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Light driven proton pump in distant relative

Researchers investigated the group of microorganisms classified as Asgard archaea, and found a protein in their membrane which acts as a miniature light-activated pump. The schizorhodopsin protein draws protons into the organisms' body. This research could lead to new biomolecular tools to control the pH in cells or microorganisms, and possibly more.

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Does CBD help with arthritis pain?

If you have chronic arthritis pain, you may be wondering about cannabidiol (CBD) as a treatment. CBD, along with delta-9-tetrahydrocannabinol (THC) and other chemicals, is found in marijuana. But unlike THC, CBD is not “psychoactive” — that is, it does not cause the intoxication or high associated with marijuana use.

There’s a good chance you’ve tried it already: according to a Gallup poll in August of 2019, about 14% of Americans report using CBD products, and the number one reason is pain. The Arthritis Foundation conducted its own poll and found that 29% reported current use of CBD (mostly in liquid or topical form), and nearly 80% of respondents were either using it, had used it in the past, or were considering it. Of those using it, most reported improvement in physical function, sleep, and well-being; of note, a minority reported improvement in pain or stiffness.

Perhaps you’ve been tempted to try it. After all, most types of arthritis are not cured by other treatments, and CBD is considered a less addictive option than opiates. Or maybe it’s the marketing that recommends CBD products for everything from arthritis to anxiety to seizures. The ads are pretty hard to miss. (Now here’s a coincidence: as I was writing this, my email preview pane displayed a message that seemed to jump off the screen: CBD Has Helped Millions!! Try It Free Today!)

What’s the evidence it works? And what do experts recommend? Until recently, there’s been little research and even less guidance for people (or their doctors) interested in CBD products that are now increasingly legal and widely promoted.

But now, there is.

A word about arthritis pain

It’s worth emphasizing that there are more than 100 types of arthritis, and while pain is a cardinal feature of all of them, these conditions do not all act alike. And what works for one may not work for another. Treatment is aimed at reducing pain and stiffness and maintaining function for all types of arthritis. But for certain conditions, such as rheumatoid arthritis, conventional prescription medications are highly recommended, because these drugs help prevent permanent joint damage and worsening disability.

In addition, individuals experience pain and respond to treatment in different ways. As a result, it’s highly unlikely that there is a single CBD-containing product that works for all people with all types of arthritis.

What’s the evidence that CBD is effective for chronic arthritis pain?

While there are laboratory studies suggesting CBD might be a promising approach, and animal studies showing anti-inflammatory and pain-relieving effects, well-designed studies demonstrating compelling evidence that CBD is safe and effective for chronic arthritis pain in humans do not exist. A randomized trial of topical CBD for osteoarthritis of the knee has been published, but in abstract form only (meaning it’s a preliminary report that summarizes the trial and has not been thoroughly vetted yet); the trial lasted only 12 weeks, and results were mixed at best. One of the largest reviews examined the health effects of cannabis and CBD, and concluded that there is “substantial evidence that cannabis is an effective treatment for chronic pain in adults.” But there was no specific conclusion regarding CBD, presumably because definitive studies were not available.

Of course, there is anecdotal evidence and testimonials galore, including reports of dramatic improvement by people who tried CBD in its various forms (including capsule, liquid, topical, and spray) for their pain. But we are still waiting for well-designed, scientifically valid, and rigorous clinical trials (such as this one in progress) that are so badly needed to answer the question of just how helpful CBD may be to people with chronic arthritis pain.

Are there downsides to CBD treatment?

As with any treatment, there can be downsides. CBD is generally considered safe; however, it can still cause lightheadedness, sleepiness, dry mouth, and rarely, liver problems. There may be uncertainty about the potency or purity of CBD products (since they are not regulated as prescription medications are), and CBD can interact with other medications. For pregnant women, concern has been raised about a possible link between inhaled cannabis and lower-birthweight babies; it’s not clear if this applies to CBD. Some pain specialists have concerns that CBD may upset the body’s natural system of pain regulation, leading to tolerance (so that higher doses are needed for the same effect), though the potential for addiction is generally considered to be low.

There is one definite downside: cost. Prices range widely but CBD products aren’t inexpensive, and depending on dose, frequency, and formulation, the cost can be considerable — I found one brand that was $120/month, and health insurance does not usually cover it.

Are there guidelines about the use of CBD for chronic arthritis pain?

Until recently, little guidance has been available for people with arthritis pain who were interested in CBD treatment. Depending on availability and interest, patients and their doctors had to decide on their own whether CBD was a reasonable option in each specific case. To a large degree that’s still true, but some guidelines have been published. Here’s one set of guidelines for people pursuing treatment with CBD that I find quite reasonable (based on recommendations from the Arthritis Foundation and a recent commentary published in the medical journal Arthritis Care & Research):

Dos:

If considering a CBD product, choose one that has been independently tested for purity, potency, and safety — for example, look for one that has received a “Good Manufacturing Practices” (GMP) certification.
CBD should be one part of an overall pain management plan that includes nonmedication options (such as exercise) and psychological support.
Choose an oral treatment (rather than inhaled products) and start with a low dose taken in the evening.
Establish initial goals of treatment within a realistic period of time — for example, a reduction in knee pain that allows you to walk around the block within two weeks of starting treatment; later, if improved, the goals can be adjusted.
Tell your doctor(s) about your planned and current CBD treatment; monitor your pain and adjust medications with your medical providers, rather than with nonmedical practitioners (such as those selling CBD products).

Don’ts:

Don’t make CBD your first choice for pain relief; it is more appropriate to consider it if other treatments have not been effective enough.
Don’t have nonmedical practitioners (such as those selling CBD products) managing your chronic pain; pain management should be between you and your healthcare team, even if it includes CBD.
For people with rheumatoid arthritis or related conditions, do not stop prescribed medications that may be protecting your joints from future damage; discuss any changes to your medication regimen with your doctor.

The bottom line

If you’re interested in CBD treatment for chronic arthritis pain or if you’re already taking it, review the pros, cons, and latest news with your healthcare providers, and together you can decide on a reasonable treatment plan. Depending on the type of arthritis you have, it may be quite important to continue your conventional, prescribed medications even if you pursue additional relief with CBD products.

We may not have all the evidence we’d like, but if CBD can safely improve your symptoms, it may be worth considering.

Follow me on Twitter @RobShmerling

The post Does CBD help with arthritis pain? appeared first on Harvard Health Blog.

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Licorice Inhibits Replication of Coronavirus

During the COVID-19 pandemic, social distancing and hygiene seem to be having some effect on "flattening the curve" and slowing the spread of the virus. The use of ultraviolet (UV) light to decontaminate medical facilities, proper hand-washing and disinfectants, equipment and even protective facemasks also seems to be useful.

But people will still contract COVID-19, and effective treatments are lacking and needed. That’s why some scientific studies are looking at a natural product that has long been known to have antiviral effects¹ – glycyrrhizin, the major active constituent in licorice root.

Glycyrrhizin was valued in ancient Arabia and Greece for treating coughs and in China for relieving irritation of the mucous membranes. In modern times, glycyrrhizin has been shown to be a formidable antiviral, fighting herpes, HIV, hepatitis, influenza, encephalitis and pneumonia as well as less known viruses like respiratory syncytial virus, arboviruses, vaccinia virus and vesicular stomatitis virus.²

Still, it’s glycyrrhizin's effectiveness against SARS (severe acute respiratory syndrome) that has scientists hoping this important natural substance may be a tool against COVID-19.

Glycyrrhizin Has Medicinal Properties

You may think of licorice as an extract, a sweetener or even a candy, like Good and Plenty, but it’s actually complex biochemically and offers important medical benefits. According to PubChem, a database of chemical molecules maintained by the National Center for Biotechnology Information,³

"Glycyrrhizic acid is extracted from the root of the licorice plant; Glycyrrhiza glabra. It is a triterpene glycoside with glycyrrhetinic acid that possesses a wide range of pharmacological and biological activities ... potential immunomodulating, anti-inflammatory, hepato- and neuro-protective, and antineoplastic activities.

Glycyrrhizin modulates certain enzymes involved in inflammation and oxidative stress, and downregulates certain pro-inflammatory mediators, thereby protecting against inflammation- and reactive oxygen species (ROS)-induced damage. Glycerrhizin may also suppress the growth of susceptible tumor cells."

According to Botanical Medicine, the anti-inflammatory actions of glycyrrhizin (GL) may stem from suppression of cytokines:⁴

"As testimony to its anti-inflammatory properties, glycyrrhizin alleviated allergic asthma in an experimental mouse model, increased the IL-4 and IL-5 levels, decreased eosinophil counts and IgE levels, and upregulated total IgG2a in serum.

These results indicated that glycyrrhizin interfered with the production of IgE by decreasing the IgE-stimulating cytokines. It also attenuated lung inflammation and mucus production in mice."

Glycyrrhizin Works Against SARS, a COVID-19-Like Virus

SARS-CoV-2,⁵ the virus that causes COVID-19, is similar to SARS-CoV-1, the coronavirus that surfaced in 2003. Its genome shares 79.5% of the SARS-CoV-1 genome's information and both enter human alveolar epithelial cells through binding with ACE2 receptors.⁶

Early SARS-CoV-1 patients were given the viral compound ribavirin, but it showed little benefit.⁷ Corticosteroids were also tried in SARS-CoV-1 patients and patients with MERS (Middle East Respiratory Syndrome), which occurred 10 years later, but there was "no evidence showing that the mortality of SARS-CoV-1 and MERS patients was reduced," as reported in the International Journal of Biological Sciences.⁸

Soon after the SARS-CoV-1 outbreak, the medical journal The Lancet published a research letter suggesting that glycyrrhizin might fight SARS:⁹

"The outbreak of SARS warrants the search for antiviral compounds to treat the disease. At present, no specific treatment has been identified for SARS-associated coronavirus infection. We assessed the antiviral potential of ribavirin, 6-azauridine, pyrazofurin, mycophenolic acid, and glycyrrhizin against two clinical isolates of coronavirus from patients with SARS ...

Of all the compounds, glycyrrhizin was the most active in inhibiting replication of the SARS-associated virus. Our findings suggest that glycyrrhizin should be assessed for treatment of SARS.”

Glycyrrhizin had several positive actions, wrote the researchers:¹⁰

"In addition to inhibition of virus replication, glycyrrhizin inhibits adsorption and penetration of the virus — early steps of the replicative cycle ... Glycyrrhizin was most effective when given both during and after the adsorption period ...

… glycyrrhizin and its aglycone metabolite 18β glycyrrhetinic acid upregulate expression of inducible nitrous oxide synthase and production of nitrous oxide in macrophages.

Nitrous oxide inhibits replication of several viruses — eg, Japanese encephalitis virus, which can also be inhibited by glycyrrhizin. Our preliminary results show that glycyrrhizin induces nitrous oxide synthase in Vero cells [cells used in cultures] and that virus replication is inhibited when the nitrous oxide donor is added to the culture medium."

Glycyrrhizin May Act Differently From Other Substances

According to the Journal of General Virology, glycyrrhizin's method of stopping the replication of SARS viruses may differ from other treatments that have been tried:¹¹

"Unlike IFN-α and ribavirin, there are few clues to the antiviral mechanism of glycyrrhizin. Our data indicate that, as for ribavirin, glycyrrhizin only moderately affects coronavirus replicase functions.

However, in contrast to ribavirin, glycyrrhizin has been shown to inhibit SARS-CoV replication in tissue culture. This indicates that glycyrrhizin may not target the coronavirus replication machinery and that antiviral effects may be exerted, for example, during virus adsorption or release.”¹²

Stopping replication is especially challenging because of the peculiarities of the SARS virus. According to General Cell Biology & Physiology:¹³

"These analyses revealed that SARS-CoV-2 reshapes central cellular pathways, such as translation, splicing, carbon metabolism and nucleic acid metabolism. Small molecule inhibitors targeting these pathways were tested in cellular infection assays and prevented viral replication."

Glycyrrhizin's upregulation of nitric oxide and nitric oxide synthase in macrophages, which was noted in the International Journal of Infectious Diseases, may explain its ability to stop replication of SARS and hopefully other coronaviruses like SARS-CoV-2.¹⁴

Glycyrrhizin May Be Effective Against COVID-19

The failure of Western pharmaceutical treatments for SARS has put the spotlight on Traditional Chinese Medicine (TCM), a practice in which glycyrrhizin is a staple. According to the International Journal of Biological Sciences:¹⁵

"Ranging from case reports, case series, controlled observational studies and randomized clinical trials, clinical studies aiming to examine the effect of TCM on SARS have been carried out and reported. There are quite compelling evidences support the notion that TCM has beneficial effect in the treatment or prevention of SARS ...

For example, the rate of fatality in Hong Kong and Singapore was approximately 18%, while the rate for Beijing was initially more than 52% ... The dramatic reduced fatality from late May in Beijing was believed to be associated with the use of TCM as a supplement to the conventional therapy."

As COVID-19 reportedly first surfaced in China, The Globe and Mail reported that many nationals were turning to traditional treatments, while health leaders reported “’significant’ benefits from mixing Chinese and Western medicine:”¹⁶

"For authorities in Wuhan to counsel use of traditional Chinese medicine 'makes sense,' so long as it is in conjunction with Western drugs, said Jindrich Cinatl, a virologist who co-authored the 2003 [Lancet] study. 'In Western medicine, we have drugs that attack just a concrete target,' he said in an interview. 'With traditional medicine, you can prevent virus absorption to cells, virus replication and so on.'"

Jakkapong Watcharachaijunta, a medical researcher, told Thailand Medical News he thinks glycyrrhizin is a promising COVID-19 treatment:¹⁷

“Though the new 2019-nCov virus [since renamed SARS-CoV-2] is a different strain, it is very close to the SARS coronavirus genetically wise and maybe this should be an interesting starting point."

In a Pandemic, New Drugs or Vaccines Won’t Be the Answer

With COVID-19 now present on every continent except Antarctica, it is clear that treatments are needed immediately, but rushing new drugs to the market could cause adverse side effects to be missed. Further, a commentary written by Derek Lowe, who holds a Ph.D. in organic chemistry and has worked for several major pharmaceutical companies, expresses little hope for the existing medications being tested or for the development of entirely new ones:¹⁸

"A drug discovery program from scratch against a new pathogen is … not a trivial exercise ... Many such efforts in the past have come to grief because by the time they had anything to deliver the epidemic itself had passed. Indeed, Gilead’s remdesivir had already been dropped as a potential Ebola therapy.

You will either need to have a target in mind up front or go phenotypic. For the former, what you’d see are better characterizations of the viral protease and more extensive screens against it. Two other big target areas are viral entry (which involves the “spike” proteins on the virus surface and the ACE2 protein on human cells) and viral replication."

There are many challenges to developing a new antiviral drug and the process is extremely complex and slow, which means even if they end up being effective, they may be too late to be of use. According to Lowe:¹⁹

"Phenotypic screens are perfectly reasonable against viral pathogens as well, but you’ll need to put time and effort into that assay up front, just as with any phenotypic effort, because as anyone who does that sort of work will tell you, a bad phenotypic screen is a complete waste of everyone’s time."

It has recently been determined by Nextstrain.org, which tracks viral genomes across the planet, that SARS-CoV-2 is mutating 1,000 times faster than influenza viruses and 36,000 times faster than influenza virus. This strongly suggests that vaccines’ efforts will fail 1,000 times worse than the miserable flu vaccine.

The Benefits of Glycyrrhizin Are Already Available

One of glycyrrhizin’s advantages is that it has a long history of medicinal use and could potentially help those in need much sooner than an experimental drug just entering testing, but the fact remains that infectious disease that emerges in any country or continent has the potential to spread swiftly and cause a pandemic. According to Antiviral Research, the SARS outbreak produced greater world cooperation and reporting:²⁰

"One legacy of the outbreak was the formulation of the international Health Regulations (IHR) in 2005 and their acceptance by the World Health Assembly in 2007. The IHR require countries to report unusual and unexplained outbreaks of infectious disease and to develop the public health capacity to detect and respond to such diseases ...

SARS and other contemporary zoonotic threats, such as H5N1 avian influenza, have highlighted the need for collaboration among those responsible for human and animal health, and the environment.

This led to the formalization of the concept of ‘"One Health," which fosters collaborative effects of multiple disciplines to attain optimal health for people, animals, and the environment."

The relevant international organizations now have formal working agreements and a framework within which they can coordinate activities to assess risks at the animal/human/ecosystem interface, according to the review. There is also an improved understanding of inter-species transmission and zoonotic pathogens that are behind many pandemics.

As the COVID-19 pandemic continues, a natural product like glycyrrhizin, with known medical benefits and few of the risks associated with harsh medications, is good news.

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