This diagram shows how NK cell function could in theory, result in the resolution of neuropathic pain in the context of peripheral nerve injury by directed cytotoxicity against a number of pathological cellular targets. CREDIT Kim et al./Trends in Neurosciences

In the midst of a global opioid epidemic, a team of scientists is exploring natural killer (NK) cells as an alternative treatment for neuropathic pain. In an Opinion piece published June 27^th in the journal Trends in Neurosciences, the researchers gather existing evidence for the impact of NK cells in pain, pointing to their ability to prune the damaged nerve cells that may cause it. They urge the scientific community to explore biological mechanisms underlying NK cell activity to move towards a realistic pain therapy that is both effective and safe.

Neuropathic pain is a chronic condition experienced as a recurring shooting or stabbing sensation. It is caused by nerve damage, which may occur because of trauma, a disease such as diabetes, or after chemotherapy.

“The prevalence of neuropathic pain is unfortunately only likely to increase over time,” says co-author Alexander Davies, a neurophysiologist with the Neural Injury Group at Oxford University. “As we get better at treating diseases like cancer, we have survivors who may be left with pain from either the cancer treatment or the surgery that was used to remove it.”

While therapies such as opioids and antidepressants are currently used to address these pain symptoms, they do not treat the underlying cause of pain and have their own risks and side effects. The authors point out that 564,000 people overdosed on opioids in the United States between 1999 and 2020.

“The main approach is silencing the neurons,” Davies says. “While we certainly need anesthetics to deal with pain in the short term, if we use them in the long term, we can become addicted to the sensation of removing pain, which is in itself pleasurable.”

Alongside T cells and B cells, NK cells are a type of white blood cell called lymphocytes. Their existing role in the body includes attacking tumors or viruses. NK cells increase activity during acute pain. However, they appear to decline in frequency or potency in people who experience chronic pain. Not having a fully functional NK cell population may therefore prevent people from resolving neuropathic pain in the long term.

“We first became interested in this idea when one of my colleagues found a T cell response after nerve injury, but I noticed that NK cells were also involved,” says senior author Seog Bae Oh, a neurobiologist at Seoul National University. “NK cells are typically explored in the context of cancer, but I thought it was worth looking at them in pain as well.”

NK cells may resolve pain because they are involved in the process by which neurons are pruned. Injury and disease can cause neurons to become incorrectly wired or to stop functioning as intended, resulting in pain symptoms. Introducing NK cells could help to remove these anomalies. Experiments in mice have shown that if a neuron is in distress, its axon, the segment responsible for transmitting messages, displays a molecule called the RAE1 stress ligand. This could alert the NK cells to their need for pruning. A similar ligand, belonging to what is known as the ULBP family, is also seen in sensory neurons in humans with pain.

Conversely, NK cells may have a negative effect in the central nervous system, such as the brain and spinal cord, where neurons cannot regenerate so easily if they are removed. Their impact here should be considered carefully in the design of any possible therapies.

The authors stress that our understanding of the processes by which NK cells support pain relief is still limited, and their potential viability as a future treatment depends on further research. Both Davies and Oh are continuing to explore their NK cells in pain. Oh and his colleagues are investigating the therapeutic potential of NK cells in a range of preclinical models as well as their activity in patients who experience pain, while Davies is working to identify the cellular targets of NK cells following nerve injury.

“We need to have a better mechanistic understanding of how NK cells work and what they can target before we can develop realistic therapies, and we need to minimize their side effects,” Davies says. “However, the more prongs we have to treat neuropathic pain, the more likely we are ultimately to be able to address it.”

Women suffering from the autoimmune disease multiple sclerosis temporarily get much better when pregnant. Researchers have now identified the beneficial changes naturally occurring in the immune system during pregnancy. The findings, published in Journal of Neuroinflammation, can show the way to new treatments.

Pregnancy is a very special condition from an immunological point of view. The immune system serves to defend us against foreign substances. However, although half of the genetic material of the foetus comes from the father, it is not rejected by the mother’s immune system. One reason why this balancing act is almost always successful is that during pregnancy the mother’s immune system is adapted to become more tolerant.

In multiple sclerosis, MS, nerve function is hampered due to the immune system attacking the fat that serves as an insulating sheath around the nerve fibres. The nerves become inflamed, which could lead to nerve damage. Although new and more effective treatment options are available, most MS patients deteriorate over time.

Researchers believe that the temporary dampening of the immune response could explain why women with MS actually get better when pregnant. Periods of symptoms, i.e. relapses, decrease by 70 percent during the last third of pregnancy. Also some other autoimmune diseases, such as rheumatoid arthritis, temporarily ameliorate during pregnancy. But the reason for this has not been clear. This is why the researchers behind this study wanted to investigate what mechanisms that could be of particular importance for the decrease in symptoms during pregnancy, as a step to finding future treatment strategies that give the same effect in MS and possibly also other similar diseases.

The researchers were particularly interested in T cells, which play an important role in the immune system. Moreover, T cells play a key role in driving MS and are important during pregnancy. The study compared 11 women with MS to 7 healthy women who had blood samples taken before, during and after pregnancy.

To understand what happens in the immune cells, the researchers identified the genes used in the T cells at various points in time during pregnancy. They also studied changes regulating how genes are switched on and off, i.e. epigenetic changes. In their study, the researchers looked more specifically at one such regulation mechanism called DNA methylation.

“What was possibly most striking is that we couldn’t find any real differences between the groups during pregnancy, as it seems that the immune system of a pregnant woman with MS looks roughly like that of a healthy pregnant woman, says Sandra Hellberg, assistant professor at the Department of Biomedical and Clinical Sciences at Linköping University and one of the researchers behind the study.

The researchers found networks of interacting genes that are affected during pregnancy. Their study shows that these genes are to a large extent linked to the disease and to important processes in the immune system.

“We can see that the changes in the T cells mirror the amelioration in relapse frequency.  The biggest changes happen in the last third of pregnancy, and this is where women with MS improve the most. These changes are then reversed after pregnancy at the point in time when there is a temporary increase in disease activity. It is important to stress that disease activity thereafter goes back to what it was prior to the pregnancy,” says Sandra Hellberg.

The network of genes affected during pregnancy also included genes regulated by pregnancy hormones, mainly progesterone. The researchers are now testing various hormones in the lab in an attempt to mimic the effects observed in the study, to see if these can be part of a possible future treatment strategy.

Sandra Hellberg, assistant professor at Linköping University. CREDIT Linköping University

This research is the result of long-standing collaboration between researchers in medicine and bioinformatics. A key part of the project has been understanding the large amount of data by analysing it using what is known as network analysis, developed over many years by, among others, a research group led by Mika Gustafsson at Linköping University. Network analysis is a tool for finding genes that interact extensively with the genes the researchers are interested in. It often turns out that other genes in the network are regulated in an abnormal manner and indirectly affect key processes in a disease.

“Such insights can be used to find alternative medication and find new biomarkers to be able to differentiate between subgroups of a disease. We have used this strategy successfully for analysis in research into for instance allergy and multiple sclerosis”, says Mika Gustafsson, professor of Bioinformatics, who is now making the analysis available to other researchers through a newly founded company.

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Cannabis has gradually been moving away from longstanding misconceptions, earning a rightful place in the realm of alternative wellness. As more research is conducted, it’s increasingly clear that various strains of cannabis can potentially contribute to human health in surprising ways. Even notable athletes are embracing cannabis for its health benefits.

Once a controversial substance, cannabis has undergone a renaissance. 

Thanks to its unique mix of cannabinoids, namely CBD (cannabidiol) and THC (tetrahydrocannabinol), cannabis offers potential therapeutic properties. However, the relationship between cannabis and human health is complex and requires a careful approach.

Benefits of Cannabis Use

Cannabis use is associated with several health benefits, including:

• Pain Relief: Cannabis can help manage chronic pain, significantly improving the quality of life for patients with conditions such as fibromyalgia and endometriosis.
• Anti-Inflammatory: Cannabis has shown potential in reducing inflammation in the body.
• Improved Mood: Many strains of cannabis are linked to elevating mood and mitigating symptoms of depression.
• Mental Health Support: Some strains can aid in managing mental health conditions like anxiety, depression, and post-traumatic stress disorder (PTSD).
• Sleep Aid: Cannabis can help insomniacs get a restful night’s sleep, improving overall health and wellness.
• Appetite Regulation: It can stimulate appetite in patients undergoing treatments like chemotherapy.

10 Cannabis Strains and Their Surprising Health Benefits

There are nearly a thousand cannabis strains in existence today. Below is a list of 10 common strains found in the market, along with their potential benefits:

Charlotte’s Web

Named after a child whose seizures were drastically reduced by this strain, Charlotte’s Web is high in CBD, the non-psychoactive compound in cannabis. Its low THC content makes it ideal for those seeking relief from conditions like epilepsy without the ‘high.’

ACDC

The ACDC strain, high in CBD and low in THC, is known for its potential in treating various ailments, including chronic pain, anxiety, and seizures. It’s also celebrated for its potential in combating the side effects of chemotherapy.

Harlequin

Harlequin has a high CBD-to-THC ratio, making it effective in managing anxiety without causing the intoxicating effects typically associated with cannabis.

Cannatonic

Famed for its low THC and high CBD content, Cannatonic is ideal for those seeking relief from migraines, muscle spasms, and psychological symptoms without significant psychoactive effects.

Girl Scout Cookies

Despite its playful name, Girl Scout Cookies have profound effects. Rich in THC, it is often used for pain relief, appetite stimulation, and managing depression.

Jack Herer

Named after a famous cannabis activist, Jack Herer is a balanced strain known to increase focus and creativity. It is commonly used by patients dealing with mental health issues, such as depression and PTSD.

Northern Lights

This potent strain is a favorite for those seeking a sleep aid. Northern Lights is known for its ability to relax the body and mind, potentially beneficial for individuals with insomnia, stress, and pain.

Sour Diesel

Named for its pungent aroma, Sour Diesel is praised for its energizing effects. This strain might assist those dealing with mental fog, chronic fatigue, and stress-related conditions.

Blue Dream

Blue Dream is a balanced strain offering both physical relaxation and mental alertness. It’s commonly used for managing pain, depression, and nausea.

Pineapple Express

Combining the benefits of pain relief and mental clarity, Pineapple Express is suitable for patients seeking a balanced approach to managing both physical and mental health symptoms.

Possible Drawbacks of Cannabis Use

While the health benefits are encouraging, it’s important to remember that cannabis use is not without potential drawbacks. These include:

Dependence and Addiction

While not everyone who uses cannabis becomes addicted, there’s a risk of developing cannabis use disorder. This disorder, which can range from mild to severe, is characterized by craving the drug and using it despite negative consequences in personal life or health.

Memory Impairment

Cannabis, particularly when used heavily, can impair short-term memory. This effect is mostly associated with strains high in THC. Long-term heavy use can potentially lead to more lasting effects on cognitive function and memory.

Mental Health Complications

While some strains of cannabis may assist in managing mental health issues, some can also exacerbate certain conditions in some individuals. There can be an increase in anxiety, paranoia, or other psychological symptoms, especially with high THC strains or heavy use.

Legal Implications

Although more states and countries are legalizing or decriminalizing cannabis, it’s crucial to understand the legal implications of cannabis use in your specific location. The legality varies greatly, from full recreational use being permitted, to only medicinal use being allowed, to complete prohibition. Violating these laws can result in serious consequences, including fines or imprisonment.

Conclusion

The medical potential of cannabis is significant, with many strains offering surprising health benefits. However, it’s important to use cannabis responsibly and under medical guidance—considering both the potential benefits and drawbacks.

 As the conversation around cannabis continues to evolve, it’s clear that this versatile plant has more to offer than just the high.

Despite getting “the munchies”, people who frequently use cannabis are leaner and less prone to diabetes than those who don’t. University of California, Irvine researchers have now uncovered a possible explanation for this paradox – and it’s not good news. The findings are reported in a new study titled, “Adolescent exposure to low-dose THC disrupts energy balance and adipose organ homeostasis in adulthood,” published today in Cell Metabolism.

Many adults who consume cannabis daily or almost daily begin using the drug when they are teenagers. During this time of rapid physical development, the new study shows, cannabis can wreak havoc in the fine-tuned processes that govern energy storage, making the body leaner and less susceptible to obesity but also less capable of mobilizing stored nutrients needed for brain and muscle activity. These alterations are rooted in striking molecular changes that occur within the body’s fat depots – also known as the adipose organ – which after exposure to cannabis start making proteins that are normally found only in muscle and the heart.

Researchers gave low daily doses of THC or its vehicle to adolescent mice. They then stopped the treatment and, after the animals had reached adulthood, carried out a thorough assessment of the animals’ metabolism. The results were surprising. Mice that had been treated as adolescents with THC, but were now drug-free, had reduced fat mass and increased lean mass, were partially resistant to obesity and hyperglycemia, had higher-than-normal body temperature, and were unable to mobilize fuel from fat stores. Several of these features are also seen in people who frequently use cannabis.

To make sense of these data, the researchers dove into the molecular changes caused by THC. What they uncovered was even more surprising: fat cells of mice treated with THC looked normal at the microscope but produced large amounts of muscle proteins, which are normally not found in fat. Muscle, on the other hand, made fewer of those same proteins. The researchers concluded that the effort required to make these ‘alien’ proteins interferes with the healthy functioning of fat cells and thus with their ability to store and release stored nutrients. This may in turn affect not only physical activity but also mental processes, such as attention, which depend on a steady influx of fuel to the brain.

“All too often we think of cannabis only as a psychoactive drug,” said Daniele Piomelli, PhD, director for the UCI Center for the Study of Cannabis, the Louise Turner Arnold Chair in the Nuerosciences, and professor in the UCI School of Medicine Department of Anatomy & Neurobiology, “But, its effects extend well beyond the brain. Its main constituent, THC, mimics a group of chemical messengers called endocannabinoids, which regulate important functions throughout the body. Our results show that interfering with endocannabinoid signaling during adolescence disrupts adipose organ function in a permanent way, with potentially far-reaching consequences on physical and mental health.”

A large-scale study led by researchers at Columbia and Brigham and Women’s Hospital/Harvard is the first to establish that a diet low in flavanols—nutrients found in certain fruits and vegetables—drives age-related memory loss.

The study found that flavanol intake among older adults tracks with scores on tests designed to detect memory loss due to normal aging and that replenishing these bioactive dietary components in mildly flavanol-deficient adults over age 60 improves performance on these tests.

“The improvement among study participants with low-flavanol diets was substantial and raises the possibility of using flavanol-rich diets or supplements to improve cognitive function in older adults,” says Adam Brickman, PhD, professor of neuropsychology at Columbia University Vagelos College of Physicians and Surgeons and co-leader of the study.

The finding also supports the emerging idea that the aging brain requires specific nutrients for optimal health, just as the developing brain requires specific nutrients for proper development. 

“The identification of nutrients critical for the proper development of an infant’s nervous system was a crowning achievement of 20^th century nutrition science,” says the study’s senior author, Scott Small, MD, the Boris and Rose Katz Professor of Neurology at Columbia University Vagelos College of Physicians and Surgeons. 

“In this century, as we are living longer research is starting to reveal that different nutrients are needed to fortify our aging minds. Our study, which relies on biomarkers of flavanol consumption, can be used as a template by other researchers to identify additional, necessary nutrients.”

Age-related memory loss linked to changes in hippocampus

The current study builds on over 15 years of research in Small’s lab linking age-related memory loss to changes in the dentate gyrus, a specific area within the brain’s hippocampus—a region that is vital for learning new memories—and showing that flavanols improved function in this brain region. 

Additional research, in mice, found that flavanols—particularly a bioactive substance in flavanols called epicatechin—improved memory by enhancing the growth of neurons and blood vessels and in the hippocampus. 

Next, Small’s team tested flavanol supplements in people. One small study confirmed that the dentate gyrus is linked to cognitive aging. A second, larger trial showed that flavanols improved memory by acting selectively on this brain region and had the most impact on those starting out with a poor-quality diet.

In the new study, the Columbia team collaborated with researchers at Brigham and Women’s Hospital studying the effects of flavanols and multivitamins in COSMOS (COcoa Supplements and Multivitamin Outcomes Study). The current study, COSMOS-Web, was designed to test the impact of flavanols in a much larger group and explore whether flavanol deficiency drives cognitive aging in this area of the brain.

Study methods

More than 3,500 healthy older adults were randomly assigned to receive a daily flavanol supplement (in pill form) or placebo pill for three years. The active supplement contained 500 mg of flavanols, including 80 mg epicatechins, an amount that adults are advised to get from food. 

At the beginning of the study, all participants completed a survey that assessed the quality of their diet, including foods known to be high in flavanols. Participants then performed a series of web-based activities in their own homes, designed and validated by Brickman, to assess the types of short-term memory governed by the hippocampus. The tests were repeated after years one, two, and three. Most of the participants identified themselves as non-Hispanic and white.

More than a third of the participants also supplied urine samples that allowed researchers to measure a biomarker for dietary flavanol levels, developed by co-study authors at Reading University in the UK, before and during the study. The biomarker gave the researchers a more precise way to determine if flavanol levels corresponded to performance on the cognitive tests and ensure that participants were sticking to their assigned regimen (compliance was high throughout the study). Flavanol levels varied moderately, though no participants were severely flavanol-deficient.

People with mild flavanol deficiency benefited from flavanol supplement

Memory scores improved only slightly for the entire group taking the daily flavanol supplement, most of whom were already eating a healthy diet with plenty of flavanols. 

But at the end of the first year of taking the flavanol supplement, participants who reported consuming a poorer diet and had lower baseline levels of flavanols saw their memory scores increase by an average of 10.5% compared to placebo and 16% compared to their memory at baseline. Annual cognitive testing showed the improvement observed at one year was sustained for at least two more years.

The results strongly suggest that flavanol deficiency is a driver of age-related memory loss, the researchers say, because flavanol consumption correlated with memory scores and flavanol supplements improved memory in flavanol-deficient adults.

The findings of the new study are consistent with those of a recent study, which found that flavanol supplements did not improve memory in a group of people with a range of baseline flavanol levels. The previous study did not look at the effects of flavanol supplements on people with low and high flavanol levels separately.

“What both studies show is that flavanols have no effect on people who don’t have a flavanol deficiency,” Small says.

It’s also possible that the memory tests used in the previous study did not assess memory processes in the area of the hippocampus affected by flavanols. In the new study, flavanols only improved memory processes governed by the hippocampus and did not improve memory mediated by other areas of the brain. 

Next steps

“We cannot yet definitively conclude that low dietary intake of flavanols alone causes poor memory performance, because we did not conduct the opposite experiment: depleting flavanol in people who are not deficient,” Small says, adding that such an experiment might be considered unethical.

The next step needed to confirm flavanols’ effect on the brain, Small says, is a clinical trial to restore flavanol levels in adults with severe flavanol deficiency. 

“Age-related memory decline is thought to occur sooner or later in nearly everyone, though there is a great amount of variability,” says Small. “If some of this variance is partly due to differences in dietary consumption of flavanols, then we would see an even more dramatic improvement in memory in people who replenish dietary flavanols when they’re in their 40s and 50s.”