In JAMA Network, researchers have published the first robust clinical study proving that medicinal cannabis effectively treats the debilitating effects of Tourette syndrome. Their findings show a statistically and clinically significant reduction in motor and vocal tics in as little as six weeks.
The researchers’ analysis found a significant association between levels of cannabis in the bloodstream and the response to active treatment.
THC (tetrahydrocannabinol) is the psychoactive compound in cannabis that produces a ‘high’ effect, while CBD (cannabidiol) is a non-psychoactive compound. Both are used medicinally in Australia.
Study co-author Professor Iain McGregor, the Academic Director of the Lambert Initiative, said: “We were delighted to be able to work with Professor Mosley and this team to deliver this important clinical trial showing the efficacy of oral THC and CBD in treating Tourette syndrome.
“This is such a difficult syndrome to treat. It severely impacts the quality of life of 1 in 100 young Australians. It is gratifying to know that our result provides strong evidence of an alternative treatment method for these patients in need.
“While there are well-known concerns about the side effects of THC on cognition and mental health, this trial demonstrates that careful dosing with THC in an oral formulation is very well tolerated in a relatively young patient group.”
The study involved testing 22 adult patients with severe Tourette symptoms. In the double-blind study, participants received both medicinal cannabis oil and a placebo over two six-week blocks.
“This is the first rigorous and methodical trial of medicinal cannabis to be undertaken in a sufficiently large group of people to make definitive conclusions about its effectiveness,” said neuropsychiatrist Dr Philip Mosley, who led the clinical trial.
“It shows that medicinal cannabis can reduce tics by a level that makes a life-changing difference for people with Tourette syndrome and their families.
“In addition, we found that other symptoms associated with Tourette syndrome in our participants also reduced, particularly symptoms of obsessive compulsive disorder and anxiety.”
Tourette syndrome affects about 1% of the population and is four times more common in men than women. The neurological disorder often begins in childhood and is characterised by involuntary movements and vocalisations, or tics.
“Cannabis interacts with specific receptors on nerve cells in the brain that are part of the body’s own ‘endocannabinoid’ system,” Dr Mosley said.
“Effectively, stimulation of these receptors tightens a leaky filter that now stops the involuntary movements and vocalisations from getting out and being expressed by our participants.”
A decade after scientists identified an over-the-counter antihistamine as a treatment for multiple sclerosis, researchers have developed an approach to measure the drug’s effectiveness in repairing the brain, making it possible to also assess future therapies for the devastating disorder. Their study is published in PNAS.
The UC San Francisco researchers, led by physician-scientist Ari Green, MD, who together with neuroscientist Jonah Chan, PhD, first identified clemastine as a potential MS therapy, used MRI scans to study the drug’s impact on the brains of 50 participants in a clinical study.
In the brain, water trapped between the thin layers of myelin that wrap nerve fibers cannot move as freely as water floating between brain cells. This unique property of myelin allowed imaging experts to develop a technique to compare the difference in myelin levels before and after the drug was administered, by measuring the so-called myelin water fraction, or the ratio of myelin water to the total water content in brain tissue.
In their study, the researchers found that patients with MS who were treated with clemastine experienced modest increases in myelin water, indicating myelin repair. They also proved that the myelin water fraction technique, when focused on the right parts of the brain, could be used to track myelin recovery.
“This is the first example of brain repair being documented on MRI for a chronic neurological condition,” said Green. “The study provides the first direct, biologically validated, imaging-based evidence of myelin repair induced by clemastine. This will set the standard for future research into remyelinating therapies.”
Myelin increased even after medication was stopped
In the study, patients with MS who enrolled in the ReBUILD trial were divided into two groups: the first group received clemastine for the first three months of the study and the second group received clemastine only in months three to five. Using the myelin water fraction as a biomarker, the researchers found that myelin water increased in the first group after participants received the drug and continued to increase after clemastine was stopped. In the second group, the myelin water fraction showed decreases in myelin water in the first portion of the study, under the placebo, and a rebound after participants received clemastine.
The findings corroborate the results of a previous study with the same 50 patients that had found the allergy medication reduced delayed nerve signalling, potentially alleviating symptoms.
In the current study, researchers looked at the corpus callosum, a region of the brain with a high myelin content that connects the right and left hemispheres. They found that significant repair occurred outside the visible lesions typically associated with MS. This underscores the need to focus on myelin repair beyond these lesion sites.
Clemastine works in this setting by stimulating the differentiation of myelin-making stem cells. This places the medication a generation ahead of existing MS drugs that work by dampening the activity of the immune system, calming inflammation and reducing the risk of relapse. It still isn’t ideal, though, making the water fraction measurement an important tool in developing better therapeutics.
“Clemastine can only be partially effective at the doses we can use,” said Green, who is also a neuro-ophthalmologist and chief of the Division of Neuroimmunology and Glial Biology in the UCSF Department of Neurology. “It can be sedating, which may be especially undesirable in patients with MS. We are hopeful better medications will be developed, but clemastine has proven to be the tool to show remyelination is possible.”
Proposed future research will examine clemastine’s potential in treating brain injury in premature infants, who often experience myelin damage.
“The death of a child affects us all. Witnessing the loss of a newborn baby who has sepsis is terribly traumatic, especially so when antibiotics used to treat the child are ineffective,” says neonatologist Professor Sithembiso Velaphi.
“It’s very heavy for a mother to carry her baby, give birth, watch as her newborn gets seriously sick from infection, suffers while being pricked with drips and pumped with drugs to try and save the child – only for her to leave the hospital empty handed. It’s painful,” says Velaphi, who is the head of Paediatrics at Chris Hani Baragwanath Academic Hospital in Johannesburg.
Professor Sithembiso Velaphi, head of Paediatrics at Chris Hani Baragwanath Academic Hospital in Johannesburg. PHOTO: Kim Cloete for GARDP
Nurses and doctors feel sad and crushed too when they cannot save a newborn’s life because of antibiotic resistance to bacterial infections. “We need to prioritise the development of antibiotics to treat these babies. For us, success is seeing a baby get better and going home,” he says.
Velaphi was speaking to Spotlight about a landmark global observational study published in the journal Plos Medicine (June 8) which found that many neonates (within 60 days of birth) get life-threatening bloodstream infections, or sepsis, and are dying because the antibiotics used to treat them are not effective. This is the first global overview to assess the extent of the problem. Spotlight last year reported on interim findings from the same study.
The study, called NeoOBS, led by the Global Antibiotic Research and Development Partnership (GARDP) recruited more than 3 200 babies in 19 hospitals in 11 countries – South Africa, Kenya, Uganda, Thailand, Vietnam, India, Greece, Italy, Bangladesh, Brazil, and China.
The researchers reported great variability in mortality rates of babies with sepsis across the 19 hospitals, ranging from 1% to 27.3%.
Sepsis affects up to 3 million babies a year globally. Importantly, the study’s 80 authors estimate that 214 000 newborns die every year from sepsis that has become antibiotic resistant, and this is mostly in low- to middle-income countries (LMIC). Many survivors suffer from neurodevelopmental problems. Treatment options have become increasingly limited as about 40% of infections are reported to be resistant to standard antibiotic treatments.
Many infections acquired in hospital
Almost 60% of infection-related deaths were due to infections acquired at the 19 hospitals under review. Klebsiella pneumoniae was the most common pathogen isolated.
Of the 40 antibiotics approved for use in adults since 2000, only four have included dosing information for neonates in their labelling. Currently, 43 adult antibiotic clinical trials are recruiting patients, compared to only six trials recruiting neonates, researchers say.
New antibiotic treatments are urgently needed, especially in LMICs where almost 1 in 5 babies with sepsis died. Premature babies are particularly vulnerable to infections because of their immature immune systems.
More than 200 different antibiotic combinations were used by hospitals included in the NeoOBS study, with repeated switching of antibiotics due to high resistance to treatments. This showed a pattern of limited use of the World Health Organization’s recommended first-line treatment.
Many doctors have had to opt for last-line antibiotics such as carbapenems because of the high degree of antibiotic resistance in their units or because they were the only treatment available.
Outlining various challenges, Velaphi says the risk of infections is very high in hospital settings where there is often a shortage of nurses, beds, and space between patients making it difficult to stop the spread of infection. Chris Hani Baragwanath has an 18-bed Intensive Care Unit (ICU) that is almost always full and when the situation is desperate there is a spillover of patients into the high-care area. The pressure on the facility is huge and the influx of people from other countries has made it even more challenging, he says.
“There is a major problem of infection control, specifically related to high-risk babies – sick babies with complications who need interventions such as drips and even surgery. This increases the chances of infection. “More than 70% of all deaths ascribed to prematurity at the hospital were due to hospital-acquired multi-drug resistant infections,” he says.
The NeoSep 1 trial
The authors say the NeoOBS study has yielded “a wealth of high-quality data” needed to design trials for much-needed and appropriate treatments for sepsis in babies. Encouragingly, and building on from the observational study the first global hospital-based neonatal sepsis trial called NeoSep 1 is underway in Kenya and South Africa. Chris Hani Baragwanath is taking part in the trial together with Tygerberg Hospital in Cape Town and KEMRI, Kilifi County Hospital in Kenya. It’s planned that the trial will be expanded to other countries and regions in 2024 with the aim of recruiting 3 000 newborns.
A Personalised Randomised Controlled Trial (PRACTical) design will be used. According to GARDP and partners the design is a new way of comparing antibiotic treatments for neonatal sepsis. In addition, doctors can choose treatment regimens that are likely to work well for newborns in their specific hospital settings.
Researchers say the development pipeline for new antibiotic treatments is limited and the lack of a universal, effective standard of care creates huge challenges in conducting research to tackle neonatal sepsis. The PRACTical design has been specifically developed to address these challenges in important public health emergencies such as neonatal sepsis. (You can read more about how this type of trial works in the Lancet.)
The trial will compare the safety and efficacy of three new combinations of older antibiotics (fosfomycin-amikacin, flomoxef-amikacin, and flomoxef-fosfomycin) against the current standard of care. It will also assess and validate the doses of two antibiotics (fosfomycin and flomoxef) for use in newborns. The trial will also evaluate new combinations of generic antibiotics.
“We are hoping the trial will provide robust evidence that the antibiotic combinations are safe and effective and that this will lead to a change in both WHO and local treatment guidelines,” says Christina Obiero, Principal Investigator for the NeoSep1 trial for KEMRI at Kilifi County Hospital in a statement.
Severity and recovery scores
Principal Investigator for the NeoSep1 trial at Tygerberg Hospital, Professor Adrie Bekker tells Spotlight, “We have so few antibiotics that work effectively against these very sick babies. And even for those that we have, we are still not 100% sure how to dose these drugs to get accurate concentrations in the blood and to also make sure that the outcomes in these babies are as good as can be. This trial will help give us confidence that we are delivering more effective treatment.”
Bekker who is also Professor in the Division of Neonatology, Department of Paediatrics and Child Health at Stellenbosch University says a positive outcome of the NeoOBS study is the development of two important tools which can be used in ICUs globally.
The first is the NeoSep Severity Score which is a compilation of common symptoms and signs that can occur in a baby with clinical sepsis. The second is the NeoSep Recovery Score, which will assist clinicians in deciding if they can stop antibiotics earlier.
The tools are expected to help prevent the often excessive and inappropriate use of antibiotics for over too long a period, which compounds the problem of antibiotic resistance globally.
Diagnosis in older age groups, children, and adults, is generally easier.
“It’s sometimes difficult for a clinician to know whether a baby actually has neonatal sepsis because it can present very subtly and not always with the same symptoms,” Bekker explains.
The blood culture is the gold standard for diagnosing neonatal sepsis, but Bekker says only around 10% of blood cultures will grow an organism even if the baby has sepsis, making it very difficult to get a diagnosis. “And because it’s such an aggressive disease and a baby can die very quickly from it, clinicians tend to rather over-treat than under-treat. That is correct but, just as important as it is to start antibiotics quickly, it’s important to stop them if they are not necessary. The NeoSeps Severity score will help doctors identify babies that are at very high risk from sepsis and those that would need treatment immediately.
Velaphi says a major challenge is the time it takes for an outcome of the blood culture and the general protocol is to start antibiotics immediately. Waiting between 24 to 48 hours can be too late for a child who may have sepsis and could die. On the other hand, antibiotics may be given to children who do not have sepsis and this adds to the frequency of antibiotic resistance. “So, you are damned if you do and you are damned if you don’t.”
He says we need new diagnostic tests that are reliable and that have a high degree of sensitivity and specificity. “We need antibiotics that work to reduce mortality,” he adds.
Dense breast tissue, which contains a higher proportion of fibrous tissue than fat, is a risk factor for breast cancer and also makes it more difficult to identify cancer on a mammogram. Many US states have enacted laws that require women with dense breasts to be notified after a mammogram, so that they can choose to undergo supplemental ultrasound screening to improve cancer detection. A recent study published by Wiley online in CANCER, a peer-reviewed journal of the American Cancer Society, evaluated the results of such additional screening to determine its benefits and harms to patients.
Although supplemental ultrasound screening may detect breast cancers missed by mammography, it requires additional imaging and may lead to unnecessary breast biopsies among women who do not have breast cancer. Therefore, it is important to use supplemental ultrasound only in women at high risk of mammography screening failure – in other words, women who develop breast cancer after a mammogram shows no signs of malignancy.
Brian Sprague, PhD, of the University of Vermont Cancer Center, and his colleagues evaluated 38 166 supplemental ultrasounds and 825 360 screening mammograms without supplemental ultrasounds during 2014–2020 at 32 US imaging facilities within three regional registries of the Breast Cancer Surveillance Consortium.
The team found that 95.3% of supplemental ultrasounds were performed in women with dense breasts. In comparison, 41.8% of mammograms without additional screening were performed in women with dense breasts.
Among women with dense breasts, a high risk of interval invasive breast cancer was present in 23.7% of women who underwent ultrasounds, compared with 18.5% of women who had mammograms without additional imaging.
The findings indicate that ultrasound screening was highly targeted to women with dense breasts, but only a modest proportion of these women were at high risk of mammography screening failure. A similar proportion of women who received only mammograms were at high risk of mammography screening failure.
“Among women with dense breasts, there was very little targeting of ultrasound screening to women who were at the highest risk of a mammography screening failure. Rather, women with dense breasts undergoing ultrasound screening had similar risk profiles to women undergoing mammography screening alone,” said Dr Sprague. “In other words, many women at low risk of breast cancer despite having dense breasts underwent ultrasound screening, while many other women at high risk of breast cancer underwent mammography alone with no supplemental screening.”
Clinicians can consider other breast cancer risk factors beyond breast density to identify women who may be appropriate for supplemental ultrasound screening. Publicly available risk calculators from the Breast Cancer Surveillance Consortium are available that also consider age, family history, and other factors (https://www.bcsc-research.org/tools).
To communicate medical results to patients, who may find them hard to understand, is a challenging task – especially when it comes to making sense of statistical information. An interdisciplinary team of scientists has published a study inPLOS ONE investigating how communication between doctors and patients about actual risks can be made more effective.
“Even doctors sometimes have difficulties in determining the right predictive value. And if the data is difficult for the doctor to interpret, it’s even harder to communicate the information accurately to patients in a way they will understand,” says study author and mathematics educationalist Karin Binder.
The following case will serve as an example: A patient has just received a conspicuous sonographic finding of his thyroid. Does this mean he has thyroid cancer? Not necessarily, because there is a certain probability that the result of the examination will be positive even though the patient does not have thyroid cancer.
To explain to patients what the statistical picture looks like after such a positive test result, there are two approaches. One of them requires some lateral thinking, while the other is much easier to interpret from the patient’s perspective, as the researchers were able to demonstrate.
Bayesian vs diagnostic information
The commonly used Bayesian approach proceeds from the number of patients who actually have the disease. First of all, the doctor explains how frequently the disease occurs overall – for example: “out of 1000 patients, 50 have thyroid cancer.” Then the doctor lays out: a) for how many of these patients with thyroid cancer, the test result is positive (20 out of 50) and b) how many people who do not have thyroid cancer nonetheless have a positive test result (110 out of the remaining 950).
This is generally the information the doctor either knows or can easily research. Positive tests as a proportion of people with the disease is also known as sensitivity – a term that may be familiar from the COVID pandemic, when it was used, for example, as a quality criterion for rapid tests. Unfortunately, however, positive tests as a proportion of people with the disease is often confused with people with the disease as a proportion of positive tests! And these two percentages can greatly differ depending on the situation.
So what do the numbers quoted above mean in relation to a person with a positive test result? How many people who test positive actually have the disease? If for you the answer is not immediately apparent, you are not alone: Without further information, only 10% of participants were able to calculate how many people with positive results actually had the disease.
“Diagnostic” communication of information proceeds very differently: First of all, the doctor explains how many patients have positive test results, irrespective of whether they actually have the disease or not. In our example, this would be 130 people with a conspicuous thyroid ultrasound (out of 1000 people examined). Next, the doctor explains how many of these people with positive tests actually have the disease (20 out of 130) and how many of the people with negative test results have the disease (30 out of 870).
The relevant information is contained here directly and without the need for mental arithmetic: If my result is positive, then the probability is a 20 out of 130 that I actually have thyroid cancer. When communicated in this form, 72% of study participants were capable of arriving at this conclusion, compared to 10% with the Bayesian approach.
How to best communicate statistical information?
“With Bayesian communication, moreover, participants were considerably slower in reaching the correct result, if they got there at all,” says Karin Binder. “And in busy doctor’s offices and hospitals, this time is often not available.” The team of authors therefore calls on doctors to use diagnostic information communication more readily in future. This would go some way to avoiding confusion, misinterpretation, and wrong decisions.
It would be even better, however, to take the time to give patients a full picture of the situation, containing both diagnostic and Bayesian information. Only this can explain the surprising phenomenon whereby even a medical test with outstanding quality criteria can have very limited predictive power under certain circumstances (eg, routine screenings).
