One Day, There Might Be a Drug for a Broken Heart
For Tony Y., 37, healing from heartbreak is slow and incomplete. Each of several exes is associated with a cluster of sore memories. Although he loves the Blue Ridge Mountains, he can't visit because they remind him of a romantic holiday years ago.
If a new drug made rejections less painful, one expert argues, it could relieve or even prevent major depression.
Like some 30 to 40 percent of depressed patients, Tony hasn't had success with current anti-depressants. One day, psychiatrists may be able to offer him a new kind of opioid, an anti-depressant for people suffering from the cruel pain of rejection.
A Surprising Discovery
As we move through life, rejections -- bullying in school, romantic breakups, and divorces -- are powerful triggers to depressive episodes, observes David Hsu, a neuroscientist at Stony Brook University School of Medicine in Long Island, New York. If a new drug made them less painful, he argues, it could relieve or even prevent major depression.
Our bodies naturally produce opioids to soothe physical pain, and opioid drugs like morphine and oxycodone work by plugging into the same receptors in our brains. The same natural opioids may also respond to emotional hurts, and painkillers can dramatically affect mood. Today's epidemic of opioid abuse raises the question: How many lives might have been saved if we had a safe, non-addictive option for medicating emotional pain?
Already one anti-depressant, tianeptine, locks into the mu opioid receptor, the target of morphine and oxycodone. Scientists knew that tianeptine, prescribed in some countries in Europe, Asia, and Latin America, acted differently than the most common anti-depressants in use today, which affect the levels of other brain chemicals, serotonin and norepinephrine. But the discovery in 2014 that tianeptine tapped the mu receptor was a "huge surprise," says co-author Jonathan Javitch, chief of the Division of Molecular Therapeutics at Columbia University.
The news arrived when scientists' basic understanding of depression is in flux; viewed biologically, it may cover several disorders. One of them could hinge on opioids. It's possible that some people release fewer opioids naturally or that the receptors for it are less effective.
Javitch has launched a startup, Kures, to make tianeptine more effective and convenient and to find other opioid-modulators. That may seem quixotic in the midst of an opioid epidemic, but tianeptine doesn't create dependency in low, prescription doses and has been used safely around the world for decades. To identify likely patients, cofounder Andrew Kruegel is looking for ways to "segment the depressed population by measures that have to do with opioid release," he says.
Is Emotional Pain Actually "Pain"?
No one imagines that the pain from rejection or loss is the same as pain from a broken leg. Physical pain is two perceptions—a sensory perception and an "affective" one, which makes pain unpleasant.
Exploration of an overlap between physical and what research psychologists call "social pain" has heated up since the mid-2000s.
The sensory perception, processed by regions of the brain called the primary and secondary somatosensory cortices and the posterior insula, tells us whether the pain is in your arm or your leg, how strong it is and whether it is a sting, ache, or has some other quality. The affective perception, in another part of the brain called the dorsal anterior cingulate cortex and the anterior insula, tells us that we want the pain to stop, fast! When people with lesions in the latter areas experience a stimulus that ordinarily would be painful, they don't mind it.
Science now suggests that emotional pain arises in the affective brain circuits. Exploration of an overlap between physical and what research psychologists call "social pain" has heated up since the mid-2000s. Animal evidence goes back to the 1970s: babies separated from their mothers showed less distress when given morphine, and more if dosed with naloxone, the opioid antagonist.
Parents, of course, face the question of whether Baby feels alone or wet whenever she howls. And the answer is: both hurt. Being abandoned is the ultimate threat in our early life, and it makes sense that a brain system to monitor social threats would piggyback upon an existing system for pain. Piggybacking is a feature of evolution. An ancestor who felt "hurt" when threatened by rejection might learn adaptive behavior: to cooperate or run.
In 2010, a large multi-university team led by Nathan DeWall at the University of Kentucky, reported that acetaminophen (Tylenol) reduced social pain. Undergraduates took 500 mg of acetaminophen upon awakening and at bedtime every day for three weeks and reported nightly about their day using a previously-tested "Hurt Feelings Scale," rating how strongly they agreed with questions like, "Today, being teased hurt my feelings."
Over the weeks, their reports of hurt feelings steadily declined, while remaining flat in a control group that took placebos. In a second experiment, the research group showed that, compared to controls, people who had taken acetaminophen for three weeks showed less brain activity in the affective brain circuits while they experienced rejection during a virtual ball-tossing game. Later, Hsu's brain scan research supported the idea that rejection triggers the mu opioid receptor system, which normally provides pain-dampening opioids.
More evidence comes from nonhuman primates with lesions in the affective circuits: They cry less when separated from caregivers or social groups.
Heartbreak seems to lie in those regions: women with major depression are more hurt by romantic rejection than normal controls are and show more activity in those areas in brain scans, Hsu found. Also, factors that make us more vulnerable to rejection -- like low self-esteem -- are linked to more activity in the key areas, studies show.
The trait "high rejection sensitivity" increases your risk of depression more than "global neuroticism" does, Hsu observes, and predicts a poor recovery from depression. Pain sensitivity is another clue: People with a gene linked to it seem to be more hurt by social exclusion. Once you're depressed, you become more rejection-sensitive and prone to pain—a classic bad feedback loop.
"Ideally, we'd have biomarkers to distinguish when loss becomes complicated grief and then depression, and we might prevent the transition with a drug."
Helen Mayberg, a neurologist renowned for her study of brain circuits in depression, sees, as Hsu does, the possibility of preventing depressions. "Nobody would suggest we treat routine bad social pain with drugs. But it is true that in susceptible people, losing a partner, for example, can lead to a full-blown depression," says Mayberg, who is the founding director of The Center for Advanced Circuit Therapeutics at Mount Sinai's Icahn School of Medicine in New York City. "Ideally, we'd have biomarkers to distinguish when loss becomes complicated grief and then depression, and we might prevent the transition with a drug. It would be like taking medication when you feel the warning symptoms of a headache to prevent a full-blown migraine."
A Way Out of the Opioid Crisis?
The exploration of social pain should lead us to a deeper understanding of pain, beyond the sharp distinctions between "physical" and "psychological." Finding our way out of the current crisis may require that deeper understanding. About half of the people with opioid prescriptions have mental health disorders. "I expect there are a lot of people using street opioids—heroin or prescriptions purchased from others--to self-medicate psychological pain," Kreugel says.
What we may need, he suggests, is "a new paradigm for using opioids in psychiatry: low, sub-analgesic, sub-euphoric dosing." But so far it hasn't been easy. Investors don't flock to fund psychiatric drugs and in 2018, the word opioid is poison.
As for Tony Y., he's struggled for three years to recover from his most serious relationship. "Driving around highways looking at exit signs toward places we visited together sometimes fills me with unbearable anguish," he admits. "And because we used to do so much bird watching together, sometimes a mere glimpse of a random bird sets me off." He perks up at the idea of a heartbreak drug. "If the side effects didn't seem bad, I would consider it, absolutely."
A startup aims to make medicines in space
Story by Big Think
On June 12, a SpaceX Falcon 9 rocket deployed 72 small satellites for customers — including the world’s first space factory.
The challenge: In 2019, pharma giant Merck revealed that an experiment on the International Space Station had shown how to make its blockbuster cancer drug Keytruda more stable. That meant it could now be administered via a shot rather than through an IV infusion.
The key to the discovery was the fact that particles behave differently when freed from the force of gravity — seeing how its drug crystalized in microgravity helped Merck figure out how to tweak its manufacturing process on Earth to produce the more stable version.
Microgravity research could potentially lead to many more discoveries like this one, or even the development of brand-new drugs, but ISS astronauts only have so much time for commercial experiments.
“There are many high-performance products that are only possible to make in zero-gravity, which is a manufacturing capability that cannot be replicated in any factory on Earth.”-- Will Bruey.
The only options for accessing microgravity (or free fall) outside of orbit, meanwhile, are parabolic airplane flights and drop towers, and those are only useful for experiments that require less than a minute in microgravity — Merck’s ISS experiment took 18 days.
The idea: In 2021, California startup Varda Space Industries announced its intention to build the world’s first space factory, to manufacture not only pharmaceuticals but other products that could benefit from being made in microgravity, such as semiconductors and fiber optic cables.
This factory would consist of a commercial satellite platform attached to two Varda-made modules. One module would contain equipment capable of autonomously manufacturing a product. The other would be a reentry capsule to bring the finished goods back to Earth.
“There are many high-performance products that are only possible to make in zero-gravity, which is a manufacturing capability that cannot be replicated in any factory on Earth,” said CEO Will Bruey, who’d previously developed and flown spacecraft for SpaceX.
“We have a team stacked with aerospace talent in the prime of their careers, focused on getting working hardware to orbit as quickly as possible,” he continued.
“[Pharmaceuticals] are the most valuable chemicals per unit mass. And they also have a large market on Earth.” -- Will Bruey, CEO of Varda Space.
What’s new? At the time, Varda said it planned to launch its first space factory in 2023, and, in what feels like a first for a space startup, it has actually hit that ambitious launch schedule.
“We have ACQUISITION OF SIGNAL,” the startup tweeted soon after the Falcon 9 launch on June 12. “The world’s first space factory’s solar panels have found the sun and it’s beginning to de-tumble.”
During the satellite’s first week in space, Varda will focus on testing its systems to make sure everything works as hoped. The second week will be dedicated to heating and cooling the old HIV-AIDS drug ritonavir repeatedly to study how its particles crystalize in microgravity.
After about a month in space, Varda will attempt to bring its first space factory back to Earth, sending it through the atmosphere at hypersonic speeds and then using a parachute system to safely land at the Department of Defense’s Utah Test and Training Range.
Looking ahead: Ultimately, Varda’s space factories could end up serving dual purposes as manufacturing facilities and hypersonic testbeds — the Air Force has already awarded the startup a contract to use its next reentry capsule to test hardware for hypersonic missiles.
But as for manufacturing other types of goods, Varda plans to stick with drugs for now.
“[Pharmaceuticals] are the most valuable chemicals per unit mass,” Bruey told CNN. “And they also have a large market on Earth.”
“You’re not going to see Varda do anything other than pharmaceuticals for the next minimum of six, seven years,” added Delian Asparouhov, Varda’s co-founder and president.
Genes that protect health with Dr. Nir Barzilai
In today’s podcast episode, I talk with Nir Barzilai, a geroscientist, which means he studies the biology of aging. Barzilai directs the Institute for Aging Research at the Albert Einstein College of Medicine.
My first question for Dr. Barzilai was: why do we age? And is there anything to be done about it? His answers were encouraging. We can’t live forever, but we have some control over the process, as he argues in his book, Age Later.
Dr. Barzilai told me that centenarians differ from the rest of us because they have unique gene mutations that help them stay healthy longer. For most of us, the words “gene mutations” spell trouble - we associate these words with cancer or neurodegenerative diseases, but apparently not all mutations are bad.
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Centenarians may have essentially won the genetic lottery, but that doesn’t mean the rest of us are predestined to have a specific lifespan and health span, or the amount of time spent living productively and enjoyably. “Aging is a mother of all diseases,” Dr. Barzilai told me. And as a disease, it can be targeted by therapeutics. Dr. Barzilai’s team is already running clinical trials on such therapeutics — and the results are promising.
More about Dr. Barzilai: He is scientific director of AFAR, American Federation for Aging Research. As part of his work, Dr. Barzilai studies families of centenarians and their genetics to learn how the rest of us can learn and benefit from their super-aging. He also organizing a clinical trial to test a specific drug that may slow aging.
Show Links
Age Later: Health Span, Life Span, and the New Science of Longevity https://www.amazon.com/Age-Later-Healthiest-Sharpest-Centenarians/dp/1250230853
American Federation for Aging Research https://www.afar.org
https://www.afar.org/nir-barzilai
https://www.einsteinmed.edu/faculty/484/nir-barzilai/
Metformin as a Tool to Target Aging
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943638/
Benefits of Metformin in Attenuating the Hallmarks of Aging https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347426/
The Longevity Genes Project https://www.einsteinmed.edu/centers/aging/longevity-genes-project/
Lina Zeldovich has written about science, medicine and technology for Popular Science, Smithsonian, National Geographic, Scientific American, Reader’s Digest, the New York Times and other major national and international publications. A Columbia J-School alumna, she has won several awards for her stories, including the ASJA Crisis Coverage Award for Covid reporting, and has been a contributing editor at Nautilus Magazine. In 2021, Zeldovich released her first book, The Other Dark Matter, published by the University of Chicago Press, about the science and business of turning waste into wealth and health. You can find her on http://linazeldovich.com/ and @linazeldovich.