Day: 04/27/2024

Food is medicine: clinical trials show the health benefits of dietary interventions

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Growing evidence shows that dietary interventions can be effective at treating or delaying some diseases, but further trials are needed for wider adoption.

The concept that diet and nutrition can directly affect human health and disease is undergoing a renaissance. A suboptimal, unhealthy diet is known to substantially increase the risk of obesity and non-communicable diseases, such as coronary heart disease and type 2 diabetes, but unhealthy diets can also increase the risk of other health conditions, such as cancer, osteoporosis and cognitive disorders. As Jordi Salas-Salvadó, professor of nutrition and bromatology at the Rovira i Virgili University in Reus, Spain, emphasizes, “Equitable access to healthy foods is one aspect of disease management that I believe is needed.”

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According to the Global Burden of Disease Study 2017, around 11 million deaths and 255 million disability-adjusted life years were attributable to dietary risk factors between 1990 and 2017 (ref. 1). Such risk factors include high sodium intake, low intake of whole grains and low intake of fruit and vegetables. A Lancet Commission with the EAT non-profit forum showed that a diet of plant-based proteins, unsaturated fats, whole grains and ample fruit and vegetables promotes well-being and lowers the risk of developing major chronic diseases, as does limiting meat, refined grains and sugar2.

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The United States has initiated strategies to guide and inform consumers about food choices, particularly in geographic areas and socioeconomic groups affected by food insecurity. Experts point to food and targeted diets as ways to manage disease and offer patients personal control over their conditions. This concept, known alternatively as ‘food is medicine’ or ‘food as medicine’, uses dietary interventions to prevent, manage and/or treat specific clinical conditions. “There are numerous diseases for which dietary changes should be prescribed as first-line treatment, according to broadly accepted clinical guidelines,” says Dariush Mozaffarian, director of the Food is Medicine Institute at Tufts University in Boston, Massachusetts, USA. “But meaningful dietary intervention very rarely happens in practice.” Despite the promise of ‘food as medicine’, there are many gaps in evidence, with only a few therapy areas showing health improvements through dietary interventions from clinical trials.

Cardiovascular disease and diabetes

Dietary interventions have shown the most direct benefits for cardiovascular disease and diabetes. The DASH (Dietary Approaches to Stop Hypertension) diet incorporates fruits, vegetables, whole grains and low-fat dairy foods and eliminates food with salt and saturated fats, as well as alcohol. Researchers showed in a meta-analysis that the DASH diet significantly reduced blood pressure, relative to results obtained with other dietary interventions, such as the Mediterranean diet, which allows moderate amounts of red wine and salt3. The reduction that the researchers saw was similar to reductions in studies of pharmaceutical monotherapies such as nitrendipine, which suggests that the DASH diet could be an alternative to medication for people with early-stage hypertension. The American Heart Association and American College of Cardiology have now recommended DASH to help adults lower their low-density lipoprotein cholesterol and blood pressure4, and studies are looking at DASH for the prevention and management of other cardiovascular conditions, such as heart failure.

In another study, Salas-Salvadó and colleagues found that a Mediterranean diet (supplemented with extra-virgin olive oil or nuts) reduced major cardiovascular events relative to results obtained with a reduced-fat diet in high-risk adults. The multi-center PREDIMED trial showed that these interventions lowered the cardiovascular event rates of acute myocardial infarction5, stroke and death, while a subsequent analysis showed lower thrombosis-related risk factors, such as elevated platelet counts6. “PREDIMED was a landmark dietary-intervention trial in the context of cardiovascular disease prevention,” argues Salas-Salvadó.

Dietary changes can also benefit people with diabetes. In the DiRECT trial, Naveed Sattar, from the School of Cardiovascular and Metabolic Health in Glasgow, UK, and colleagues tested a restricted-calorie total diet replacement in more than 300 people with type 2 diabetes after removal of all medication7. Significantly more patients on this diet managed to achieve diabetes remission at 12 months than those who received current best-practice care. Sattar also found that remission was sustained at 24 months for more than a third of the participants assigned to the dietary intervention8. “Type 2 diabetes has the most evidence for being modified by dietary interventions, since weight loss can rapidly improve glucose levels,” he says.

The DiRECT study findings have led to the National Health Service in England and Scotland now offering low-calorie diets for patients with type 2 diabetes as a path to achieving remission; the American College of Lifestyle Medicine in the United States has also acknowledged that “diet as a primary intervention for type 2 diabetes can achieve remission in many adults.”9 Sattar points out that lowering weight is a key issue for many chronic diseases that may be caused or exacerbated by excess adiposity. “It’s clear we need more trials of low-calorie and other diets that yield decent weight loss in many disease areas,” says Sattar, who is also chair of the UK government’s £20 million Obesity Mission.

Women’s health

Dietary interventions may be effective for endocrine disorders and other diseases that affect mainly women, such as polycystic ovarian syndrome (PCOS) and endometriosis. Obesity often coexists with PCOS, and a case-controlled study found an association between adherence to a Mediterranean diet and reduced disease severity10. “Diet, along with exercise, is considered first-line treatment for individuals with PCOS”, says Salas-Salvadó, although the optimal diet for such patients is, as yet, not clear.

Healthy eating could also reduce the risk of osteoporosis and fracture in older and menopausal women. A review of studies found that bone health and mineral status benefited from diets rich in fruits, vegetables, whole grains and low-fat dairy products11. By contrast, bone health was worse in people who follow ‘Western’ dietary patterns, such as consuming soft drinks, fried foods, sugar and processed meat. Dietary modifications may also benefit women with endometriosis, with a systematic review suggesting positive effects (although some of the studies included in the review displayed inherent risk biases)12.

Cognition and dementia

Growing evidence suggests that patients with neurological disorders, from migraine to Alzheimer’s disease, may benefit from dietary changes, but researchers caution that more evidence is needed. Stress, sleep and diet have each been linked to the occurrence of migraine attacks. However, “diet changes are not considered first-line treatment,” says Elizabeth K. Seng from the Albert Einstein College of Medicine in New York, New York, USA. Instead, dietary changes “are more likely to be helpful to reduce how often people get migraine attacks,” by preventing migraines, she says. Seng describes ongoing studies that are evaluating components of diet, such as specific fats, that could benefit people with migraine, as well as potential triggers. “Some patients may be more sensitive to certain dietary triggers, like caffeine and alcohol,” she says. “Certainly, diet could be a component of a comprehensive behavioral-management strategy, but the evidence for specific diets at this point remains preliminary,” she adds.

Another disease area with weak evidence, but many ongoing studies, is dementia, a growing health concern as the global population looks set to live longer. Hypertension, type 2 diabetes and obesity are themselves risk factors for the development of dementia, so modifying these risk factors through a healthy diet such as MIND (a hybrid Mediterranean–DASH diet) could delay or even prevent the development of dementia.

Personalized meal interventions might be effective in patients at risk of dementia, a concept that is already being assessed in cognitive health trials, as well as for dyslipidemia13. “APOE ε4 carries the strongest genetic risk for late-onset Alzheimer’s disease in some populations and is associated with the cellular metabolism of lipids and glucose,” explains Hussein N. Yassine, from the Keck School of Medicine of USC, Los Angeles, California, USA, and member of the Nutrition for Dementia Prevention Working Group. “People with the APOE ε4 allele might require an increased omega-3 intake at a younger age to delay the development of dementia,” he adds. Mozaffarian, an advocate for medically tailored meals, cites examples of pilots being run via Medicaid in the United States. Such personalized dietary interventions could result in both health benefits and economic benefits, with a retrospective US study suggesting that over 2 years, participants who received medically tailored meals had fewer hospital admissions than non-recipients had14.

However, experts are not yet convinced that diet is an appropriate treatment for dementia. “Currently, diet is not prescribed as a first-line treatment for patients with Alzheimer’s in most academic medical centers,” says Yassine. However, he argues that although “there is not enough evidence to support the role of diet in treatment, high-quality epidemiology studies support a role for diet in prevention.” As for general cognitive health, the role of diet is unclear. A review of studies investigating the effect of whole foods, as recommended by the EAT–Lancet Commission on Food, Planet, Health, found that the current evidence base for support of cognitive function by the reference diet was weak, despite the fact that nutritional metabolism regulates brain bioenergetics at a cellular level and indirectly affects neurodegenerative diseases through the gut–brain axis15.

Yassine notes that clinical trials are not well suited for diseases such as dementia that take years or even decades to manifest. “Diet’s effects on cognition could be indirect and might take decades to affect dementia incidence,” he says. More studies are needed to understand “how dietary patterns interact with dementia risk factors to increase cognitive decline,” he adds. These dietary patterns could then be targeted in clinical trials.

Difficult trials

Experts agree that large-scale randomized trials of dietary interventions are challenging to conduct. Trials in low-income and middle-income countries are especially difficult, mostly due to the associated costs, and often focus on under-nutrition, but “recognition is needed by funders of the massive burdens from non-communicable diseases, rather than just under-nutrition,” says Mozaffarian.

Salas-Salvadó notes that dietary interventions can be difficult to standardize, with each researcher optimizing their own ‘correct dose’ or ratio of macronutrients. Participant compliance is another issue, says Seng. “Part of the [difficulty] is the behavior-change element of dietary clinical trials — it is really hard!” she says. “Most people will struggle with implementing a new diet, even in the context of a clinical trial.” Trials in which metabolic parameters are controlled can be used to address compliance issues, but these are expensive and burdensome for the participants, and they do not reflect real-world circumstances.

Another challenge is the lack of under-represented groups in trials of dietary interventions. In the DiRECT trial of type 2 diabetes, most participants were white, despite the fact that the risk of type 2 diabetes is higher in other ethnic groups, such as people of South Asian ancestry. Sattar and co-researchers had to conduct a further randomized trial (STANDby) in a small cohort of South Asian people to show that weight loss and type 2 diabetes remission could be achieved with total diet replacement in this population16. “Poor proximity to academic centers, potential language barriers, work schedules and limited transportation access are all barriers to the inclusion of under-represented groups in clinical trials,” says Yassine. He highlights the importance of community outreach, the need to establish trust and offers of financial compensation or transportation in encouraging greater diversity in clinical trials.

Despite the challenges of dietary-intervention trials, experts agree that their importance is paramount, particularly in a digital age in which misinformation is rife. Dangerous misconceptions about diet and health can arise in the absence of solid evidence. Communication is key, argues Salas-Salvadó, with both “education and public health approaches” needed, he says.

Cheap and unhealthy

Cultural differences, availability of food and financial constraints also pose challenges for implementation, as unhealthy processed food is often more affordable than healthier alternatives. The American Heart Association has advised that nutrition is important for cardiovascular health, but noted how in the United States, for example, “subsidies have facilitated agricultural production geared toward producing cheap cereals and oils used by industry to meet consumer demand for highly processed products.” Many of these products contain high levels of sodium, refined grains, sugars and unhealthy fats.

Sattar argues that governments should restrict access to cheap calories. Only governments can “change the food environment so that people can, without much conscious effort, choose healthier foods,” he says. Such policy changes have been implemented in Singapore, which taxes sugary beverages and alcohol but also subsidizes healthier foods, such as whole-grain products. The question is not whether healthy dietary interventions should be subsidized, but how to afford research into and access to such interventions. “Societies need to take a close look at the health-promotion and treatment options we have chosen to subsidize,” says Seng. “We have the capacity to make decisions about the type of society in which we want to live, and how we want that society to optimize the health of its citizens.”

With food and nutrition insecurity widespread worldwide, and with millions lacking access to healthy and affordable foods, experts agree that equitable access to healthy foods is needed for disease management, improved health and lower healthcare costs. As Mozzafarian puts it, if we want a healthy population, equitable access to healthy foods to improve health and lower healthcare costs for all is “the only approach that will be broadly effective.”

Microplastics are everywhere — we need to understand how they affect human health

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As evidence emerges describing the accumulation of small plastic particles in various organs and tissues of the body, a much deeper understanding of the effects of these particles on human health is urgently needed.

The world is awash with plastic — 6 billion tons’ worth. In 2019, 353 million tons of plastic waste were produced, with a tripling of that number to more than one billion tons predicted by 2060 (ref. 1). More than 10,000 chemicals are present in plastics2, including carcinogens and endocrine disruptors. Plastics find their way into the human body in the form of tiny particles called microplastics (less than 5 mm in diameter) and nanoplastics (less than 1 μm in diameter). Microplastics and nanoplastics (MNPs) can arise from a variety of sources, including by design, as in the case of microbeads used in cosmetic and personal care products, or inadvertently, as the result of degradation of larger plastic products, such as through the laundering of synthetic clothes or abrasion of tires. MNPs are found everywhere on the planet, including the oceans, air and food supply.

MNPs enter the body mainly through ingestion or inhalation. For example, one might ingest MNPs by drinking liquid or eating food that has been stored or heated in plastic containers from which MNPs have leached, or by using toothpaste containing MNPs. One startling study found that infants may be exposed to high levels of microplastics by ingesting formula prepared in propylene feeding bottles3.

The biological effects of MNPs have been researched for decades, mainly in studies of laboratory rodents and human cells. In rodent studies, microplastics have been shown to have detrimental effects on a wide variety of organs, including the intestine, lungs and liver, as well as the reproductive and nervous systems4. More recently, MNPs have been found in a variety of tissues and organs in humans, including blood, lungs, placenta and breast milk5.

The effects of MNPs on human health are just beginning to be documented. For example, a recent report described a potential link between MNPs present in blood vessels and cardiovascular disease6. In samples of atherosclerotic plaques that had been surgically excised from the carotid arteries of 304 people, plastic was detected in plaques from approximately half of this cohort, with polyethylene in 150 of the samples and polyvinyl chloride in 31 of them. Using electron microscopy, the researchers found jagged-edged particles, identified as MNPs, in the plaques. Deposition of plastic in the plaques was strongly associated with the development of subsequent cardiovascular disease: over the course of 34 months, people with evidence of MNPs in their plaques had a 4.5-fold higher risk of a composite endpoint of nonfatal myocardial infarction, nonfatal stroke or death from any cause, relative to the risk for those without such evidence.

In another study focusing on a potential link between microplastics and inflammatory bowel disease, 15 types of microplastics were detected in human feces7. The concentration of fecal microplastics was higher in people with inflammatory bowel disease than in healthy people, and the level of fecal microplastics correlated with the severity of the disease.

Although these studies did not demonstrate a causal link between the presence of MNPs and disease, they underscore the need to accelerate research on this topic. Among the most pressing questions are the amounts of MNPs that are absorbed through ingestion, inhalation or skin exposure, the amounts of MNPs that accumulate in different tissues over the lifetime of a person, and how the different characteristics of MNPs — including their chemical composition, size and shape — affect those tissues. Mechanistic studies are also needed to probe how MNPs might lead to damage, including systemic effects mediated by the immune system or the microbiome, or direct cytotoxic effects. There is also a need for study of how exposure to MNPs and its consequent effects on health may be influenced by environmental, social and economic factors.

As the world’s burden of plastic becomes more and more untenable, international public health initiatives are aiming to manage the production, design and disposal of plastics more responsibly. In the case of microplastics, from October 2023, the European Union has restricted the intentional addition of microplastics to products and has set a target to reduce microplastics pollution by 30% by 2030. In a wider effort, the UN Environment Assembly, with the support of 175 nations, adopted a resolution on 2 March 2022 to develop a global plastics treaty8, with the intention of drafting the treaty by the end of 2024.

The health risks of exposure to microplastics are just beginning to be understood. More detailed and conclusive evidence of how MNPs accumulate in the body and have detrimental effects on human health can only spur the development and adoption of policies with the teeth necessary for reducing the global impact of plastics and improving public and planetary health.

Triphala: Harnessing Ancient Wisdom for Modern Gut Health and Immunity

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A tonic of three dried flowers offers a polyphenol-rich remedy known in Ayurveda to help rejuvenate and restore the body to normal function. 

Triphala: Harnessing Ancient Wisdom for Modern Gut Health and Immunity

A popular Ayurvedic herbal remedy that is packed with polyphenols has a healing effect on the gut, in part by increasing beneficial bacteria.

Triphala—a combination of three dried fruits—promotes the growth of Bifidobacteria and Lactobacillus, both of which are beneficial gut bacteria that can keep balance in the microbiome—the total community of microbes—many of which live in the colon. These commensal bacteria help minimize systemic inflammation.

The herbal tonic also has antioxidant properties that can help modulate the body’s molecules by scavenging free radicals, which are created in cell metabolism and can cause problems if they outnumber antioxidants. Too many free radicals can lead to oxidative stress, a major contributor to cancer and other diseases.

Bifidobacteria and Lactobacillus bacteria also create short-chain fatty acids (SCFA), metabolites that leave the gut and enter the bloodstream to perform health protective jobs throughout the body. SCFAs increase immunity and modulate inflammation.

While inflammation is a necessary part of the healing process, certain lifestyle factors like diet, viruses, aging, and toxins can create chronic inflammation. Johns Hopkins Medicine describes inflammation as swelling, redness, pain, and heat—the body’s response to injury—and systemic inflammation as the reaction to those lifestyle triggers that can cause disease and be addressed through diet.

Studies show triphala helps a number of diseases including heart disease, cancer, cataracts, dental caries, diabetes, and obesity. For the gut, it has an antibacterial effect on problematic bacteria such as Escherichia coli. It’s been used therapeutically for a range of gut issues such as constipation, abdominal pain, flatulence, hyperacidity, and inflammatory bowel conditions

“As both Ayurveda and Western medicine agree that health and disease begin in the gut, Triphala represents an essential foundational formula as it promotes efficient digestion, absorption, elimination, and rejuvenation,” according to a 2017 review in the Journal of Alternative and Complementary Medicine. “Triphala can be considered for use in the very young, the infirmed, and the elderly.”

Natural Laxative and Antioxidant

Triphala is exalted for its laxative effects and anti-inflammatory properties that give it a reputation for improving general gastrointestinal health.

A 2011 study in the Journal of Ayurvedic Alternative Medicine noted a significant increase in bowel movements after two weeks of using triphala, as well as less time spent on the toilet, improved stool consistency, less straining, and other signs of improved functional constipation.

The 2017 Journal of Alternative and Complementary Medicine review highlighted notable gastrointestinal research involving triphala including:

  • A human trial that showed triphala reduced constipation, abdominal pain, mucous, hyperacidity, and flatulence, while also improving consistency and frequency, and yield of stool
  • A rat study indicating triphala had a gastroprotective effect on stress-induced ulcers
  • A rodent study showing triphala replenished protein in intestinal villi, as well as improving glutathione levels, which help the body repair itself
  • A mouse study of triphala that reduced colitis, or inflammation in the bowel

The review pointed out triphala’s polyphenols—beneficial plant compounds such as quercetin and gallic acid—are capable of promoting the growth of Bifidobacteria and Lactobacillus. That change in microbial makeup is what creates an antioxidant, anti-inflammatory, and immunomodulating gut environment.

“Triphala-derived polyphenols such as chebulinic acid are transformed by the human gut microbiota into metabolites such as urolithins, which have the potential to prevent oxidative damage. The authors speculate that the bioactivity of triphala is elicited by the gut microbiome to generate a widened spectrum and abundance of anti-inflammatory compounds,” the review article concluded.

Three Fruit Formula

Ayurvedic practitioners often promote triphala—a Sanskrit word that means three fruits. The formula is described as a “rasayana,” or rejuvenator, and contains equal amounts of the fruits amalaki, bibhitaki, and haritaki.

Amalaki: Known for increasing secretions, amalaki helps with fat digestion, making it beneficial for liver and gallbladder health, according to John Immel, founder of the Joyful Belly School of Ayurveda.

“It is an anti-inflammatory for the gut. One of the special things about amalaki is it dilates capillary beds,” he told The Epoch Times. “It does generally rejuvenate gut tissue. It improves digestion by improving blood flow.”

Haritaki: Haritaki increases enzyme secretions and saliva. Mr. Immel said it’s good for a person suffering from dry digestion, constipation, gas and bloating. It does this with a laxative effect, pushing food through the digestive system and depressing fermentation.

Bibhitaki: Capable of cleaning up mucus, bibhitaki is a bit more harsh and drying.

“Sometimes I tell my more delicate clients to take biphala instead of triphala—two fruits instead of three—and cut out the bibhitaki,” Mr. Immel said. “It’s harsh and more of a diuretic to drain excess fluids.”

One common side effect of triphala can be the need to urinate in the middle of the night. Also, because of the laxative effect of triphala, anyone already experiencing diarrhea should be cautious.

Pregnant women are sometimes advised to avoid laxatives because they may induce labor. But Mr. Immel pointed out that constipation is often common in pregnancy, and the herbal tonic can help alleviate discomfort if used cautiously.

How to Take Triphala

Dosing is typically one teaspoon daily, but a lower dose might also be beneficial, according to Luke Coutinho, a nutrition expert, author, teacher, and influencer in India. Triphala comes in powder form—and may taste bitter or sour—but can also be taken by capsule.

Mr. Coutinho suggests a popular way of eating it blended with equal parts raw honey and ghee taken first thing in the morning. It can be taken daily, but he suggests carefully observing how the body and digestion respond, perhaps starting with one-quarter teaspoon or a small pinch mixed with water.

“By the third day, you’ll find this amazing energy that gets you through your day, this lightness,” Mr. Coutinho says in a You Tube video called “The Power in Triphala.” “Your stools get better, your bloating reduces, acidity gets better … You still have to make other lifestyle changes. It’s not magic.”

Mr. Immel advises to take triphala seasonally—usually in the spring and fall when seasonal allergies can be bothersome. The goal, he said, is to return the body to a state of proper functionality that doesn’t need support—herbal or otherwise.

“A cleansing herb like triphala not only has an action for decongesting mucus in the lungs but cleansing generally that helps reset the body,” Mr. Immel said. “What we are trying to do is strengthen the body, so that the body does what it’s supposed to do and maintains health.”

Helpful as they might be, herbs aren’t typically advised for long-term use, he said, adding the more an herb seems necessary, the more likely it is that it’s not doing its job to solve the underlying problem.

When triphala begins to taste more sweet, Mr. Immel said that’s usually a sign that your body has come into balance.

A Revered Tool

He’s seen the herbal blend work to alleviate a number of health symptoms, which is why it’s considered one of the top Ayurvedic tools. Haritaki fruit on its own is considered an Ayurvedic cure-all—found in both hands of the “Medicine Buddha,” an important icon in South Asia.

“Triphala as a formula deserves more attention. It’s an all-around wonderful tonic for the body,” he said. “It really is a panacea herb that I think deserves more attention.”

Coffee Compound May Help Counteract Age-Related Muscle Loss

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Your morning brew may give you more than an energy boost.

Coffee Compound May Help Counteract Age-Related Muscle Loss

One of the world’s favorite brews may hold the key to keeping muscles strong and healthy as we age.

According to recent research, a natural compound found in coffee could be the secret weapon against age-related muscle loss.

The Muscle-Preserving Molecule

Mitochondria, the powerhouses of our cells, play a crucial role in muscle health. An issue linked to sarcopenia, the age-related loss of muscle mass and strength, is that these cellular components generate less energy as we get older. Compounding this problem, levels of the crucial substance NAD+ (which stands for nicotinamide adenine dinucleotide), a coenzyme that helps cells regenerate and protects them from damage, also decline with age.

Researchers already know that NAD+ levels can be boosted using various dietary precursors, including the essential amino acid L-tryptophan and different forms of vitamin B3, such as nicotinic acid, nicotinamide, nicotinamide riboside, and nicotinamide mononucleotide.

In a recent study published in Nature Metabolism, scientists investigated whether an alkaline compound called trigonelline could help reverse these age-related changes in muscle health.

The researchers analyzed trigonelline levels in the blood of mice and worms and found that high levels of the substance were positively associated with muscle strength and function.

Conversely, low trigonelline levels were linked to sarcopenia, the typical loss of muscle size and strength that occurs with aging.

Trigonelline Promoted Healthy Longevity

Trigonelline is structurally related to vitamin B3 and is produced naturally in the body, in addition to being found in certain foods

“We discovered that older people with low endogenous levels of trigonelline in their blood lose more muscle mass and strength during aging,” Katharina Fischer, research and development and scientific communications manager at Nestle Research in Switzerland, where the study was conducted, told The Epoch Times. “We also discovered that trigonelline is a precursor to NAD.”

Providing trigonelline promoted longevity in test animals by activating cellular energy production in mitochondria and increasing muscle strength and function during aging, according to Ms. Fischer.

These findings open new opportunities to test the clinical efficacy of increasing trigonelline consumption through food products or supplements to improve muscle health, she noted.

Foods That Contain Trigonelline

Trigonelline is an alkaloid compound found in various plant sources. While it may not be as well-known as some other beneficial plant compounds, trigonelline is present in a variety of dietary sources. About 5 percent of the niacin we consume is converted into trigonelline.

Coffee Beans

Trigonelline is more abundant in coffee beans than in any other food source, and it contributes to coffee’s characteristic bitterness. However, during the roasting process, trigonelline partly breaks down to form nicotinic acid (niacin or vitamin B3), another nutrient with significant health benefits.

Fenugreek Seeds

Fenugreek, a plant commonly used in Indian and Middle Eastern cuisines, contains about 35 percent alkaloids, with trigonelline being the primary one in the seeds.

Other Foods

Trigonelline can be found in a variety of other foods, including barley, cantaloupe, corn, onions, peas, soybeans, and tomatoes.

You can also obtain trigonelline by eating fish, mussels, and crustaceans.

Never Too Late to Address Age-Related Muscle Loss: Expert

It’s natural to lose muscle mass as we age.

“Sarcopenia can occur due to a myriad of factors, such as immobility, lack of proper nutrition, obesity, and lack of physical activity,” Macie Smith, a licensed gerontology social worker, told The Epoch Times. “Since the senior population tends to be more sedentary, you’ll see it show up more prevalently in persons over the age of 65, but the process can begin as early as 30–40 years of age.”

However, while we cannot prevent aging, we can reduce muscle mass loss caused by it.

This can be done through proper exercise; a balanced, nutritional diet; and managing any underlying health conditions.

“It’s never too late to build and strengthen muscle to counter the effects of sarcopenia,” Ms. Smith said. “You can always develop a new exercise regimen that will allow you to become active and to maintain the active lifestyle.”

New Insights into Protein Accumulation in Alzheimer’s

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Summary: Researchers made a significant discovery in understanding the mechanisms behind protein accumulation in neurodegenerative diseases like Alzheimer’s. By studying fruit flies, the team found that a reduction in mitochondria within neuron axons leads directly to this detrimental protein buildup.

They pinpointed a rise in the protein eIF2β as a critical factor; reducing its levels restored protein recycling and improved neuron function. This breakthrough suggests a new target for therapies aimed at treating conditions like Alzheimer’s and ALS, potentially improving outcomes for patients.

Key Facts:

  1. The study revealed that depletion of mitochondria in neuron axons causes abnormal protein accumulation, a hallmark of diseases like Alzheimer’s.
  2. Researchers identified an increase in the protein eIF2β as a key contributor to this process; adjusting its levels could reverse the effects.
  3. The findings, derived from genetic studies in fruit flies, open the door to developing new treatments that could target mitochondrial health or regulate protein levels to combat neurodegenerative diseases.

Source: Tokyo Metropolitan University

Researchers from Tokyo Metropolitan University have identified how proteins collect abnormally in neurons, a feature of neurodegenerative diseases like Alzheimer’s. They used fruit flies to show that depletion of mitochondria in axons can directly lead to protein accumulation.

At the same time, significantly high amounts of a protein called eIF2β were found. Restoring the levels to normal led to a recovery in protein recycling. Such findings promise new treatments for neurodegenerative diseases.

This shows neurons.
It is known that the levels of mitochondria in axons can drop with age, and during the progress of neurodegenerative diseases.

Every cell in our bodies is a busy factory, where proteins are constantly being produced and disassembled. Any changes or lapses in either the production or recycling phases can lead to serious illnesses. Neurodegenerative diseases such as Alzheimer’s and Amyotrophic Lateral Sclerosis (ALS), for example, are known to be accompanied by an abnormal build-up of proteins in neurons. However, the trigger behind this accumulation remains unknown.

A team led by Associate Professor Kanae Ando of Tokyo Metropolitan University have been trying to determine the causes of abnormal protein build-up by studying Drosophila fruit flies, a commonly studied model organism that has many key similarities with human physiology.

They focused on the presence of mitochondria in axons, the long tendril-like appendages that stretch out of neurons and form the necessary connections that allow signals to be transmitted inside our brains. It is known that the levels of mitochondria in axons can drop with age, and during the progress of neurodegenerative diseases.

Now, the team have discovered that the depletion of mitochondria in axons has a direct bearing on protein build-up. They used genetic modification to suppress the production of milton, a key protein in the transport of mitochondria along axons.

It was found that this led to abnormal levels of protein building up in fruit fly neurons, a result of the breakdown of autophagy, the recycling of proteins in cells. Through proteomic analysis, they were able to identify a significant upregulation in eIF2β, a key subunit of the eIF2 protein complex responsible for the initiation of protein production (or translation).

The eIF2α subunit was also found to be chemically modified. Both of these issues hamper the healthy action of eIF2.

Importantly, by artificially suppressing levels of eIF2β, the team discovered that they could restore the autophagy that was lost and regain some of the neuron function that was impaired due to axonal mitochondria loss. This not only shows that depletion of mitochondria in axons can cause abnormal protein accumulation, but that this happens via upregulation of eIF2β.

As populations age and the prevalence of neurodegenerative conditions continues to increase, the team’s findings present a vital step in developing therapies to combat these serious illnesses.

Abstract

Axonal distribution of mitochondria maintains neuronal autophagy during aging via eIF2β

Neuronal aging and neurodegenerative diseases are accompanied by proteostasis collapse, while cellular factors that trigger it are not identified.

Impaired mitochondrial transport in the axon is another feature of aging and neurodegenerative diseases. Using Drosophila, we found that genetic depletion of axonal mitochondria causes dysregulation of translation and protein degradation.

Axons with mitochondrial depletion showed abnormal protein accumulation, and autophagic defects. Lowering neuronal ATP levels by blocking glycolysis did not reduce autophagy, suggesting that autophagic defects are associated with mitochondrial distribution.

We found eIF2β was upregulated by depletion of axonal mitochondria via proteome analysis. Phosphorylation of eIF2α, another subunit of eIF2, was lowered, and global translation was suppressed.

Neuronal overexpression of eIF2β phenocopied the autophagic defects and neuronal dysfunctions, and lowering eIF2β expression rescued those perturbations caused by depletion of axonal mitochondria.

These results indicate the mitochondria-eIF2β axis maintains proteostasis in the axon, of which disruption may underly the onset and progression of age-related neurodegenerative diseases.

CBD’s Neuroprotective Properties Explored

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Summary: Cannabinol (CBN), a cannabinoid derived from cannabis, offers neuroprotective properties that could treat neurological disorders like Alzheimer’s, Parkinson’s, and traumatic brain injuries. Their study details how CBN and its newly developed analogs prevent mitochondrial dysfunction in neurons, a common factor in these diseases.

The team synthesized four CBN-based compounds, finding one, in particular, to be highly effective in a fruit fly model of brain injury. These findings not only highlight CBN’s therapeutic potential but also pave the way for future treatments aimed at mitigating brain cell death in various neurological conditions.

Key Facts:

  1. CBN and its derivatives show promise in protecting neurons by enhancing mitochondrial function, crucial for preventing cell death in neurological disorders.
  2. The Salk team developed four new CBN analogs, with one showing significant efficacy in treating traumatic brain injury in fruit flies, indicating potential for human therapeutic use.
  3. This research was supported by multiple foundations and NIH grants, underscoring its significance and potential impact on treating age-related neurological disorders.

Source: Salk Institute

One in every 10 individuals above the age of 65 develops an age-related neurological disorder like Alzheimer’s or Parkinson’s, yet treatment options remain sparse for this population.

Scientists have begun exploring whether cannabinoids — compounds derived from the cannabis plant, like well-known THC (tetrahydrocannabinol) and CBD (cannabidiol) — may offer a solution.

A third, lesser-known cannabinoid called CBN (cannabinol) has recently piqued the interest of researchers, who have begun exploring the clinical potential of the milder, less psychoactive substance.

This shows a brain and plants.
After uncovering this mechanism of CBN’s neuroprotective activity, they began applying both academic and industrial drug discovery methods to further characterize and attempt to improve that activity.

In a new study, scientists at the Salk Institute help explain how CBN protects the brain against aging and neurodegeneration, then use their findings to develop potential therapeutics.

The researchers created four CBN-inspired compounds that were more neuroprotective than the standard CBN molecule — one of which was highly effective in treating traumatic brain injury in a Drosophila fruit fly model.

The findings, published in Redox Biologyon March 29, 2024, suggest promise for CBN in treating neurological disorders like traumatic brain injury, Alzheimer’s disease, and Parkinson’s disease, and also highlight how further studies of CBN’s effects on the brain could inspire the development of new therapies for clinical use.

“Not only does CBN have neuroprotective properties, but its derivatives have the potential to become novel therapeutics for various neurological disorders,” says Research Professor Pamela Maher, senior author of the study.

“We were able to pinpoint the active groups in CBN that are doing that neuroprotection, then improve them to create derivative compounds that have greater neuroprotective ability and drug-like efficacy.”

Many neurological disorders involve the death of brain cells called neurons, due to the dysfunction of their power-generating mitochondria. CBN achieves its neuroprotective effect by preventing this mitochondrial dysfunction — but how exactly CBN does this, and whether scientists can improve CBN’s neuroprotective abilities, has remained unclear.

The Salk team previously found that CBN was modulating multiple features of mitochondrial function to protect neurons against a form of cell death called oxytosis/ferroptosis.

After uncovering this mechanism of CBN’s neuroprotective activity, they began applying both academic and industrial drug discovery methods to further characterize and attempt to improve that activity.

First, they broke CBN into small fragments and observed which of those fragments were the most effective neuroprotectors by chemically analyzing the fragment’s properties. Second, they designed and constructed four novel CBN analogs — chemical look-alikes — in which those fragments were amplified, then moved them on to drug screening.

“We were looking for CBN analogs that could get into the brain more efficiently, act more quickly, and produce a stronger neuroprotective effect than CBN itself,” says Zhibin Liang, first author and postdoctoral researcher in Maher’s lab.

“The four CBN analogs we landed on had improved medicinal chemical properties, which was exciting and really important to our goal of using them as therapeutics.”

To test the chemical medicinal properties of the four CBN analogs, the team applied them to mouse and human nerve cell cultures. When they initiated oxytosis/ferroptosis in three different ways, they found that each of the four analogs 1) were able to protect the cells from dying, and 2) had similar neuroprotective abilities compared to regular CBN.

The successful analogs were then put to the test in a Drosophila fruit fly model of traumatic brain injury. One of the analogs, CP1, was especially effective in treating traumatic brain injury — producing the highest survival rate after condition onset.

“Our findings help demonstrate the therapeutic potential of CBN, as well as the scientific opportunity we have to replicate and refine its drug-like properties,” says Maher.

“Could we one day give this CBN analog to football players the day before a big game, or to car accident survivors as they arrive in the hospital? We’re excited to see how effective these compounds might be in protecting the brain from further damage.”

In the future, the researchers will continue to screen and characterize these CBN analogs and refine their chemical designs. They will also begin looking more closely at age-related neurodegeneration and changes in brain cells, particularly in mitochondria, asking how we can better suit these drug-like compounds to promote cellular health and prevent neuronal dysfunction with age.

Abstract

Fragment-based drug discovery and biological evaluation of novel cannabinol-based inhibitors of oxytosis/ferroptosis for neurological disorders

The oxytosis/ferroptosis regulated cell death pathway is an emerging field of research owing to its pathophysiological relevance to a wide range of neurological disorders, including Alzheimer’s and Parkinson’s diseases and traumatic brain injury.

Developing novel neurotherapeutics to inhibit oxytosis/ferroptosis offers exciting opportunities for the treatment of these and other neurological diseases.

Previously, we discovered cannabinol (CBN) as a unique, potent inhibitor of oxytosis/ferroptosis by targeting mitochondria and modulating their function in neuronal cells.

To further elucidate which key pharmacophores and chemical space are essential to the beneficial effects of CBN, we herein introduce a fragment-based drug discovery strategy in conjunction with cell-based phenotypic screens using oxytosis/ferroptosis to determine the structure-activity relationship of CBN.

The resulting information led to the development of four new CBN analogs, CP1-CP4, that not only preserve the sub-micromolar potency of neuroprotection and mitochondria-modulating activities seen with CBN in neuronal cell models but also have better druglike properties.

Moreover, compared to CBN, the analog CP1 shows improved in vivo efficacy in the Drosophila model of mild traumatic brain injury. Together these studies identify the key molecular scaffolds of cannabinoids that contribute to neuroprotection against oxytosis/ferroptosis.

They also highlight the advantageous approach of combining in vitro cell-based assays and rapid in vivo studies using Drosophila models for evaluating new therapeutic compounds.

Treatment Relieves Chronic Lyme Disease’s Neurological Symptoms

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Summary: Fibroblast growth factor receptor inhibitors, commonly used in cancer treatment, could effectively reduce neurological symptoms in patients with post-treatment Lyme disease syndrome. The study shows these inhibitors can decrease inflammation and cell death in brain and nerve tissues affected by Lyme disease.

This discovery paves the way for potential treatments aimed at the persistent neuroinflammation seen in some patients after standard antibiotic therapy. With promising initial results, further research is essential to move these findings from the lab to clinical applications.

Key Facts:

  1. Lyme disease can cause persistent neurological symptoms such as memory loss and fatigue, known as post-treatment Lyme disease syndrome, even after antibiotics.
  2. The study found that targeting FGFR pathways with specific inhibitors can significantly reduce inflammation and neuronal damage in tissue samples infected with Lyme disease bacteria.
  3. The research, supported by the Bay Area Lyme Foundation and resources from the Tulane National Primate Research Center, marks a critical step toward developing new interventions for chronic Lyme disease complications.

Source: Tulane University

Tulane University researchers have identified a promising new approach to treating persistent neurological symptoms associated with Lyme disease, offering hope to patients who suffer from long-term effects of the bacterial infection, even after antibiotic treatment.

Their results were published in Frontiers in Immunology. 

Lyme disease, caused by the bacterium Borrelia burgdorferi and transmitted through tick bites, can lead to a range of symptoms, including those affecting the central and peripheral nervous systems.

While antibiotics can effectively clear the infection in most cases, a subset of patients continues to experience symptoms such as memory loss, fatigue, and pain—a condition often referred to as post-treatment Lyme disease syndrome. 

Principal investigator Geetha Parthasarathy, PhD, an assistant professor of microbiology and immunology at the Tulane National Primate Research Center, has discovered that fibroblast growth factor receptor inhibitors, a type of drug previously studied in the context of cancer, can significantly reduce inflammation and cell death in brain and nerve tissue samples infected with Borrelia burgdorferi.

This discovery suggests that targeting FGFR pathways may offer an exciting new therapeutic approach to addressing persistent neuroinflammation in patients with post-treatment Lyme disease syndrome.  

“Our findings open the door to new research approaches that can help us support patients suffering from the lasting effects of Lyme disease,” Parthasarathy said.

“By focusing on the underlying inflammation that contributes to these symptoms, we hope to develop treatments that can improve the quality of life for those affected by this debilitating condition.”

Researchers treated nerve tissue with live or inactivated Borrelia burgdorferi, followed by an application of FGFR inhibitors. Study results revealed a significant reduction in both inflammatory markers and of cell death. 

While further research is needed to translate these findings into clinical treatments, the study represents an important step forward in understanding and potentially managing the complex aftermath of Lyme disease.

Funding: This study was funded by the Bay Area Lyme Foundation and supported with resources from the Tulane National Primate Research Center base grant of the National Institutes of Health, P51 OD011104. 

Abstract

Fibroblast growth factor receptor inhibitors mitigate the neuropathogenicity of Borrelia burgdorferi or its remnants ex vivo

In previous studies, we showed that fibroblast growth factor receptors (FGFRs) contribute to inflammatory mediator output from primary rhesus microglia in response to live Borrelia burgdorferi.

We also demonstrated that non-viable B. burgdorferi can be as pathogenic as live bacteria, if not more so, in both CNS and PNS tissues. In this study we assessed the effect of live and non-viable B. burgdorferi in inducing FGFR expression from rhesus frontal cortex (FC) and dorsal root ganglion (DRG) tissue explants as well as their neuronal/astrocyte localization.

Specific FGFR inhibitors were also tested for their ability to attenuate inflammatory output and apoptosis in response to either live or non-viable organisms. Results show that in the FC, FGFR2 was the most abundantly expressed receptor followed by FGFR3 and FGFR1.

Non-viable B. burgdorferi significantly upregulated FGFR3 more often than live bacteria, while the latter had a similar effect on FGFR1, although both treatments did affect the expressions of both receptors.

FGFR2 was the least modulated in the FC tissues by the two treatments. FGFR1 expression was more prevalent in astrocytes while FGFR2 and FGFR3 showed higher expression in neurons.

In the DRG, all three receptor expressions were also seen, but could not be distinguished from medium controls by immunofluorescence. Inhibition of FGFR1 by PD166866 downregulated both inflammation and apoptosis in both FC and DRG in response to either treatment in all the tissues tested.

Inhibition of FGFR1-3 by AZD4547 similarly downregulated both inflammation and apoptosis in both FC and DRG in response to live bacteria, while with sonicated remnants, this effect was seen in one of the two FC tissues and 2 of 3 DRG tissues tested.

CCL2 and IL-6 were the most downregulated mediators in the FC, while in the DRG it was CXCL8 and IL-6 in response to FGFR inhibition. Downregulation of at least two of these three mediators was observed to downregulate apoptosis levels in general.

We show here that FGFR inhibition can be an effective anti-inflammatory treatment in antibiotic refractive neurological Lyme. Alternatively, two biologics may be needed to effectively curb neuroinflammation and pathology in the CNS and PNS

How Drugs Hijack the Brain’s Reward System

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Summary: Researchers made significant advances in understanding how drugs like cocaine and morphine disrupt the brain’s natural reward mechanisms. Their study reveals that these drugs manipulate the same brain cells responsible for processing natural rewards, leading to compulsive drug-seeking behaviors.

By employing advanced neuroscientific techniques in mouse models, the team tracked how neurons in the nucleus accumbens respond to both natural rewards and drugs. This research not only deepens our understanding of addiction but also identifies potential targets for innovative treatments.

Key Facts:

  1. The study identifies specific neurons in the nucleus accumbens that are affected by both natural rewards and drugs, explaining the mechanism behind the powerful grip of addiction.
  2. Advanced tools allowed researchers to observe how repeated drug exposure alters neuronal responses, increasing the preference for drugs over natural rewards.
  3. The findings point to the mTORC1 signaling pathway and the Rheb gene as potential therapeutic targets, offering hope for new addiction treatments.

Source: Mount Sinai Hospital

Mount Sinai researchers, in collaboration with scientists at The Rockefeller University, have uncovered a mechanism in the brain that allows cocaine and morphine to take over natural reward processing systems.

Published online in Science on April 18, these findings shed new light on the neural underpinnings of drug addiction and could offer new mechanistic insights to inform basic research, clinical practice, and potential therapeutic solutions.

This shows a brain and pills.
Moreover, the research team identified a well-established intracellular signaling pathway—mTORC1—that facilitates the disruption of natural reward processing by the drugs.

“While this field has been explored for decades, our study is the first to demonstrate that psychostimulants and opioidsengage and alter functioning of the same brain cells that are responsible for processing natural rewards,” explains senior author Eric J. Nestler, MD, PhD, Nash Family Professor of Neuroscience, Director of The Friedman Brain Institute, and Dean for Academic Affairs of the Icahn School of Medicine at Mount Sinai, and Chief Scientific Officer of the Mount Sinai Health System.

“These findings provide an explanation for how these drugs can  interfere with normal brain function and how that interference becomes magnified with increasing drug exposure to ultimately redirect behavior compulsively towards drugs —a hallmark of addiction pathology.”

The study focused on identifying convergent mechanisms of addiction in mouse models across two different classes of drugs: cocaine, a psychostimulant, and morphine, an opioid.

This groundbreaking work required the amalgamation of a highly interdisciplinary team, organized by Dr. Nestler and long-time collaborator Jeffrey M. Friedman, MD, PhD, Marilyn M. Simpson Professor at The Rockefeller University, Investigator of the Howard Hughes Medical Institute, and co-senior author of the study.

Among its members were two biophysicists: Alipasha Vaziri, PhD, Professor of Neuroscience and Behavior at The Rockefeller University and a co-senior author of the study, and Tobias Nöbauer, PhD, Assistant Research Professor at The Rockefeller University and a co-first author of the study. Working closely together, the team employed a suite of cutting-edge tools and methodologies spanning behavioral, circuit, cellular, and molecular domains of neuroscience.

Through these innovative efforts, researchers were able to track how individual neurons in a forebrain region called the nucleus accumbens respond to natural rewards like food and water, as well as to acute and repeated exposure to cocaine and morphine in a cell-type-specific manner.

They discovered a largely overlapping population of cells that respond to both  addictive drugs and natural rewards, and demonstrated that repeated exposure to the drugs progressively disrupts the cells’ ability to function normally, resulting in behavior being directed toward drug-seeking and away from natural rewards.

“By tracking these cells, we show that not only are similar cells activated across reward classes, but also that cocaine and morphine  elicit initially stronger responses than food or water, and this actually magnifies with increasing exposure,” notes co-first author Caleb Browne, PhD, a former Instructor in Dr. Nestler’s lab who is now a Scientist in the Campbell Family Mental Health Research Institute at the Centre for Addiction and Mental Health (CAMH) in Toronto.

“After withdrawal from the drugs, these same cells exhibit disorganized responses to natural rewards in a manner that may resemble some of the negative affective states seen in withdrawal in substance use disorder.”

Moreover, the research team identified a well-established intracellular signaling pathway—mTORC1—that facilitates the disruption of natural reward processing by the drugs.

As part of that discovery, investigators found a gene (Rheb) that encodes an activator of the mTORC1 pathway that may mediate this relationship, potentially providing a novel therapeutic target for future discovery in a field of medicine that currently offers few effective treatments.

To that end, the research team plans to dig deeper into the cellular biology behind addiction neuroscience to better characterize molecular pathways that could be critical to basic research and, eventually, clinical practice.

“Through our work we have also established a landmark dataset that integrates drug-induced brain-wide neural activation with input circuit mapping from the nucleus accumbens, which could be useful to the broad scientific community conducting substance use disorder research,” says Bowen Tan, the other co-first author of the study, and a graduate student in the laboratory of Dr. Friedman.

“We’ve known for decades that natural rewards, like food, and addictive drugs can activate the same brain region,” says Dr. Friedman.

“But what we’ve just learned is that they impact neural activity in strikingly different ways.

“One of the big takeways here is that addictive drugs have pathologic effects on these neural pathways, that are distinct from, say, the physiologic response to eating a meal when you are hungry or drinking a glass of water when you are thirsty.”

“A major part of our ongoing research will be directed to defining how the flow of multimodal information is incorporated into value computations in brain cells and how that crucial mechanism enables drugs to overtake the processing of natural rewards, leading to addiction,” says Dr. Nestler.

Funding: Research reported in this press release was supported by the National Institute on Drug Abuse and the National Institute of Neuronal Disorders and Stroke, both part of the National Institutes of Health under award numbers P01DA047233, R01DA014133, 5U01NS115530, 1RF1NS110501, and 1RF1NS113251. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

About this addiction and neuroscience research news

Abstract

Drugs of abuse hijack a mesolimbic pathway that processes homeostatic need

INTRODUCTION

Drugs of abuse produce pleasurable feelings and reinforce consummatory behavior directed toward their acquisition. These same properties are characteristic of natural rewards that satisfy innate needs, such as food or water. Decades of research has shown that brain systems processing natural rewards are also impacted by drugs of abuse at the physiological, circuit, cellular, and molecular levels.

These findings raise the hypothesis that drugs of abuse cause addiction by “hijacking” a common reward pathway, ultimately promoting drug intake while curbing other healthy goals. However, the specific neural substrates for such a shared reward pathway remain unidentified.

RATIONALR

Identification of a neural substrate that processes multiple classes of rewards necessitates multimodal analysis of neurobiological functions. This includes pinpointing central nodes that respond to reward exposure, examining specific cell types within this brain node that encode distinct rewarding experiences within the same individual, and identifying molecular effectors that mediate cellular and physiological adaptations.

For this purpose, we employ a combination of approaches including whole-brain neuronal activity mapping, in vivo two-photon longitudinal calcium imaging at single-neuron resolution, and single-cell sequencing after in vivo CRISPR perturbation of a candidate gene. These multifaceted approaches enable the exploration of multiple components that comprise a common reward pathway and allow us to study how repeated drug exposure “hijacks” innate needs through this shared conduit.

RESULTS

Using whole-brain FOS mapping combined with chemogenetic inhibition approaches, we identify the nucleus accumbens (NAc) as a central hub necessary for both cocaine and morphine to disrupt natural reward (food and water) consumption. In vivo longitudinal tracking of individual dopaminoceptive neuron activity in the NAc in awake, behaving mice revealed overlapping ensemble responses across drugs of abuse and natural rewards, with drugs producing greater levels of activation.

Repeated exposure to drugs of abuse augmented cell type–specific neural dynamics indicative of an escalation of drug responses, and subsequently disorganized natural reward processing in the NAc after drug withdrawal. We then developed a “FOS-Seq” approach to correlate brain-wide FOS patterns with brain-wide in situ gene expression data. We identified Rheb, a gene encoding a small GTPase that activates the mTOR pathway, as being correlated with FOS induction by chronic exposure to either cocaine or morphine.

By integrating in vivo CRISPR perturbation of Rheb with single-nucleus RNA sequencing in the NAc, we demonstrated an essential role of Rheb in regulating signal transduction pathways associated with drug action in dopaminoceptive cells, and in diminishing natural reward consumption after chronic exposure to drugs of abuse.

Finally, functional mapping of NAc-projecting neurons from regions that are activated by drugs of abuse points to orbitofrontal cortex as a potential ascending node that curbs natural reward consumption as verified with chemogenetic activation.

CONCLUSION

We delineated a common reward pathway that enables drugs of abuse to interfere with the fulfillment of homeostatic needs for food or water. These findings provide mechanistic insights into the intensification of drug-directed behavior in substance use disorders