. She wasn't able to fall asleep until 4 a.m. because she just had cluster after cluster [of seizures]...250 in a 6 hour period," Annie blogged on Valentine's Day in 2012, days before receiving approval. "I felt so helpless and frustrated I would have done anything to help her (like give her vigabatrin). I guess God is giving me a sign."

It cut her seizures in half, but the Koozers wanted a better therapy with less harsh side effects. They were out of options.

Their neurologist in Tennessee supports the couple's decision to try cannabis, which they learned about through support groups on Facebook.

"He understands we've reached the end of the line. There's one more drug, but it has a high chance of liver failure and he recommended waiting to try it when Piper is older," said Justin.

CBD mystery • Scientists are still learning how CBD works. One theory is that it modulates the transmission of electrical signals in the brain.

The human body makes endocannnabaniods similar, but not identical, to cannabinoid compounds in marijuana, said Gedde. "We have receptors to cannabinoids all throughout our bodies."

In our brains and nervous systems, messages are sent through electricity from cell to cell, directing them to perform activities. With epilepsy, those signals get out of control, like an electrical storm.

The research is incomplete but some studies suggest cannabinoids, when released, have a dampening effect on those signals, calming the seizures, Gedde said. "So kids with epilepsy, it could be that their natural cannabinoid system is insufficient."

But Igor Grant, director of the Center for Medicinal Cannabis Research at the University of California, San Diego, urges caution.

"What we don't know is, do most children benefit or is there some subset who uniquely benefit?" he said. "We also don't know if it's doing some harm ... CBD is not psychoactive, but that doesn't mean it's harmless."

Another big question is how long CBD's curative effects will last.

"What can happen with  any new anti-seizure medicine is you get seizure reduction for awhile — they call it the honeymoon — but then it stops working," said Gedde.

Realm has documented two children — Charlotte and Zaki (pronounced Za-chai) — who have used the oil successfully for more than a year. And both children are not only virtually seizure-free, they're gaining developmental ground as their brains appear to be forming new connections.

"It works really well, it appears to keep working and it doesn't have the side effects and toxicity of other anti-seizure meds," Gedde said.

Evidence of cannabinoids' anti-seizure potential dates back to the 1840s, including studies in labs, animals and humans. And GW Pharmaceuticals is running clinical trials of a purified form of CBD.

The 11 children Gedde has been monitoring all have "convulsive-type seizures and severe [developmental] delays," she said. "We focused on them because they are the most severe and we wanted the results to be comparable to [GW Pharmaceuticals'] studies."

Some of the children have genetic disorders, she said, and "others had brain damage from not getting enough oxygen at birth. Another family had a storage disease where metabolytes build up in the body and become toxic."

'Stay objective' • It could take years for GW's drug to win federal approval and Gedde wonders if it will work as well as the whole plant extract, which also contains trace amounts of other cannabinoids.

And for families like the Koozers, time is brain matter.

Piper is about 4 to 5 months of age developmentally. She can't talk but is pretty easygoing, said Annie. "She gets that from her Dad."

On a bad day Piper has three to four 10-minute clusters of seizures. She's unable to sleep through the night and as she's gotten older, they seem to upset her more, said Annie. "It could mean she's developing. Since she turned 2 she has things that she really dislikes, such as having her clothes changed or brushing her hair. But it's hard to see her scream and cry."

The Stanley brothers feel the urgency, too.

On Oct. 25 they moved 20 patients off the waiting list, including Piper, providing them with their first batch at one of their dispensaries in Colorado Springs.

On any given morning, there's a line of customers waiting to be buzzed inside, some in pin-stripe shirts, others covered in tattoos — and lately, moms pushing strollers and wheelchairs.

After they show their red card and sign in, they're escorted to a glass case in the back filled with jars of bud with names such as Orange Kush and Choco-lope, pre-rolled joints and pot brownies.

Parents receive bottles of liquid medicine mixed to order, based on their child's weight.

"We tell parents not to expect miracles, to stay objective and have no loyalty to the medicine and to stop using it if it doesn't work or they see any ill side effects," said Joel Stanley. "It's just like any other medicine."

Found by parents • The waiting list for Charlotte's Web is carefully managed because once someone comes off, Realm of Caring guarantees them a future supply. They reserve Charlotte's Web, the highest of their high-CBD strains, for children so they don't run out.

They sell the oil to parents for children at about cost, $6 per dose, and provide it free to families who can't afford it.

Raised in Colorado Springs, a conservative military town with strong Protestant leanings, the Stanley brothers were educated at a Christian prep school. Josh Stanley started growing marijuana about five years ago and later convinced his brothers to help expand operations.

"There were times where we worked without pay. We were spending no time with our families; we had no life," said Jordan Stanley. "I was just about to throw in the towel when we discovered Charlotte."

The brothers are uncomfortable with the idea that some customers feign symptoms to get red cards. Marijuana is abused by some people, acknowledges Joel Stanley. "But it's those people who subsidize patients like Piper."

The Stanley brothers aren't the only source of high-CBD strains of cannabis. In fact, Charlotte Figi's mom, Paige, decided to try it after seeing a video of a child in California who used a strain called R4, said Gedde.

But they grow the highest CBD strain that Figi has been able to find. The oil has helped Charlotte, now 7, behaviorally and intellectually.

Her autism-like behaviors of self-injury, crying and violence are a thing of the past and she is clear-headed and bright-eyed, said Paige Figi. "We are almost two years into this. We hit our peak seizure control at about six months but she's gaining skills and learning new words every week," she said.

"Most moms take for granted that when you look in your baby's eyes they'll hold your gaze. To see that happen for the first time is just..." she said, searching for a word to convey the depth of that emotion.

Figi now advises other parents and helps raise money for Realm of Caring, which is exploring an expansion to California to meet growing demand for its oil there.

She and an epileptologist are co-authoring an article for the journal Neurology in which they debate with other researchers the benefits of whole plant CBD extracts versus pharmaceutical-grade CBD.

The argument that long-term effects are unknown doesn't hold water for Figi, who hasn't seen negative side effects in Charlotte. "But I'm happy to check that box and work with scientists to prove it. The answer to 'We don't know enough' is going to be found, and it's going to be found by parents."

The 'what-ifs' • The Koozers arrived in Denver in August and made speedy work of applying for a red card. But it's a big change from Tennessee, where no pro-marijuana movement exists, though they hope to stir debate by sharing their story.

They've had to downsize, having moved from a four-bedroom home to a cramped, two-bedroom apartment in Denver, located near the airport so Justin can commute to work and close to a hospital in case of emergencies.

Annie, now 30 weeks pregnant with their second child, a boy, spends long stretches of time alone changing diapers, hand-feeding Piper and monitoring her seizures while Justin, a manager for a supplier to the mining industry, travels for work.

"You're completely re-establishing your whole life," said Justin, 28. "We don't have a support system. We don't have friends. We had to find a new church, new doctors and therapists."

Family can visit, but the Koozers are staying indefinitely. "We can't leave the state with the extract or it would be a federal offense," said Annie, 33. "We just felt like if we knew something was out there that might work and we didn't try it we'd be doing the 'what if's' our whole life."

The Koozers were given a two-month supply of oil, which they'll introduce gradually, starting with three .1 milliliter doses a day. If they see improvements, they'll start weaning Piper off her other medications.

A neurologist is monitoring Piper's progress and the Koozers document her seizures.

But there is no playbook to follow. Some kids, like Charlotte, have stopped seizing immediately and others have taken months to see results.

The night of her first dose Piper got 10 hours of sleep. Two weeks later, she is still seizing. "It's been up and down," Annie said last week.

But on Halloween the Koozers got a glimpse of a hoped-for future.

"It was the best day she's ever had her whole life," Annie said. Piper was happy and alert, laughing at appropriate intervals during a game of peek-a-boo with Justin, who had just returned from a trip, she explained. "It was almost like she knew he was back. Most of the time he comes home and she doesn't even notice."

Annie tries to keep expectations in check.

"I'm not expecting her to stand up and walk," she said. "But it's kind of like she's waking up a little bit, more able to experience things, laugh and be a kid. That would be really huge for us." —

Join us for a Trib Talk

On Monday at 12:15 p.m., reporter Kirsten Stewart, marijuana grower Josh Stanley and others join Jennifer Napier-Pearce to discuss Colorado's experience with medical refugees.

You can join the discussion by sending questions and comments using the hashtag #TribTalk on Twitter and Google+.