Ketamine Treatment for Depression

10/08/2025

https://apple.news/Ax2SLUpTCS1WB7ZBEHw0U-w

Researchers at Penn Medicine have identified specific brain circuits that are impacted by psilocybin—the active compound found in some psychedelic mushrooms—which could lead to new paths forward for pain and mental health management options.

09/17/2025

Ketamine repairs reward circuitry to reverse stress-induced anhedonia

by Eric W. Dolan July 9, 2025in Depression, Ketamine

A single low dose of the anesthetic ketamine restored the ability to enjoy sweet treats and social contact in mice that had been made apathetic by long-term stress, according to new research published in Neuron. The same injection also repaired weakened connections onto a specific group of reward-related brain cells. When those repaired connections were blocked, the animals’ recovery disappeared—suggesting the synaptic fix is a key part of ketamine’s sustained antidepressant effects.

Originally developed as an anesthetic in the 1960s, ketamine has more recently drawn attention for its fast-acting antidepressant properties. Over the past two decades, clinicians have found that sub-anesthetic doses can lift mood within hours in many people with major depression who do not respond to conventional medications. That rapid action stands in contrast to commonly prescribed drugs like selective serotonin reuptake inhibitors, which often take weeks to alleviate symptoms.

One symptom of depression that appears to respond especially well to ketamine is anhedonia—the loss of pleasure in normally rewarding experiences. Yet it remains unclear which brain circuits are responsible for the drug’s lasting effects on mood and motivation. The new study set out to identify those changes down to the level of individual synapses.

“Depression is a leading cause of morbidity and mortality worldwide, and it is projected to become the second leading cause of disability by 2030,” said study author Marco Pignatelli, an assistant professor of psychiatry at Washington University School of Medicine in St. Louis.

“Despite the urgent need to address depression as a public health priority, current pharmacotherapies require prolonged administration—weeks, if not months—for clinical improvement, and are often associated with high non-response rates. In contrast, a single sub-anesthetic dose of ketamine induces a rapid antidepressant effect in about 70% of treatment-resistant patients.”

“Importantly, this improvement often occurs within the context of anhedonia,” he added. “Conventional antidepressants do poorly in relieving anhedonia, which is one of the two core symptoms used to diagnose major depression. That makes ketamine a promising and unique pharmacological option. However, without understanding the circuits and synapses that support this effect, our ability to design safer, more targeted medications is limited.”

To model anhedonia in mice, the researchers implanted slow-release corticosterone pellets under the animals’ skin to mimic chronic stress. Over three weeks, the hormone reduced the animals’ interest in sweetened water, decreased time spent with other mice, and lowered their willingness to work for rewards in a progressive ratio task where nose-pokes earned sugar pellets.

Twenty-four hours before each test, half the stressed mice received a single injection of ketamine at 10 milligrams per kilogram—a dose well below what’s used for anesthesia. The rest received saline, as did a group of unstressed control mice. Ketamine restored reward-seeking behavior across all tasks, while saline had no effect. The drug did not increase overall activity levels, ruling out general stimulation as an explanation.

To uncover what had changed in the brain, the researchers prepared thin slices from another group of similarly treated mice and recorded electrical activity in the nucleus accumbens, a key hub for processing reward. They focused on medium spiny neurons that express dopamine receptor type 1, a subtype linked to motivation and approach behavior.

Chronic stress reduced the strength and frequency of excitatory inputs to these neurons, but ketamine reversed this effect within a day—possibly as soon as one hour after injection. These changes were not observed in neighboring neurons that express dopamine receptor type 2, highlighting the cell-type specificity of the effect.

To test whether these restored synapses were necessary for ketamine’s behavioral benefits, the researchers used a molecular technique to block them. They introduced a HaloTag protein into dopamine receptor type 1 neurons, allowing them to tether a glutamate receptor blocker to just those cells. Delivering the blocker into the nucleus accumbens 24 hours after ketamine erased the previously observed improvements in sugar preference, sociability, and motivation. Blocking the same receptors on dopamine receptor type 2 neurons had no effect, pinpointing the importance of the type 1 cells.

The team then asked whether strengthening the same synapses—without ketamine—would be enough to reverse anhedonia. They inserted a light-sensitive version of Rac1, a protein that clusters glutamate receptors, into the dopamine receptor type 1 neurons. Mice exposed to blue light showed restored motivation and sociability, while exposure to red light had no effect. The findings suggest that targeted synaptic enhancement alone can substitute for ketamine in relieving anhedonia.

To identify where the restored signals were coming from, the researchers injected a light-activated protein into several brain areas that send input to the nucleus accumbens. They found that chronic stress weakened glutamatergic connections from the medial prefrontal cortex and ventral hippocampus—regions involved in decision-making and memory. Ketamine restored both pathways but did not affect inputs from the amygdala, thalamus, or ventral tegmental area.

Further analysis revealed distinct mechanisms for each pathway. The prefrontal input gained stronger unitary synaptic responses, while the hippocampal input showed both stronger responses and increased release events. These changes indicate different modes of adaptation at the two inputs.

To confirm that both inputs were required for ketamine’s effects, the team used a two-virus strategy to express a designer inhibitory receptor specifically in either the prefrontal or hippocampal projection to the nucleus accumbens. Administering a drug that silenced the targeted neurons before ketamine blocked the behavioral rescue.

Interestingly, the type of failure depended on which pathway was silenced. Turning off the ventral hippocampal input delayed the animals’ first approach to a social partner and the first attempt to obtain a reward. In contrast, silencing the prefrontal input did not affect initiation, but reduced overall engagement. These results suggest that hippocampal input helps trigger reward-seeking, while prefrontal input helps sustain it.

“We’ve uncovered a brain mechanism through which ketamine restores reward-related behavior after chronic stress in mice, and we believe these mechanisms are likely conserved across species,” Pignatelli said. “That makes this discovery relevant for clinical applications.”

But, as with all research, there are limitations. “It is always important to highlight that our mechanistic studies are taking place by using murine animal models,” Pignatelli noted. “In general, the findings of a study in mice may not directly translate to humans or other species, but they offer valuable insights into biological processes within that model.”

Future studies could use brain imaging to examine whether similar changes occur in patients who recover from anhedonia after ketamine treatment. Identifying specific synapses that support antidepressant effects may eventually allow researchers to design drugs that improve motivation without the dissociative side effects associated with ketamine.

“I hope that results from this body of work will have a sustained impact on the field by propelling the rational design of more targeted treatments, thereby facilitating more effective and safer therapies aiming at alleviating anhedonia,” Pignatelli said.

The study, “Ketamine rescues anhedonia by cell-type- and input-specific adaptations in the nucleus accumbens,” was authored by Federica Lucantonio, Jacob Roeglin, Shuwen Li, Jaden Lu, Aleesha Shi, Katherine Czerpaniak, Francesca R. Fiocchi, Leonardo Bontempi, Brenda C. Shields ,Carlos A. Zarate, Jr., Michael R. Tadross, and Marco Pignatelli.

05/09/2024

Three Conditions for Which Cannabis Appears to Help
Publish date: May 3, 2024
By Marcia Frellick

The utility of cannabinoids to treat most medical conditions remains uncertain at best, but for at least three indications the data lean in favor of effectiveness, Ellie Grossman, MD, MPH, told attendees recently at the 2024 American College of Physicians Internal Medicine meeting.

Those are neuropathic pain, chemotherapy-induced nausea or vomiting, and spasticity in people with multiple sclerosis, said Dr. Grossman, an instructor at Harvard Medical School in Boston and medical director for primary care/behavioral health integration at Cambridge Health Alliance in Somerville, Massachusetts.

Dearth of Research Persists
Research is sorely lacking and of low quality in the field for many reasons, Dr. Grossman said. Most of the products tested come from outside the United States and often are synthetic and taken orally — which does not match the real-world use when patients go to dispensaries for cannabis derived directly from plants (or the plant product itself). And studies often rely on self-report.

Chronic pain is by far the top reason patients say they use medical cannabis, Dr. Grossman said. A Cochrane review of 16 studies found only that the potential benefits of cannabis may outweigh the potential harms for chronic neuropathic pain.

No Evidence in OUD
Dr. Grossman said she is frequently asked if cannabis can help people quit taking opioids. The answer seems to be no. A study published earlier this year in states with legalized medical or recreational cannabis found no difference between rates of opioid overdose compared with states with no such laws. “It seems like it doesn’t do anything to help us with our opioid problem,” she said.

Nor does high-quality evidence exist showing use of cannabis can improve sleep, she said. A 2022 systematic review found fewer than half of studies showed the substance useful for sleep outcomes. “Where studies were positives, it was in people who had chronic pain,” Dr. Grossman noted. Research indicates cannabis may have substantial benefit for chronic pain compared with placebo.

Potential Harms
If the medical benefits of cannabis are murky, the evidence for its potential harms, at least in the short term, are clearer, according to Dr. Grossman. A simplified guideline for prescribing medical cannabinoids in primary care includes sedation, feeling high, dizziness, speech disorders, muscle twitching, hypotension, and several other conditions among the potential hazards of the drug.

But the potential for long-term harm is uncertain. “All the evidence comes from people who have been using it for recreational reasons,” where there may be co-use of to***co, self-reported outcomes, and recall bias, she said. The characteristics of people using cannabis recreationally often differ from those using it medicinally.

Use With Other Controlled Substances
Dr. Grossman said clinicians should consider whether the co-use of cannabis and other controlled substances, such as benzodiazepines, opioids, or Adderall, raises the potential risks associated with those drugs. “Ultimately it comes down to talking to your patients,” she said. If a toxicity screen shows the presence of controlled substances, ask about their experience with the drugs they are using and let them know your main concern is their safety.

Dr. Grossman reported no relevant financial conflicts of interest.

A version of this article appeared on Medscape.com.

04/17/2024

Are E-Cigarettes Bad for the Heart?
Publish date: April 15, 2024
By Ute Eppinger

E-ci******es entered the market as consumer products without comprehensive toxicological testing,based on the assessment that they were 95% less harmful than traditional ci******es. Further, consumer dvertising suggests that e-ci******es are a good alternative to conventional combustible ci******es and can serve as a gateway to quitting smoking.

However, hen considering damage to the endothelium and toxicity, e-ci******es have a negative impact like that of conventional ci******es. Moreover, switching to e-ci******es often leads to dual use, said Stefan Andreas, MD, director of the Lungenfachklinik in Immenhausen, Germany, at the Congress of the German Respiratory Society and Intensive Care Medicine.

Subclinical Atherosclerosis
Because e-ci******es have emerged relatively recently, long-term studies on their cardiac consequences are not yet available. Dr. Andreas explained that the impact on endothelial function is relevant for risk assessment. Endothelial function is a biomarker for early, subclinical atherosclerosis. “If endothelial function is impaired, the risk for heart attack and stroke is significantly increased 5-10 years later,” said Dr. Andreas.

The results of a crossover study showed reduced vascular elasticity after consuming both to***co ci******es and e-ci******es. The study included 20 smokers, and endothelial function was measured using flow-mediated vasodilation.

Significant effects on the vessels were also found in a study of 31 participants who had never smoked. The study participants inhaled a ni****ne-free aerosol from e-ci******es. Before and after, parameters of endothelial function were examined using a 3.0-T MRI. After aerosol inhalation, the resistance index was 2.3% higher (P < .05), and flow-mediated vascular dilation was reduced by 34% (P < .001).

A recent review involving 372 participants from China showed that e-ci******es lead to an increase in pulse wave velocity, with a difference of 3.08 (P < .001). “Pulse wave velocity is also a marker of endothelial function: The stiffer the vessels, the higher the pulse wave velocity,” said Dr. Andreas. The authors of the review concluded that “e-ci******es should not be promoted as a healthier alternative to to***co smoking.”

No Harmless Alternative
A recent review compared the effects of to***co smoking and e-ci******es. The results showed that va**ng e-ci******es causes oxidative stress, inflammation, endothelial dysfunction, and related cardiovascular consequences. The authors attributed the findings to overlapping toxic compounds in v***r and to***co smoke and similar pathomechanical features of va**ng and smoking. Although the toxic mixture in smoke is more complex, both e-ci******es and to***co ci******es “impaired endothelial function to a similar extent,” they wrote. The authors attributed this finding to oxidative stress as the central mechanism.

“There is increasing evidence that e-ci******es are not a harmless alternative to to***co ci******es,” wrote Thomas Münzel, MD, professor of cardiology at the University of Mainz and his team in their 2020 review, which examined studies in humans and animals. They provided an overview of the effects of to***co/hookah smoking and e-cigarette va**ng on endothelial function. They also pointed to emerging adverse effects on the proteome, transcriptome, epigenome, microbiome, and circadian clock.

Finally, a toxicological review of e-ci******es also found alarmingly high levels of carcinogens and toxins that could have long-term effects on other organs, including the development of neurological symptoms, lung cancer, cardiovascular diseases, and cavities.

Dr. Andreas observed that even small amounts, such as those obtained through secondhand smoking, can be harmful. In 2007, Dr. Andreas and his colleagues showed that even low exposure to to***co smoke can lead to a significant increase in cardiovascular events.

Conflicts of Interest
Dr. Andreas recommended closely examining the studies that suggest that e-ci******es are less risky. “It is noticeable that there is a significant difference depending on whether publications were supported by the to***co industry or not,” he emphasized.

Danish scientists found that a conflict of interest (COI) has a strong influence on study results. “In studies without a COI, e-ci******es are found to cause damage 95% of the time. In contrast, when there is a strong conflict of interest, the result is often ‘no harm,’” said Dr. Andreas.

This effect is quite relevant for the discussion of e-ci******es. “If scientists make a critical statement in a position paper, there will always be someone who says, ‘No, it’s different, there are these and those publications.’ The true nature of interest-driven publications on e-ci******es is not always easy to discern,” said Dr. Andreas.

No Gateway to Quitting
E-ci******es are used in clinical studies for to***co cessation. The results of a randomized study showed that significantly more smokers who were switched to e-ci******es quit smoking, compared with controls. But there was no significant difference in complete smoking cessation between groups. Moreover, 45% of smokers who switched to e-ci******es became dual users, compared with 11% of controls.

“Translating these results means that for one person who quits smoking by using e-ci******es, they gain five people who use both traditional ci******es and e-ci******es,” explained Dr. Andreas.

In their recent review, Münzel and colleagues pointed out that the assessment that e-ci******es could help with quitting might be wrong. Rather, it seems that “e-ci******es have the opposite effect.” They also note that the age of initiation for e-ci******es is generally lower than for to***co ci******es: Consumption often starts at age 13 or 14 years. And the consumption of e-ci******es among children and adolescents increased by 7% from 2016 to 2023.

A meta-analysis published at the end of February also shows that e-ci******es are about as dangerous as to***co ci******es. They are more dangerous than not smoking, and dual use is more dangerous than to***co ci******es alone. “There is a need to reassess the assumption that e-cigarette use provides substantial harm reduction across all cigarette-caused diseases, particularly accounting for dual use,” wrote the authors.

“One must always consider that e-ci******es have only been available for a relatively short time. We can only see the cumulative toxicity in 10, 20 years when we have patients who have smoked e-ci******es only for 20 years,” said Dr. Andreas. Ultimately, however, e-ci******es promote dual use and, consequently, additive toxicity.

Ni****ne Replacement Therapies
Quitting smoking reduces the risk of cardiovascular events and premature death by 40%, even among patients with cardiovascular disease, according to a Cochrane meta-analysis. Smoking cessation reduces the risk for cardiovascular death by 39%, the risk for major adverse cardiovascular events by 43%, the risk for heart attack by 36%, the risk for stroke by 30%, and overall mortality by 40%.

Quitting smoking is the most effective measure for risk reduction, as a meta-analysis of 20 studies in patients with coronary heart diseasefound. Smoking cessation was associated with a 36% risk reduction compared with 29% risk reduction for statin therapy, 23% risk reduction with beta-blockers and ACE inhibitors and 15% risk reduction with aspirin.

Dr. Andreas emphasized that ni****ne replacement therapies are well-researched and safe even in cardiovascular disease, as shown by a US study that included patients who had sustained a heart attack. A group of the participants was treated with ni****ne patches for 10 weeks, while the other group received a placebo. After 14 weeks, 21% of the ni****ne patch group achieved abstinence vs 9% of the placebo group (P = .001). Transdermal ni****ne application does not lead to a significant increase in cardiovascular events in high-risk patients.

The German “Nonsmoker Heroes” app has proven to be an effective means of behavioral therapeutic coaching. A recent study of it included 17 study centers with 661 participants. About 21% of the subjects had chronic obstructive pulmonary disease, 19% had asthma. Smoking onset occurred at age 16 years. The subjects were highly dependent: > 72% had at least moderate dependence, > 58% had high to very high dependence, and the population had an average of 3.6 quit attempts. The odds ratio for self-reported abstinence was 2.2 after 6 months. “The app is not only effective, but also can be prescribed on an extrabudgetary basis,” said Dr. Andreas.

04/15/2024

Drug Derived from L*D Granted FDA Breakthrough Status for Anxiety
Publish date: March 8, 2024
By Megan Brooks

The US Food and Drug Administration (FDA) has granted breakthrough designation to an L*D-based treatment for generalized anxiety disorder (GAD) based on promising topline data from a phase 2b clinical trial. Mind Medicine (MindMed) Inc is developing the treatment — MM120 (lysergide d-tartrate).

In a news release, the company reports that a single oral dose of MM120 met its key secondary endpoint, maintaining “clinically and statistically significant” reductions in Hamilton Anxiety Scale (HAM-A) score, compared with placebo, at 12 weeks with a 65% clinical response rate and 48% clinical remission rate.

The company previously announced statistically significant improvements on the HAM-A compared with placebo at 4 weeks, which was the trial’s primary endpoint.

“I’ve conducted clinical research studies in psychiatry for over two decades and have seen studies of many drugs under development for the treatment of anxiety. That MM120 exhibited rapid and robust efficacy, solidly sustained for 12 weeks after a single dose, is truly remarkable,” study investigator David Feifel, MD, PhD, professor emeritus of psychiatry at the University of California, San Diego, and director of the Kadima Neuropsychiatry Institute in La Jolla, California, said in the news release.

“These results suggest the potential MM120 has in the treatment of anxiety, and those of us who struggle every day to alleviate anxiety in our patients look forward to seeing results from future phase 3 trials,” Dr. Feifel added.

MM120 was administered as a single dose in a monitored clinical setting with no additional therapeutic intervention. Prior to treatment with MM120, study participants were clinically tapered and then washed out from any anxiolytic or antidepressant treatments and did not receive any form of study-related psychotherapy for the duration of their participation in the study.

MM120 100 µg — the dose that demonstrated optimal clinical activity — produced a 7.7-point improvement over placebo at week 12 (P < .003; Cohen’s d = 0.81), with a 65% clinical response rate and a 48% clinical remission rate sustained to week 12.

Also at week 12, Clinical Global Impressions–Severity (CGI-S) scores on average improved from 4.8 to 2.2 in the 100-µg dose group, representing a two-category shift from ‘markedly ill’ to ‘borderline ill’ at week 12 (P < .004), the company reported.

Improvement was noted as early as study day 2, and durable with further improvements observed in mean HAM-A or CGI-S scores between 4 and 12 weeks.

MM120 was generally well-tolerated with most adverse events rated as mild to moderate and transient and occurred on the day of administration day, in line with the expected acute effects of the study drug.

The most common adverse events on dosing day included illusion, hallucinations, euphoric mood, anxiety, abnormal thinking, headache, paresthesia, dizziness, tremor, nausea, vomiting, feeling abnormal, mydriasis, and hyperhidrosis.

The company plans to hold an end-of-phase 2 meeting with the FDA in the first half of 2024 and start phase 3 testing in the second half of 2024.

“The FDA’s decision to designate MM120 as a breakthrough therapy for GAD and the durability data from our phase 2b study provide further validation of the important potential role this treatment can play in addressing the huge unmet need among individuals living with GAD,” Robert Barrow, director and CEO of MindMed said in the release.

The primary data analyses from the trial will be presented at the American Psychiatric Association (APA) annual meeting in May.

03/22/2024

Drug Derived from L*D Granted FDA Breakthrough Status for Anxiety

Publish date: March 8, 2024
By Megan Brooks

The US Food and Drug Administration (FDA) has granted breakthrough designation to an L*D-based treatment for generalized anxiety disorder (GAD) based on promising topline data from a phase 2b clinical trial. Mind Medicine (MindMed) Inc is developing the treatment — MM120 (lysergide d-tartrate).

In a news release, the company reports that a single oral dose of MM120 met its key secondary endpoint, maintaining “clinically and statistically significant” reductions in Hamilton Anxiety Scale (HAM-A) score, compared with placebo, at 12 weeks with a 65% clinical response rate and 48% clinical remission rate.

The company previously announced statistically significant improvements on the HAM-A compared with placebo at 4 weeks, which was the trial’s primary endpoint.

“I’ve conducted clinical research studies in psychiatry for over two decades and have seen studies of many drugs under development for the treatment of anxiety. That MM120 exhibited rapid and robust efficacy, solidly sustained for 12 weeks after a single dose, is truly remarkable,” study investigator David Feifel, MD, PhD, professor emeritus of psychiatry at the University of California, San Diego, and director of the Kadima Neuropsychiatry Institute in La Jolla, California, said in the news release.

“These results suggest the potential MM120 has in the treatment of anxiety, and those of us who struggle every day to alleviate anxiety in our patients look forward to seeing results from future phase 3 trials,” Dr. Feifel added.

MM120 was administered as a single dose in a monitored clinical setting with no additional therapeutic intervention. Prior to treatment with MM120, study participants were clinically tapered and then washed out from any anxiolytic or antidepressant treatments and did not receive any form of study-related psychotherapy for the duration of their participation in the study.

MM120 100 µg — the dose that demonstrated optimal clinical activity — produced a 7.7-point improvement over placebo at week 12 (P < .003; Cohen’s d = 0.81), with a 65% clinical response rate and a 48% clinical remission rate sustained to week 12.

Also at week 12, Clinical Global Impressions–Severity (CGI-S) scores on average improved from 4.8 to 2.2 in the 100-µg dose group, representing a two-category shift from ‘markedly ill’ to ‘borderline ill’ at week 12 (P < .004), the company reported.

Improvement was noted as early as study day 2, and durable with further improvements observed in mean HAM-A or CGI-S scores between 4 and 12 weeks.

MM120 was generally well-tolerated with most adverse events rated as mild to moderate and transient and occurred on the day of administration day, in line with the expected acute effects of the study drug.

The most common adverse events on dosing day included illusion, hallucinations, euphoric mood, anxiety, abnormal thinking, headache, paresthesia, dizziness, tremor, nausea, vomiting, feeling abnormal, mydriasis, and hyperhidrosis.

The company plans to hold an end-of-phase 2 meeting with the FDA in the first half of 2024 and start phase 3 testing in the second half of 2024.

“The FDA’s decision to designate MM120 as a breakthrough therapy for GAD and the durability data from our phase 2b study provide further validation of the important potential role this treatment can play in addressing the huge unmet need among individuals living with GAD,” Robert Barrow, director and CEO of MindMed said in the release.

The primary data analyses from the trial will be presented at the American Psychiatric Association (APA) annual meeting in May.

03/05/2024

Is Stretching Now Underrated? Accumulating Research Says Yes
Publish date: February 27, 2024
By Lou Schuler
For many, stretching is the fitness equivalent of awkward small talk. It’s the opening act, the thing you tolerate because you know it will be over soon.

Others have challenged the practice, suggesting that stretching isn’t necessary at all. Some research has found that a preworkout stretch may even be disadvantageous, weakening muscles and hindering performance.

To put it plainly, no one seems terribly enthusiastic about touching their toes.

That’s why a 2020 study on exercise and mortality was such a head-scratcher. The study found that stretching was uniquely associated with a lower risk for all-cause mortality among American adults. That’s after controlling for participation in other types of exercise.

The finding seemed like a fluke, until a 2023 study found essentially the same thing.

Among Korean adults, those who did flexibility exercise at least five times a week had a 20% lower risk of dying during the follow-up period than those who didn’t stretch at all. That was slightly better than the risk reduction associated with high volumes of aerobic exercise and resistance training.

How can that be ? It turns out, stretching is linked to several health benefits that you might not expect.

The Surprising Benefits of Stretching
When we talk about stretching, we usually mean static stretching — getting into and holding a position that challenges a muscle, with the goal of improving range of motion around a joint.

It doesn’t need to be a big challenge. “Research shows you can get increases in flexibility by stretching to the initial point of discomfort,” said David Behm, PhD, an exercise scientist at Memorial University of Newfoundland in Canada who’s published dozens of studies on stretching over the past quarter-century.

That brings us to the first benefit.

Stretching Benefit #1: More Strength
At first glance, flexibility training and strength training have little in common. You lengthen muscles in the former and contract them in the latter.

But in both cases, Dr. Behm said, you’re applying tension to muscles and connective tissues. Tension activates proteins called integrins, which send and receive signals across cellular membranes. Those signals are the start of a cascade that leads to protein synthesis. That’s how muscles get bigger and stronger when you lift weights.

That mechanism could explain the small gains in muscle strength and size associated with static stretching, Dr. Behm said.

But can you really stretch your way to muscle growth? Theoretically, yes. But strength training is far more time-efficient, Dr. Behm says. Studies showing increases in muscle mass have typically stretched a single muscle (usually the calves, using a specialized device) for > 30 min/session, 6 d/wk for 6 weeks. And that’s for just one leg.

Still, stretching may be more accessible for some patients — research suggested that older and more sedentary people are most likely to benefit from stretching-induced gains in strength.

Stretching Benefit #2: Reduced Arterial Stiffness
“Most people don’t think about the cardiovascular benefits of stretching,” Dr. Behm said. There are some big ones.

If your body doesn’t move well, it’s not unreasonable to assume your blood doesn’t flow well. That is indeed the case: Poor flexibility is associated with arterial stiffness.

Stretching is associated not only with improved arterial function but also with reductions in resting heart rate and blood pressure and increased vasodilation.

Mobility improvements may have an indirect benefit on cardiovascular health as well.

“Studies show runners are more economical when they’re more flexible,” Dr. Behm said. If your movement is more efficient, you’ll probably do more of it. Doing more, in turn, would lead to improved fitness.

Stretching Benefit #3: Improved Performance
Research is equivocal on whether stretching improves athletic performance, said Joe Yoon, a sports massage therapist in Orlando, Florida, and author of Better Stretching.

“But I’ve always taken the approach that if you can improve your range of motion and get into positions” required for your sport, you’ll probably perform better, with less risk for injury, Mr. Yoon said.

It’s worth noting that some research over the past 30 years has linked pre-exercise static stretching with a loss of strength, power, and/or speed.

But consider this: In a 2016 review, Dr. Behm and his coauthors showed that performance reductions were most likely to occur in two situations:

When participants did extremely long stretches (duration, ≥ 60 sec per muscle).

When researchers tested the participants’ strength, power, or speed immediately after they stretched.

Avoiding those problems is easy, Dr. Behm said: Stretch each muscle for < 60 sec, and combine static stretches with more active warm-up exercises.

“Stretching can impair your performance but only if you do it wrong,” he said.

Stretching Benefit #4: Fewer Injuries
When you stretch, the point where you feel tension is where the muscle is most vulnerable. “That’s where injuries usually happen,” Dr. Behm said.

More flexibility in those areas allows your muscles to safely generate force at longer lengths. For an athlete, that means fewer injuries when they’re doing explosive movements or changing direction.

For nonathletes, flexibility reduces injuries by improving balance. Better balance reduces the risk of falling and helps mitigate the damage if you do take a tumble.

Help Your Patients Get the Benefits of Stretching
Stretching, like training for endurance or strength, can be as complex as you want to make it. But Mr. Yoon advocates a simpler approach.

“You see this flashy stuff online,” he said. “But if you see those trainers in real life or you book a session with them, they go right back to the basics.”

Ideally, Mr. Yoon said, a flexibility routine will work the entire body. But if that’s too big a stretch for your patient, he recommends starting with one or two stretches for the most problematic area.

For example, for a stiff back, try doing the puppy pose at least once a day, although twice is better. Hold the position for 30 seconds to 2 minutes, said Mr. Yoon. Even if you combine it with a dynamic movement like the cat-cow, the two exercises would take just a few minutes a day.

“There’s this misconception that you have to do a lot of it to be successful,” Mr. Yoon said.

Consistency is far more important than volume. Mr. Yoon recommends “a little bit every day — the minimum viable dose.”

As a bonus, stretching an area like your upper back will probably improve your shoulder mobility, Mr. Yoon said. Same with your lower body: Stretches for your hips, over time, should also benefit your knees and lower back.

And thanks to a phenomenon called nonlocal flexibility transfer, lower-body stretches should improve upper-body flexibility, at least temporarily. Shoulder stretches can also have an immediate effect on hip mobility.

“It’s all connected,” Mr. Yoon said, which brings us back to where we started.

If stretching can indeed reduce mortality risk, it’s probably because of interconnected pathways, rather than any single mechanism.

Most obviously, stretching improves flexibility, which makes movement easier, improves balance, and reduces the risk for falls and other types of injuries. It can also lead to small improvements in strength. Less obviously, stretching improves several aspects of cardiovascular function, including circulation.

“There seems to be a global effect in everything we do,” Dr. Behm said. “Whether you’re stretching or weight training, the message is sent throughout your body."