Ketamine Treatment for Depression

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.

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.

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.

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.

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."

Original Investigation
August 24, 2022

Percentage of Heavy Drinking Days Following Psilocybin-Assisted Psychotherapy vs Placebo in the Treatment of Adult Patients With Alcohol Use Disorder
A Randomized Clinical Trial

Michael P. Bogenschutz, MD1; Stephen Ross, MD1; Snehal Bhatt, MD2; et al Tara Baron, MA1; Alyssa A. Forcehimes, PhD3; Eugene Laska, PhD1,4; Sarah E. Mennenga, PhD1; Kelley O’Donnell, MD, PhD1; Lindsey T. Owens, MA1,5; Samantha Podrebarac, MA1; John Rotrosen, MD1; J. Scott Tonigan, PhD6; Lindsay Worth, MA2

JAMA Psychiatry. 2022;79(10):953-962.

Key Points
Question Does psilocybin-assisted treatment improve drinking outcomes in patients with alcohol use disorder relative to outcomes observed with active placebo medication?

Findings In this double-blind randomized clinical trial with 93 participants, the percentage of heavy drinking days during 32 weeks of follow-up was significantly lower in the psilocybin group than in the diphenhydramine group.

Meaning The results in this trial showed that psilocybin administered in combination with psychotherapy produced robust decreases in the percentage of heavy drinking days compared with those produced by active placebo and psychotherapy.

Psilocybin reduces symptoms, disability in major depression
Publish date: September 6, 2023
By Kelli Whitlock Burton

FROM JAMA

A single dose of an experimental psilocybin drug offered significant sustained improvement in symptoms and disability in patients with major depressive disorder (MDD) over a 6-week period, results of a study suggest.

The randomized, phase 2 trial was conducted at 11 sites across the United States and is the latest to demonstrate the psychedelic drug’s potential as a treatment for depression.

The project was funded by Usona Institute, a nonprofit medical research organization based in Madison, Wisc. The institute issued a press statement, but researchers did not comment further on the findings.

“As the largest and most rigorous study conducted across a wide spectrum of individuals with major depressive disorder, the results show promise for all people struggling with this condition,” lead author Charles Raison, MD, director of clinical and translational research at Usona, said in the statement.

The 34 coauthors on the study are affiliated with public universities, research centers, and private companies. Eight of the investigators are identified as employees of Usona Institute.

Declining further comment, an institute spokesperson told this news organization that, “Usona has chosen the approach of no interviews, and this applies for all coauthors.”

The findings were published online in JAMA.

Largest study to date
Usona’s investigational psilocybin drug has been granted a breakthrough designation by the Food and Drug Administration, a process designed to speed drug development and review.

Previous smaller studies have suggested a rapid antidepressant response with psilocybin, but they have been small, unblinded, and have had short duration of follow-up, they write. This randomized, double-blind, phase 2 clinical trial is the largest study of psilocybin for depression to date, the researchers note.

It included 104 adults aged 21-65 years with MDD who had a current depressive episode of at least 60 days and a Montgomery-Åsberg Depression Rating Scale (MADRS) total score of 28 or more at baseline.

Participants had to be free of psychedelic drugs for at least 5 years, have had no active suicidal ideation or suicidal behavior in the prior 12 months, no personal or first-degree family history of psychosis or mania, and no history of moderate/severe alcohol or drug use disorder.

Before the study, participants had a 7- to 35-day screening period for psychiatric medication tapering, underwent baseline assessments, and received 6-8 hours of preparation with two facilitators who would be with them during dosing.

Dosing occurred within 7 days of baseline assessments. During the 6- to 8-hour session, participants received either a single 25-mg oral dose of psilocybin or 100-mg dose of niacin. One participant randomly assigned to receive psilocybin received the incorrect treatment, resulting in 50 participants receiving psilocybin and 54 receiving niacin.

Participants returned the next day, the next week, and then every 2 weeks for assessments, for a follow-up of 6 weeks.

Psychosocial support
Participants who received psilocybin reported significantly greater improvements in MDD symptoms, compared with those who received niacin. MADRS scores – a scale from 0 to 60 where higher scores indicate more severe depression – showed greater reductions with treatment vs. placebo at 8 days (mean difference, −12.0; 95% confidence interval, −16.6 to −7.4; P < .001), and at day 43 (mean difference, −12.3; 95% CI, −17.5 to −7.2; P < .001).

More participants receiving psilocybin had sustained depressive symptom response (42% vs. 11%; P = .002) and more improvement in the Sheehan Disability Scale score, which measures functional disability, 43 days after treatment (P < .001).

The effects persisted through the end of the study, although the differences between groups were no longer significant by week 6.

Center for Psychedelic Research and Therapy at the University of Texas at Austin, Dell Medical School
Dr. Greg Fonzo

“This is another exciting piece of evidence that adds to the current literature regarding the potential efficacy of psilocybin for the treatment of mental health conditions, particularly depression,” said Greg Fonzo, MD, codirector of the Center for Psychedelic Research and Therapy at the University of Texas at Austin, who commented on the findings.

Significantly more people in the psilocybin group reported at least one treatment-related adverse event (AE, 82% vs. 44%), although most were mild to moderate. Headache and nausea were the most common side effects and most resolved within 1 day of dosing.

While those numbers are high, Dr. Fonzo said they’re not out of line with AEs reported in other studies.

“Particularly with the types of adverse events reported here, like headache and nausea, those are things you would typically expect to see in this treatment,” said Dr. Fonzo, who was not part of the research.

“But it is high, and it underscores that this is not a treatment without certain risks, even though it was good that they were primarily mild in severity,” he added.

A ‘stepping stone’ to FDA approval?
The use of tools to measure disability in addition to symptoms of depression severity is a strength of the study, Dr. Fonzo added. The use of an active comparator and the 6-week follow-up also offer something new over previous studies.

Despite the longer follow up, questions remain about the durability of response, something only a longer study could answer, Dr. Fonzo said. The small and homogeneous sample-size are also a concern. Nearly 90% of participants were White, and more than half had an income of $75,000 a year or higher.

“It’s another stepping stone in the process to FDA approval, but the next step in that process would be much larger phase 3 trials that would have much larger samples, a longer follow-up, and hopefully have a more inclusive swath of the population,” Dr. Fonzo said.

But perhaps one of the most significant limitations is the use of niacin as an active comparator, said Caleb Alexander, MD, codirector of the Center for Drug Safety and Effectiveness at Johns Hopkins University in Baltimore.

Center for Drug Safety and Effectiveness at Johns Hopkins University in Baltimore
Dr. Caleb Alexander

The use of an agent that doesn’t produce effects similar to those expected from a psychedelic introduced the potential for functional unblinding, Dr. Alexander said. Investigators did not ask participants to guess whether they received psilocybin or niacin, so the quality of the blinding was not assessed in the study.

“We’d like to see the use of [an] active comparator that might have a chance of obscuring to people as to whether they’ve been randomized to the treatment arm or control arm,” said Dr. Alexander, who wasn’t involved in the study. “Why not use a benzodiazepine or another drug that produces a transient euphoria that would better obscure whether or not people were receiving the psilocybin?”

The authors of an accompanying editorial shared these concerns, also noting that the study included “a significant number of patients who did not respond to therapy.”

“It is important to analyze and understand adverse outcomes in psychedelic trials and conduct longitudinal studies to determine how sustained the effects will be and what may initiate a recrudescence of symptoms,” write Rachel Yehuda, PhD.

“Future studies will help identify who is most likely to benefit from psychedelics, whether booster or repeated treatment is safe and beneficial, and what the optimal dose and therapeutic frameworks are.”

A long-term follow-up of the current trial was terminated last year because of low enrollment. The spokesperson with Usona Institute did not respond to questions about that study, and the institute’s statement only added that preparations are underway to launch another study that “will provide additional safety and efficacy data to support submission of a new drug application to the FDA.”

Usona published its manufacturing process that it used to synthesize psilocybin in an open-access journal and signed a statement on “open science and open praxis” with psilocybin and similar substances, which appears on their website. That statement was signed by 31 research and service organizations around the world and nearly 150 scientists, scholars, and practitioners.

The study was funded by Usona Institute. Dr. Raison reported receiving personal fees from Usona Institute and grants to Usona Institute from Dr. Bronner’s All-One, Fournier Family Foundation, Good Ventures, Steven and Alexandra Cohen Foundation, Tiny Blue Dot Foundation, Turnbull Family Foundation, and William A. Linton during the conduct of the study; and personal fees from Novartis, Sage/Biogen, Emory Healthcare, and Vail Health outside the submitted work. Dr. Fonzo and Dr. Alexander report no relevant financial relationships. Dr. Yehuda reports receiving nonfinancial support from the Multidisciplinary Association for Psychedelic Studies Public Benefit (MAPS PBC) and grants from COMPASS Pathways. Dr. Lehrner is an investigator on trials sponsored by MAPS PBC and COMPASS Pathways.

A version of this article first appeared on Medscape.com.