A decade ago, Elizabeth Summers' options for birth control suddenly narrowed. Doctors diagnosed her with Factor V Leiden, a rare genetic disorder, after discovering blood clots in her lungs. The condition increases the risk of clotting, so physicians told Summers to stay away from the pill and other hormone-laden contraceptives. "Modern medicine has generally failed to provide me with an effective and convenient option," she says.
But new birth control options are emerging for women like Summers. These alternatives promise to provide more choices to women who can't ingest hormones or don't want to suffer their unpleasant side effects.
These new products have their own pros and cons. Still, doctors are welcoming new contraceptives following a long drought in innovation. "It's been a long time since we've had something new in the world of contraception," says Heather Irobunda, an obstetrician and gynecologist at NYC Health and Hospitals.
On social media, Irobunda often fields questions about one of these new options, a lubricating gel called Phexxi. San Diego-based Evofem, the company behind Phexxi, has been advertising the product on Hulu and Instagram after the gel was approved by the Food and Drug Administration in May 2020. The company's trendy ads target women who feel like condoms diminish the mood, but who also don't want to mess with an IUD or hormones.
Here's how it works: Phexxi is inserted via a tampon-like device up to an hour before sex. The gel regulates vaginal pH — essentially, the acidity levels — in a range that's inhospitable to sperm. It sounds a lot like spermicide, which is also placed in the vagina prior to sex to prevent pregnancy. But spermicide can damage the vagina's cell walls, which can increase the risk of contracting sexually transmitted diseases.
"Not only is innovation needed, but women want a non-hormonal option."
Phexxi isn't without side effects either. The most common one is vaginal burning, according to a late-stage trial. It's also possible to develop a urinary tract infection while using the product. That same study found that during typical use, Phexxi is about 86 percent effective at preventing pregnancy. The efficacy rate is comparable to condoms but lower than birth control pills (91 percent) and significantly lower than an IUD (99 percent).
Phexxi – which comes in a pack of 12 – represents a tiny but growing part of the birth control market. Pharmacies dispensed more than 14,800 packs from April through June this year, a 65 percent increase over the previous quarter, according to data from Evofem.
"We've been able to demonstrate that not only is innovation needed, but women want a non-hormonal option," says Saundra Pelletier, Evofem's CEO.
Beyond contraception, the company is carrying out late-stage tests to gauge Phexxi's effectiveness at preventing the sexually transmitted infections chlamydia and gonorrhea.
Phexxi is inserted via a tampon-like device up to an hour before sex.
Phexxi
A New Pill
The first birth control pill arrived in 1960, combining the hormones estrogen and progestin to stop sperm from joining with an egg, giving women control over their fertility. Subsequent formulations sought to ease side effects, by way of lower amounts of estrogen. But some women still experience headaches and nausea – or more serious complications like blood clots. On social media, women recently noted that birth control pills are much more likely to cause blood clots than Johnson & Johnson's COVID-19 vaccine that was briefly paused to evaluate the risk of clots in women under age 50. What will it take, they wondered, for safer birth control?
Mithra Pharmaceuticals of Belgium sought to create a gentler pill. In April, the FDA approved Mithra's Nextstellis, which includes a naturally occurring estrogen, the first new estrogen in the U.S. in 50 years. Nextstellis selectively acts on tissues lining the uterus, while other birth control pills have a broader target.
A Phase 3 trial showed a 98 percent efficacy rate. Andrew London, an obstetrician and gynecologist, who practices at several Maryland hospitals, says the results are in line with some other birth control pills. But, he added, early studies indicate that Nextstellis has a lower risk of blood clotting, along with other potential benefits, which additional clinical testing must confirm.
"It's not going to be worse than any other pill. We're hoping it's going to be significantly better," says London.
The estrogen in Nexstellis, called estetrol, was skipped over by the pharmaceutical industry after its discovery in the 1960s. Estetrol circulates between the mother and fetus during pregnancy. Decades later, researchers took a new look, after figuring out how to synthesize estetrol in a lab, as well as produce estetrol from plants.
"That allowed us to really start to investigate the properties and do all this stuff you have to do for any new drug," says Michele Gordon, vice president of marketing in women's health at Mayne Pharma, which licensed Nextstellis.
Bonnie Douglas, who followed the development of Nextstellis as part of a search for better birth control, recently switched to the product. "So far, it's much more tolerable," says Douglas. Previously, the Midwesterner was so desperate to find a contraceptive with fewer side effects that she turned to an online pharmacy to obtain a different birth control pill that had been approved in Canada but not in the U.S.
Contraceptive Access
Even if a contraceptive lands FDA approval, access poses a barrier. Getting insurers to cover new contraceptives can be difficult. For the uninsured, state and federal programs can help, and companies should keep prices in a reasonable range, while offering assistance programs. So says Kelly Blanchard, president of the nonprofit Ibis Reproductive Health. "For innovation to have impact, you want to reach as many folks as possible," she says.
In addition, companies developing new contraceptives have struggled to attract venture capital. That's changing, though.
In 2015, Sabrina Johnson founded DARÉ Bioscience around the idea of women's health. She estimated the company would be fully funded in six months, based on her track record in biotech and the demand for novel products.
But it's been difficult to get male investors interested in backing new contraceptives. It took Johnson two and a half years to raise the needed funds, via a reverse merger that took the company public. "There was so much education that was necessary," Johnson says, adding: "The landscape has changed considerably."
Johnson says she would like to think DARÉ had something to do with the shift, along with companies like Organon, a spinout of pharma company Merck that's focused on reproductive health. In surveying the fertility landscape, DARÉ saw limited non-hormonal options. On-demand options – like condoms – can detract from the moment. Copper IUDs must be inserted by a doctor and removed if a woman wants to return to fertility, and this method can have onerous side effects.
So, DARÉ created Ovaprene, a hormone-free device that's designed to be inserted into the vagina monthly by the user. The mesh product acts as a barrier, while releasing a chemical that immobilizes sperm. In an early study, the company reported that Ovaprene prevented almost all sperm from entering the cervical canal. The results, DARÉ believes, indicate high efficacy.
A late-stage study, slated to kick off next year, will be the true judge. Should Ovaprene eventually win regulatory approval, drug giant Bayer will handle commercializing the device.
Other new forms of birth control in development are further out, and that's assuming they perform well in clinical trials. Among them: a once-a-month birth control pill, along with a male version of the birth control pill. The latter is often brought up among women who say it's high time that men take a more proactive role in birth control.
For Summers, her search for a safe and convenient birth control continues. She tried Phexxi, which caused irritation. Still, she's excited that a non-hormonal option now exists. "I'm sure it will work for others," she says.
This fall, Robert Reinhart of Boston University published a study finding that electrical stimulation can boost memory - and Reinhart was surprised to discover the effects lasted a full month.
Scientists believe brain circuits tend to uncouple as we age. Since brain neurons communicate by exchanging electrical impulses with each other, the breakdown of these links and associations could be what causes the “senior moment”—when you can’t remember the name of the movie you just watched.
In 2019, Boston University researchers led by Robert Reinhart, director of the Cognitive and Clinical Neuroscience Laboratory, showed that memory loss in healthy older adults is likely caused by these disconnected brain networks. When Reinhart and his team stimulated two key areas of the brain with mild electrical current, they were able to bring the brains of older adult subjects back into sync — enough so that their ability to remember small differences between two images matched that of much younger subjects for at least 50 minutes after the testing stopped.
Reinhart wowed the neuroscience community once again this fall. His newer study in Nature Neuroscience presented 150 healthy participants, ages 65 to 88, who were able to recall more words on a given list after 20 minutes of low-intensity electrical stimulation sessions over four consecutive days. This amounted to a 50 to 65 percent boost in their recall.
Even Reinhart was surprised to discover the enhanced performance of his subjects lasted a full month when they were tested again later. Those who benefited most were the participants who were the most forgetful at the start.
An older person participates in Robert Reinhart's research on brain stimulation.
Robert Reinhart
Reinhart’s subjects only suffered normal age-related memory deficits, but NIBS has great potential to help people with cognitive impairment and dementia, too, says Krista Lanctôt, the Bernick Chair of Geriatric Psychopharmacology at Sunnybrook Health Sciences Center in Toronto. Plus, “it is remarkably safe,” she says.
Lanctôt was the senior author on a meta-analysis of brain stimulation studies published last year on people with mild cognitive impairment or later stages of Alzheimer’s disease. The review concluded that magnetic stimulation to the brain significantly improved the research participants’ neuropsychiatric symptoms, such as apathy and depression. The stimulation also enhanced global cognition, which includes memory, attention, executive function and more.
This is the frontier of neuroscience.
The two main forms of NIBS – and many questions surrounding them
There are two types of NIBS. They differ based on whether electrical or magnetic stimulation is used to create the electric field, the type of device that delivers the electrical current and the strength of the current.
Transcranial Current Brain Stimulation (tES) is an umbrella term for a group of techniques using low-wattage electrical currents to manipulate activity in the brain. The current is delivered to the scalp or forehead via electrodes attached to a nylon elastic cap or rubber headband.
Variations include how the current is delivered—in an alternating pattern or in a constant, direct mode, for instance. Tweaking frequency, potency or target brain area can produce different effects as well. Reinhart’s 2022 study demonstrated that low or high frequencies and alternating currents were uniquely tied to either short-term or long-term memory improvements.
Sessions may be 20 minutes per day over the course of several days or two weeks. “[The subject] may feel a tingling, warming, poking or itching sensation,” says Reinhart, which typically goes away within a minute.
The other main approach to NIBS is Transcranial Magnetic Simulation (TMS). It involves the use of an electromagnetic coil that is held or placed against the forehead or scalp to activate nerve cells in the brain through short pulses. The stimulation is stronger than tES but similar to a magnetic resonance imaging (MRI) scan.
The subject may feel a slight knocking or tapping on the head during a 20-to-60-minute session. Scalp discomfort and headaches are reported by some; in very rare cases, a seizure can occur.
No head-to-head trials have been conducted yet to evaluate the differences and effectiveness between electrical and magnetic current stimulation, notes Lanctôt, who is also a professor of psychiatry and pharmacology at the University of Toronto. Although TMS was approved by the FDA in 2008 to treat major depression, both techniques are considered experimental for the purpose of cognitive enhancement.
“One attractive feature of tES is that it’s inexpensive—one-fifth the price of magnetic stimulation,” Reinhart notes.
Don’t confuse either of these procedures with the horrors of electroconvulsive therapy (ECT) in the 1950s and ‘60s. ECT is a more powerful, riskier procedure used only as a last resort in treating severe mental illness today.
Clinical studies on NIBS remain scarce. Standardized parameters and measures for testing have not been developed. The high heterogeneity among the many existing small NIBS studies makes it difficult to draw general conclusions. Few of the studies have been replicated and inconsistencies abound.
Scientists are still lacking so much fundamental knowledge about the brain and how it works, says Reinhart. “We don’t know how information is represented in the brain or how it’s carried forward in time. It’s more complex than physics.”
Lanctôt’s meta-analysis showed improvements in global cognition from delivering the magnetic form of the stimulation to people with Alzheimer’s, and this finding was replicated inan analysis in the Journal of Prevention of Alzheimer’s Disease this fall. Neither meta-analysis found clear evidence that applying the electrical currents, was helpful for Alzheimer’s subjects, but Lanctôt suggests this might be merely because the sample size for tES was smaller compared to the groups that received TMS.
At the same time, London neuroscientist Marco Sandrini, senior lecturer in psychology at the University of Roehampton, critically reviewed a series of studies on the effects of tES on episodic memory. Often declining with age, episodic memory relates to recalling a person’s own experiences from the past. Sandrini’s review concluded that delivering tES to the prefrontal or temporoparietal cortices of the brain might enhance episodic memory in older adults with Alzheimer’s disease and amnesiac mild cognitive impairment (the predementia phase of Alzheimer’s when people start to have symptoms).
Researchers readily tick off studies needed to explore, clarify and validate existing NIBS data. What is the optimal stimulus session frequency, spacing and duration? How intense should the stimulus be and where should it be targeted for what effect? How might genetics or degree of brain impairment affect responsiveness? Would adjunct medication or cognitive training boost positive results? Could administering the stimulus while someone sleeps expedite memory consolidation?
Using MRI or another brain scan along with computational modeling of the current flow, a clinician could create a treatment that is customized to each person’s brain.
While Sandrini’s review reported improvements induced by tES in the recall or recognition of words and images, there is no evidence it will translate into improvements in daily activities. This is another question that will require more research and testing, Sandrini notes.
Scientists are still lacking so much fundamental knowledge about the brain and how it works, says Reinhart. “We don’t know how information is represented in the brain or how it’s carried forward in time. It’s more complex than physics.”
Where the science is headed
Learning how to apply precision medicine to NIBS is the next focus in advancing this technology, says Shankar Tumati, a post-doctoral fellow working with Lanctôt.
There is great variability in each person’s brain anatomy—the thickness of the skull, the brain’s unique folds, the amount of cerebrospinal fluid. All of these structural differences impact how electrical or magnetic stimulation is distributed in the brain and ultimately the effects.
Using MRI or another brain scan along with computational modeling of the current flow, a clinician could create a treatment that is customized to each person’s brain, from where to put the electrodes to determining the exact dose and duration of stimulation needed to achieve lasting results, Sandrini says.
Above all, most neuroscientists say that largescale research studies over long periods of time are necessary to confirm the safety and durability of this therapy for the purpose of boosting memory. Short of that, there can be no FDA approval or medical regulation for this clinical use.
Lanctôt urges people to seek out clinical NIBS trials in their area if they want to see the science advance. “That is how we’ll find the answers,” she says, predicting it will be 5 to 10 years to develop each additional clinical application of NIBS. Ultimately, she predicts that reigning in Alzheimer’s disease and mild cognitive impairment will require a multi-pronged approach that includes lifestyle and medications, too.
Sandrini believes that scientific efforts should focus on preventing or delaying Alzheimer’s. “We need to start intervention earlier—as soon as people start to complain about forgetting things,” he says. “Changes in the brain start 10 years before [there is a problem]. Once Alzheimer’s develops, it is too late.”