Leah Kuntz

In the first placebo-controlled efficacy study completed to date exploring a short-duration psychedelic for depression, intravenous (IV) N,N-Dimethyltryptamine (DMT)—SPL026—with supportive therapy for the treatment of major depressive disorder (MDD), met the primary endpoint and demonstrated a statistically significant and clinically relevant reduction in depressive symptoms at 2-weeks post-dose as compared with placebo.

The phase 2a trial included 2 stages, and enrolled 34 participants with moderate/severe MDD, who were dosed with a 21.5 mg IV infusion of SPL026 that resulted in a 20- to 30-minute psychedelic experience. In the blinded, randomized, placebo-controlled phase, the primary endpoint was to assess the efficacy of a single dose of SPL026 with supportive therapy (N=17) versus placebo with therapy (N=17) at 2-weeks post-dose. Subsequently, all study participants were enrolled in an open-label phase in which they received a single dose of SPL026 with supportive therapy and were followed-up for 12 weeks.

“The results are exciting for the field of psychiatry. We now have the first evidence that SPL026 DMT, combined with supportive therapy, may be effective for people suffering from MDD,” said David Erritzoe, MD, a clinical psychiatrist at Imperial College London and chief investigator of the phase 1/2a study. “For patients who are unfortunate to experience little benefit from existing antidepressants, the potential for rapid and durable relief from a single treatment, as shown in this trial, is very promising.”

Efficacy was assessed using the Montgomery-Asberg Depression Rating scale (MADRS). Independent raters who were not present for dosing and were blinded to overall treatment assessed MADRS. Compared with placebo, SPL026 with supportive therapy demonstrated a statistically significant and clinically relevant reduction in depressive symptoms 2-weeks, with a -7.4 point difference in MADRS (p=0.02). Analysis of key secondary endpoints demonstrated a rapid onset of antidepressant effect 1-week post-dose, with a statistically significant difference in MADRS score between the active and placebo groups of -10.8 (p=0.002).

“We are pleased that a significant number of patients benefited from the treatment in our trial. SPL026 with supportive therapy was shown to have a significant antidepressant effect that was rapid and durable, with a remission rate of 57% at 3 months following a single dose of SPL026,” said Carol Routledge, Chief Medical and Scientific Officer of Small Pharma. “It was encouraging to see that SPL026 demonstrated a favorable safety and tolerability profile in MDD patients in this study, consistent with our phase 1 study. The results are clinically meaningful and enable us to progress into an international multi-site phase 2b study where we seek to further explore the efficacy and safety profile of SPL026 in a larger MDD patient population.”

George Tziras, the Chief Executive Officer of Small Pharma had this to say on the data: “MDD affects the lives of hundreds of millions of people worldwide. The scale of the unmet need indicates the importance of investigating alternative new treatments. Our goal is to develop proprietary, scalable, and reimbursable short-duration psychedelics with supportive therapy to address this need. I am delighted with our top-line results, which demonstrate proof-of-concept for SPL026 and provide encouraging support for our broader portfolio. I want to thank each patient who took part in this trial, as well as their families, the trial investigators, the employees of the trial sites and everyone who has supported the successful completion of this study.”

This article originally appeared in Pyschiatric Times. 

1. Small Pharma reports positive top-line results from phase IIa trial of SPL026 in major depressive disorder. News release. 

https://edmontonjournal.com/globe-newswire/small-pharma-reports-positive-top-line-results-from-phase-iia-trial-of-spl026-in-major-depressive-disorder

Articles

SPL026 with supportive therapy sees positive results in patients with major depressive disorder.

2a Trial of Psychedelic for Major Depressive Disorder Shows Positive Results

To encourage sponsor application for over-the counter naloxone, the US Food and Drug Administration (FDA) today issued a Federal Register notice, “Safety and Effectiveness of Certain Naloxone Hydrochloride Drug Products for Nonprescription Use,” that could help facilitate the development and potential approval of nonprescription naloxone drugs.

“Today’s action supports our efforts to combat the opioid overdose crisis by helping expand access to naloxone,” said FDA Commissioner Robert M. Califf, MD. “The agency will keep overdose prevention and reduction in substance use disorders as a key priority and area of intense strategic focus for action as rapidly as possible.”

The notice states that naloxone drug products up to 4 mg nasal spray and up to 2 mg autoinjector for intramuscular or subcutaneous use may be safe and effective for nonprescription use. Although this notice does not mean nonprescription/over-the-counter naloxone is immediately available, it does make application holders aware of the willingness of the FDA to consider nonprescription naloxone drug products. First, the FDA needs additional data, including product-specific data on the user interface design, such as packaging and labeling.

This is not the first step the FDA has taken to improve access to naloxone. In September, the FDA issued guidance to clarify that certain Drug Supply Chain Security Act requirements do not apply to naloxone distribution to harm reduction programs during the Opioid Public Health Emergency.

“The agency remains focused on responding to all facets of substance use, misuse, substance use disorders, overdose, and death in the US through the four priorities of the framework, including: supporting primary prevention by eliminating unnecessary initial prescription drug exposure and inappropriate prolonged prescribing; encouraging harm reduction through innovation and education; advancing development of evidence-based treatments for substance use disorders; and protecting the public from unapproved, diverted, or counterfeit drugs presenting overdose risks,” the FDA shared in a new release.

This article originally appeared on Psychiatric Times.

1. FDA announces preliminary assessment that certain naloxone products have the potential to be safe and effective for over-the-counter use. US Food and Drug Administration. News release. November 15, 2022. 

https://www.fda.gov/news-events/press-announcements/fda-announces-preliminary-assessment-certain-naloxone-products-have-potential-be-safe-and-effective

We may be one step closer to nonprescription naloxone.

FDA Releases Notice on Safety and Effectiveness of Certain Nonprescription Naloxone Products

“Can adults have ADHD?” Andrew J. Cutler, MD, laughingly asked at the beginning of his 2022 NEI Congress session on optimizing adult ADHD treatment.

Approximately 80% of adults with ADHD go undiagnosed and untreated, Cutler shared.

 Furthermore, 87% of adults with ADHD have at least 1 comorbid psychiatric condition, like major depressive disorder (60%), substance use disorder (57%), and anxiety (56%).

“This is a big deal. Morbidity and mortality are much higher if you have ADHD, especially with comorbidities. No. 1, it’s critical to recognize ADHD when someone presents with it, but no. 2, it’s critical when you do diagnose ADHD to look for and address these comorbidities, which again, are so common,” Cutler said.

\As to stimulant treatments, the evidence currently supports methylphenidate in children and adolescents and amphetamines in adults, as first choice at the group level.

 However, Cutler stressed that a positive response to stimulants does not confirm the diagnosis of ADHD, and up to 30% of adults with ADHD do not have a beneficial response to the first stimulant trial.

“Data suggests amphetamine may work better for adults, but there’s a lot of individual variability and methylphenidate can definitely work for adults,” Cutler said.

Additionally, according to the results of a meta-analysis of within-subject comparative trials evaluating response to stimulant medications, 28% of participants responded best to amphetamine treatment, 16% responded best to methylphenidate treatment, and 41% had an equal response to either stimulant.

“What I really encourage you to look at is the delivery system, the formulation. This makes all the difference because the thing with stimulants is both methylphenidate and amphetamine have short half-lives, 4 to 6 hours,” said Cutler. “In the old days, the kid would have to go to the school nurse to get that second dose of Ritalin. Now what we want is some kind of mechanism to extend the release throughout the day. As I said, ADHD is an all-day affair.”

A note that Cutler shared about formulations: chewing or crushing pills to make them easier to consume may alter their pharmacokinetics and is inadvisable for most stimulants.

Although there are many methylphenidate and amphetamine stimulant options, there are only 2 nonstimulants approved for adults: atomoxetine and viloxazine ER. Research suggests moderate efficacy of stimulants and atomoxetine for emotional lability in adults with ADHD.

 Viloxazine ER, a norepinephrine reuptake inhibitor, was FDA approved for use in children/adolescents in April 2021 and for adults in April 2022. According to the results of a phase II double-blind, placebo-controlled, efficacy and safety study of extended-release viloxazine in children with ADHD, improvement in ADHD symptoms versus placebo were seen in the 200 mg dose (0.547), the 300 mg dose (0.596), and 400 mg dose (0.623).

 Adverse events in adults include insomnia, fatigue, and nausea.

“ADHD is not just there when you’re trying to study or doing a project for work. It’s there 24/7. It affects every aspect of your life whether you realize it or not,” Cutler shared.

1. Ginsberg Y, Quintero J, Anand E, et al. 

Underdiagnosis of attention-deficit/hyperactivity disorder in adult patients: a review of the literature.

ADHD in adults: a study of clinical characteristics, impairment and comorbidity.

3. Ohnishi T, Kobayashi H, Yajima T, et al. 

Psychiatric comorbidities in adult attention-deficit/hyperactivity disorder: prevalence and patterns in the routine clinical setting.

4. Quenneville AF, Kalogeropoulou E, Nicastro R, et al. 

Anxiety disorders in adult ADHD: a frequent comorbidity and a risk factor for externalizing problems.

5. Cortese S, Adamo N, Del Giovane C, et al. 

Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis.

Distinct acute effects of LSD, MDMA, and D-amphetamine in healthy subjects.

Problems in the management of attention-deficit-hyperactivity disorder.

8. Rapoport JL, Buchsbaum MS, Zahn TP, et al. 

Dextroamphetamine: cognitive and behavioral effects in normal prepubertal boys.

9. Rapoport JL, Buchsbaum MS, Weingartner H, et al. 

Dextroamphetamine. Its cognitive and behavioral effects in normal and hyperactive boys and normal men.

10. Moukhtarian TR, Cooper RE, Vassos E, et al. 

Effects of stimulants and atomoxetine on emotional lability in adults: a systematic review and meta-analysis.

11. Johnson JK, Liranso T, Saylor K, et al. 

A phase II double-blind, placebo-controlled, efficacy and safety study of SPN-812 (extended-release viloxazine) in children with ADHD.

ADHD is an all-day affair, and treating it in an adult population can be difficult.

Optimizing ADHD Treatment in Adults

A recent study investigated the effect of psychostimulants modafinil, atomoxetine, and guanfacine on the differentiation of mesenchymal stem cells to osteoblasts and on their cell functions, including migration. Researchers determined that the 3 medications commonly used to treat attention-deficit/hyperactivity disorder (ADHD) negatively affect hMSC differentiation to bone-forming osteoblasts and cell migration through different intracellular pathways.

With an increasing number of children and adolescents receiving a diagnosis of ADHD,

 and 60% of children continuously affected by ADHD into adulthood,

 the potentially high number of patients with controlled or uncontrolled use of psychostimulants increases the impact of possible adverse effects.

 Previous research has shown that the early ADHD drug methylphenidate, another cognitive enhancer inhibiting the DAT and NET system, influences bone metabolism negatively by causing a growth reduction of 1.38 cm/year and decreasing the mineral density of bone tissue.

Researchers monitored the expression of NET and DAT receptors in hMSCs to determine the ability of modafinil, atomoxetine and guanfacine to disrupt the physiology of bone cells.

 Transcript expression of human beta-2 adrenoreceptor was strongly increased compared to other receptors in hMSC and in hOB, the researchers reported. Additionally, they detected significant amounts of the majority of alpha- and beta adrenoreceptors (ha1-AR, ha1B-AR, ha1D-AR, ha2-AR and hB3-AR), and the norepinephrine transporter (NET) and the dopamine transporters D1 and D2, consistent with the findings of Ma et al.

Researchers then hypothesized a possible effect of modafinil, atomoxetine and guanfacine on both mesenchymal stem cells and osteoblasts. As such, they chose to analyze the influence of the medications on osteogenic differentiation. “Modafinil and guanfacine caused a significant upregulation of the transcript of 

They also compared the effects of the medications on cell viability and apoptosis/necrosis, cell migration, and the osteogenic differentiation of differentiated bone cells derived from hMSCs, to illuminate the mechanism of bone formation inhibition. Although the administration of the maximum therapeutic plasma concentration of modafinil, atomoxetine, and guanfacine caused a significant reduction of cell viability, neither induction of apoptosis nor necrosis could be observed in hMSCs. Within 72 hours after treatment with modafinil, atomoxetine, and guanfacine, cell viability recovered.

Researchers also studied the effect of ADHD medication on cell migration. Modafinil, atomoxetine, and guanfacine abolished the cell migration, therefore meaning these compounds could impact bone formation, wound healing, and bone remodeling/repair—as all require stem cell migration.

The in vitro design limited this study. Researchers recommended future studies in vivo, potentially “using a fracture healing model in the mouse/rat to simulate the homing function of the hMSCs and studying the influence on bone healing via in-vivo CT analysis and bone histology of different stages of bone healing.”

Results determined therapeutic plasma concentration of modafinil, atomoxetine, and guanfacine impaired the cell migration of hMSCs, via beta-2 agonism for modafinil and atomoxetine. The drugs also caused a significantly decreased matrix calcification without promotion of apoptotic cell death.

1. Wagener N, Lehmann W, Weiser L, et al. 

Psychostimulants modafinil, atomoxetine and guanfacine impair bone cell differentiation and MSC migration.

2. ADHD statistics: numbers, facts and information about add. ADDitude. Updated July 13, 2022. Accessed October 13, 2022. 

https://www.additudemag.com/statistics-of-adhd/

3. Callahan BL, Bierstone D, Stuss DT, Black SE. 

Adult ADHD: risk factor for dementia or phenotypic mimic?

4. Uddin SMZ, Robinson LS, Fricke D, et al. 

Methylphenidate regulation of osteoclasts in a dose- and sex-dependent manner adversely affects skeletal mechanical integrity.

5. Tyurin-Kuzmin PA, Fadeeva JI, Kanareikina MA, et al. 

Activation of β-adrenergic receptors is required for elevated α1A-adrenoreceptors expression and signaling in mesenchymal stromal cells.

Mesenchymal stem cell migration during bone formation and bone diseases therapy.

7. Aragona M, Dekoninck S, Rulands S, et al. 

Defining stem cell dynamics and migration during wound healing in mouse skin epidermis.

8. Iaquinta MR, Mazzoni E, Bononi I, et al. 

Adult stem cells for bone regeneration and repair.

Recent research determined the psychostimulants modafinil, atomoxetine, and guanfacine negatively impact bones.

Bone Density Negatively Impacted by ADHD Drugs

The National Commission on Correctional Health Care (NCCHC) and 166 national organizations recently signed a letter to Senate leadership advocating for increased access to buprenorphine, an FDA-approved medication for opioid use disorder (OUD). They urged US Senate to pass the bipartisan 

Mainstreaming Addiction Treatment (MAT) Act

“In the midst of a deadly and accelerating overdose crisis, the MAT Act is a common-sense solution that will prevent overdoses, increase access to treatment, and reduce stigma,” the letter reads.

Buprenorphine, along with methadone and extended-release naltrexone, is 1 of 3 medications currently approved by the FDA to treat OUD and is considered the “gold standard” treatment. It also keeps individuals with OUD from returning to illicit drug use—and to jail.

However, the X-waiver severely hinders access to buprenorphine by preventing health care providers from prescribing it. According to the Substance Abuse and Mental Health Services Administration (SAMHSA), only about 1 in 10 people with OUD receive medications for the condition because of the X-waiver. Furthermore, the Department of Health and Human Services claims that fully 40% of US counties do not have any health care providers who can prescribe buprenorphine.

If passed, the MAT Act will eliminate the X-waiver and make buprenorphine more available and accessible for Americans with OUD.

The letter was sent to Majority Leader Chuck Schumer, Minority Leader Mitch McConnell, Chair Patty Murray, and Ranking Member Richard Burr on August 31, Overdose Awareness Day. The letter can be found 

1. NCCHC Supports Access to MOUD. National Commission on Correctional Health Care. September 9, 2022. Accessed September 21, 2022. 

https://www.ncchc.org/ncchc-supports-access-to-moud/

2. The Mainstreaming Addiction Treatment Act (“MAT Act”, S. 445 / H.R. 1384). August 31, 2022. Accessed September 21, 2022. 

https://static1.squarespace.com/static/5eb15fa07d53aa0e85b448d7/t/6317704dfeb1183bfc5ada54/1662480461791/MAT+Act+(S+445)+-+167+Organizations+Submit+Letter+to+Senate+Leadership+Urging+Passage+with+Sept.+CR+(Aug22).pdf

The National Commission on Correctional Health Care and 166 other national organizations recently signed a letter to Senate leadership advocating for increased access to buprenorphine.

Advocating for Increased Access to Medication for Treating Opioid Use Disorder

In his presentation, “Psychiatric Complications of COVID-19” at the 

2022 Annual Psychiatric Times™ World CME Conference

 in San Diego, John J. Miller, MD, explored the broad range of psychiatric and neuropsychiatric effects of COVID-19.

“We’ve all seen it and we’re still dealing with them,” said Miller. “The mental health crisis is not only for people with the infection itself, but care for their parents, their families, and us as clinicians.”

According to research, the most common psychiatric symptoms include depression, anxiety, insomnia, posttraumatic stress disorder (PTSD), fear, grief, phobias, social avoidance/isolation, increased substance abuse, suicidal ideation, psychosis, and obsessive-compulsive behaviors.1 One systematic review and meta-analysis of long term physical and mental sequelae found at least 1 sequelae symptom occurred in 50.1% of COVID-19 survivors for up to 12 months after infection. Some of the symptoms included cognitive deficits (19.7%), depression (18.3%), and PTSD (17.9%).2

“We know that any type of stress will only bring out underlying genetic and biological and epigenetic vulnerabilities,” Miller said.

As to neuropsychiatric symptoms, some of the most common are delirium (50% of COVID-19 ICU patients), confusion, fatigue, memory impairment, encephalopathy, seizures, cerebral vascular accidents, and more.3

“The bottom line is every person is going to have a different trajectory in terms of how their immune system, how their body, the probabilities of their genetics, other psychosocial circumstances, how their comorbidities will impact their journey through the virus.”

SARS-CoV-2 may traverse the olfactory mucosa—causing loss of smell, especially in the original variants—to gain access to infect the brain, potentially through the olfactory tract, vagal nerve, or trigeminal nerve. Damage to endothelial cells can lead to inflammation and thrombi, which can cause direct damage to the brain, Miller shared. He noted that astrocytes appear to be the primary brain cell type infected and can contribute to fatigue and “brain fog.”4,5

“It will probably take us another 5 or 10 years to figure out the real story. At the end of the day, we must say vaccinate, vaccinate, vaccinate, and remember our role as educators and health promoters is to be compassionate and provide accurate education to our patients and communities,” Miller concluded. “No one is safe until everyone is safe.”

A systematic review and meta-analysis of long term physical and mental sequelae of COVID-19 pandemic: call for research priority and action.

3. Manolis TA, Apostolopoulos EJ, Manolis AA, et al. 

COVID-19 infection: a neuropsychiatric perspective.

COVID and the brain: researchers zero in on how damage occurs.

What are the long term psychiatric and neuropsychiatric complications of COVID-19?