Vicodin, ketamine, and caffeine: The ingredients of a good space pharmacy

In space, no one can hear you sneeze. But if an astronaut does catch the flu, it can be a major problem. With the nearest Walgreens several hundred kilometers away, every medication an astronaut could possibly need on a space mission must be packed beforehand. It makes designing a pharmacy for space extremely complicated.

On top of that, of course, space itself poses potential medical issues. That extreme environment is known to warp the human body, shift fluids, and shrink bones, among other things. But microgravity can also affect how medications are metabolized, potentially making drugs less effective or even toxic.

Yet, despite 60 years of humanity sending individuals to space, there has been alarmingly little research into how meds work differently off-planet. While self-medicating in space has been common, there aren’t great records of who took what, when they took it, and how it did or didn’t help. There is some evidence that certain meds can be less potent in space and radiation may even degrade medications—but really, experts just aren’t sure.

“If you go to the doctor, there are basically three things they can do for you,” Dr. Virginia Wotring, a professor at the International Space University in Strasbourg, France, told Ars. “They can perform surgery, they can advise you to change your behavior—you know, stop smoking or whatever—or they can give you a medication. Which means [for space travel], a physician’s best tool is going to be the medication kit… This is something that merits attention, that astronauts deserve to know.”

The great unknowns

If all the careful preparation NASA astronauts Dog Hurley and Bob Behnken did recently to ride to the International Space Station in the middle of a pandemic doesn’t give it away, astronauts already abide by extremely strict health regimens. Even in healthier times, they quarantine for weeks before launches. Not much of their behavior needs changing. Surgery in space carries tremendous risk and luckily has never happened. Medication represents the best choice for out-of-this-world treatment by default, making the lack of research around the topic increasingly curious.

“At this point, we’re making an assumption that medications get absorbed and distributed to tissues and metabolized and excreted mostly the same way in space,” Worting said. “That might not be the truth.”

For example, a 2014 study measured sleep deprivation in astronauts aboard the International Space Station (ISS) and the drugs they took to get to some rest, such as zolpidem, brand name Ambien. The researchers, some from Harvard Medical School, found the astronauts often took a second dose in the middle of the night, presumably because the first dose didn’t provide enough relief.

But multiplying medications can mean increasing risk of side effects, or in the case of Ambien, potential grogginess during an emergency. Imagine trying to respond coherently after waking suddenly to a warning alarm while being “ambientoxicated.”

To better understand the mysteries surrounding what drugs would be effective for long-term stays in space, Wotring designed an iOS app that six crewmembers aboard the ISS volunteered to use for logging their meds in 2017. Every time they took a pill, the astronaut would record the drug name, the dose, the indication for taking the medicine, and whether they thought it worked, plus any side effects.

Wotring and her co-author LaRona Smith, a clinic administrator at Johnson Space Center, collected 5766 records of medication use—around 38 times more than the records from all previous space flights combined. “We were expecting more data,” Wotring said. “I was completely blown away when we saw how much data were coming in.” The results were published in the journal Aerospace Medicine and Human Performance this past January.

Medication use, on average, was somewhat more than on Earth, Wotring and Smith found. Sleep was the most common reason for taking a drug, but mild painkillers like ibuprofen were also frequently swallowed. “Most medications were considered partially effective,” they wrote. Even though the app apparently suffered from usability issues, causing the study to conclude early (insert Apple snark here), Wotring says NASA is in the process of adopting a similar protocol so they can better track their cosmonaut’s drug needs. Until then, a lot of unknowns remain.

“We know that there are physiologic changes to the human body in spaceflight. It makes sense that the effects of medications may be different in the altered physiology of the astronauts,” Dr. Tina Bayuse, lead pharmacist at Johnson Space Center Pharmacy Operations, said in an email. In 2002, she became the lead pharmacist for NASA’s first and only pharmacy.

“Changes in gastric motility may impact the absorption of medications,” Bayuse explained. “Fluid shift alterations may influence how medications are distributed or metabolized. The outcome of any of the known physiologic changes may result in medications that cause more side effects or are less effective.”

Medicine on Mars

Although this has been identified as an area for more research and studies like Wotring and Smith’s have begun, that work may have to happen relatively quickly given today’s space ambitions. To fully prep for future space flights, including lunar stations or long trips to Mars, we need a lot more data first, according to Rebecca Blue, a research collaborator at the Aerospace Medicine and Vestibular Research Laboratory at The Mayo Clinic in Arizona. The reason we know so little about drug metabolism in space, Blue told Ars, is because humans haven’t ventured too far from Earth yet, and tight budgets have prioritized other aerospace research.

“When we go to the Moon or Mars for longer and longer durations, we may not have this capability to provide, resupply, or replenish stock,” Blue told Ars in a call. “Suddenly, we have to start thinking about that.”

Another issue is that the quality of little research done on space and drugs thus far frankly isn’t great. Like Wotring’s dose tracking experiment, studies usually have small sample sizes or lack controls. Going to space is also incredibly expensive, so it’s difficult to repeat experiments or gather much data. To get around this, a lot of research is performed on rodents or in “analog” environments—not with human volunteers in outer space itself.

For example, a NASA-funded study published in April tried to simulate how drug metabolism works in space by exposing male Wistar rats to X-ray radiation and collecting their urine after being injected with methamphetamine. It may sound strange to give rats the same stuff fromBreaking Bad instead of a drug astronauts actually use, but this was medical-grade speed, which does have health applications.

More importantly, how meth is metabolized in rats has been well-studied, making it easier to trace how the stimulant moves through the body. The amount of radiation some rats were exposed to was “approximately what one would be exposed to on a round trip to Mars,” Dr. Michael Hambuchen, one of the study’s lead authors, explained in an email. Others got a dose equivalent to a “round trip with a 10 year stay on the planet’s surface.” Rats not exposed to radiation were used as controls.

Ultimately, it didn’t seem like the radiation had any impact on the pharmacokinetics of the drug—a good sign for astronauts who might take similar stimulants like Adderall. But more research is still needed.

“The main weakness of this approach is the acute radiation exposure rather than a gradual irradiation over time, as would occur in human astronauts,” said Hambuchen, who is an assistant professor at the Marshall University School of Pharmacy. “It’s bizarre how well worked out and described methamphetamine pharmacokinetics are in rats … While I stand by my rationale for using meth as a probe in this study, it may be beneficial to repeat this experiment with drugs in the NASA spaceflight formulary.”

Analog space environments have been used for studies involving humans, too. A study published in Clinical Pharmacology in 2005 described six patients given ciprofloxacin, a common antibiotic, while under the effects of simulated microgravity at a hospital in Gainesville, Florida. Compared to blood samples in normal gravity, plasma concentrations of ciprofloxacin were “almost identical,” although the results suggested tissue penetration of the drug might be slightly impaired in microgravity. In other words, not a very worrying difference.

To make these volunteers feel like they were in space, the researchers used a widespread technique called antiorthostatic bed rest (ABR). The way ABR works is pretty simple: patients lie in a hospital bed for days or even weeks with their heads down at a 6º to 12º angle (fun!). This, of course, rushes fluid from the legs to the brain, which is also sort of what happens in space.

However, while a 2016 review in Applied Physiology highlighted the strengths of this experiment design, it noted ABR is “probably not a true simulation of space flight.”

“When we are exposed to the normal gravitational force of the Earth, as you’re standing or sitting upright, the fluid in your body is pulled down,” Blue said. “However, when you go into a microgravity environment—we call it a gravitational gradient—that pull of the fluid down towards your legs and your feet goes away. And so, as a result, the fluid redistributes.”

This sounds alarming, but it’s not life threatening. Astronaut bodies eventually do adjust to microgravity, an ambiguous condition called “space normal.” Still, we aren’t entirely sure if this fluid redistribution changes the way the body absorbs drugs, let alone other space-related variables like radiation, disrupted circadian rhythms, or the thickening of artery walls.

“It’s measurably different from Earth, but there’s not necessarily anything bad about it. It’s normal for space,” Wotring said. But she noted that aerospace pharmacologists have to account for this change. “One of our concerns is if you changed blood volume by any significant number, well, do you need to change the dose of a drug? We don’t know.”

Blue also noted that just taking medications in and of themselves is not without risk. “It’s very hard to tease out reality when we don’t have a perfect analog or the perfect ability to do dedicated controlled research studies during spaceflight,” she said.

Bringing drugs to space

So after all this, how do you decide what drugs to pack for Saturn’s moons? Since 1977, the World Health Organization has kept a growing list of “Essential Medicines” designed to meet the most important health needs of any population. It works as an excellent guide for developing nations to know what to keep stocked. But the current tally is 433 medications—you can’t bring all these aboard a spaceship, as the added weight would make a big difference.

NASA has narrowed down what ends up in their pharmacopeia. “For the most part, the medications we pack for our current missions are for common issues like congestion, headache, or motion sickness,” NASA’s Bayuse said. “Medications needed that provide a smaller footprint, don’t require special storage, or that can cover multiple indications are part of the consideration for inclusion into the medical kit.”

For example, if one medication calls for a higher dosing frequency to treat an indication—say, three times a day—and another in the same class for the same indication only once per day, NASA would consider the medication that needs to be taken less.

A 2016 FOIA request from NASA revealed some of what’s in the medicine cabinet onboard the ISS. Caffeine, of course, makes the cut, but so did modafinil, an alertness drug used to treat narcolepsy. If you need help dozing off instead, there’s melatonin and Ambien. If you’re having trouble relieving yourself, there’s Dulcolax, a stool softener, and Flomax for urination, or Imodium, an antidiarrheal med, if you require the opposite. To treat stomach issues, there’s Pepto Bismol, Prilosec, and other drugs for nausea and altitude sickness.

For allergies, there’s Allegra, Benadryl, and Claritin, plus epinephrine pens and pseudoephedrine, a decongestant. For pain, there’s everything from acetaminophen to hydrocodone to aspirin to ketamine, not to mention topical anesthetics like lidocaine. There’s a whole suite of antibiotics, from azithromycin to tobramycin, plus valacyclovir, for treating viruses like herpes.

Don’t forget the albuterol inhalers, eye drops, antifungal tablets, carbamide peroxide for earwax removal, several classes of steroids and hormones, as well as drugs for seizures, high blood pressure, and plenty more. There are even drugs to treat mental health, including antidepressants like Zoloft and Effexor, plus Valium for anxiety.

All that is just for the small crew aboard the ISS, however. This list could change for longer missions to the Moon and beyond. NASA is already thinking about what to add or throw out. “Exploration missions have and will require us to re-evaluate what is part of the medical kit in the future,” Bayuse said.

Medication stability

Longer missions bring more variables to how drugs work differently in space, including expiring faster. “Typically what we purchase and what is approved by the FDA or the equivalent European organizations has a 24 month shelf life,” Wotring said. Unfortunately, it takes about 36 months to get to Mars, which could be a major issue. It’s not like astronauts can get a new shipment of Vicodin.

“The stability of medications as a result of the spaceflight environment is largely unknown,” Bayuse said. “There has been some evidence that suggests that some medications may degrade [in space] before the listed manufacturer expiration date. Unfortunately, there have been some issues highlighted with those studies, such as not having ground controls to compare the results to, confounding variables and limited sample sizes hindering the reproducibility of the results.”

“Currently we do not have enough data to fully characterize what those results mean or how the care of our astronauts may need to be adjusted, if at all,” she added.

If some medications degrade and simply become useless, it could be a relief. In other cases, disintegrating drugs could create concentrations of toxic chemicals. “Tetracycline antibiotics are the poster child for this,” Wotring said. Tetracycline antibiotics are used to treat everything from syphilis to malaria to anthrax infections. But when they expire, tetracyclines seem to degrade into chemicals that cause kidney failure according to studies in past decades. (Doxycycline is one tetracycline antibiotic included on the ISS. Others, such as amoxicillin, may not have this issue.)

If stored correctly, some meds will work for years, even decades after expiration. But space is a different environment and some early evidence suggests the rate of decay is faster off-planet. A 2011 analysis published by the American Association of Pharmaceutical Scientists examined 35 drugs that had been stored on the ISS for 28 months. The meds came in different forms, including pills, creams, and liquids and the researchers also used ground controls to ensure accuracy.

“The rate of degradation was faster in space than on the ground for many of the medications,” the authors wrote, noting that drugs like promethazine and dextroamphetamine (Adderall) were especially susceptible to these changes, perhaps because they are light sensitive. Space radiation, excessive vibrations and abnormal gravity may also play a role.

All of this again ties into a massive lack of research. There’s just so much we don’t know about how drugs work in space. For now, that hasn’t been a huge issue, but it’s something NASA and other exploration agencies will need to consider sooner than later if we want to spread out from Earth.

“We’ve been able to manage the uncertainties of medication stability and effectiveness with routine resupply and crews that have been living and working in the spaceflight environment for a year or less,” Bayuse said. “As we transition to exploration missions where resupply is not certain and crews will be away for longer than a year, providing safe and effective pharmacy care will be more challenging.”

Improving pharmacies in space has broad implications for healthcare on the ground, too, Bayuse said. Innovations and new insights into the mechanisms of pharmaceuticals under extreme conditions could translate to better medicine on Earth, just like many aerospace innovations have improved our lives.

Ultimately, we may even discover that the issues with medication stability and how drugs are metabolized in space is a relatively minor issue with easy fixes. But until we have more data, it’s difficult to say.

“We may, through further study, find that this isn’t as big of an issue,” Blue said. “I don’t want to make it sound like I’m unnecessarily raising alarm bells because the truth is, we just don’t know.”

Troy Farah is an independent journalist from Southwest California. His reporting on drug policy and science has appeared in WIRED, The Guardian, Discover Magazine, VICE and more. Previously at Ars, he shared the story of Dr. Aniru Conteh’s battle against Lassa fever and explored the current state of bioplastics. He co-hosts the drug policy podcast Narcotica. Follow him on Twitter @filth_filler