The patient, who we'll call Alice, was a 78-year-old woman who had enjoyed excellent health until six months earlier when her younger sister had a stroke. Rather than see her sister cared for by strangers in a hospital, she had decided to nurse her at home, which meant many trips up and down the stairs to her sister's bedroom on the second floor. Being so busy, she found herself eating a lot of easy-to-prepare carbohydrate foods rather than her usual high-protein diet.
About a month into this routine, Alice first noticed pain and swelling in her joints and began taking 8-10 aspirin tablets a day, which only took the edge off her discomfort. She had always been able to go up and down stairs without difficulty, but now she climbed the stairs gripping the banister with her left hand and pulling herself upward step by step or sometimes crawling, hand-over-hand and foot-over-foot, "like an animal."
Alice's sister was improving, and she was back on her lower-carbohydrate diet, yet she still experienced constant severe pain in her neck, low back pain, and painful swelling of the knees, ankles, wrists, hands, elbows and shoulder joints. Her hands, she said, were always numb or "tingling." They were swollen, and she couldn't make a fist for the doctor.
She felt stiff every morning for several hours before the aspirin "took hold," and the stiffness returned in the evening when the medication was of no help. She was not sleeping well because of the pain.
The cold, damp weather made her condition worse, she noticed. Plus, she'd lost 16 pounds in the past three months and felt she was becoming progressively weaker. She almost always felt exhausted.
The doctor examining Alice noticed that her wrists and ankles were hot to the touch. "She seems dull mentally," he observed in his detailed physical exam, which included measurements of the range of motion in 20 joints indicating "severe joint dysfunction."
Her posture was forward-bent. Her joints were swollen as in "classic rheumatoid arthritis." Additionally, he noted that her skin was yellowish-brown, and her liver was slightly enlarged and tender when palpated. Her tongue was slightly swollen, as were her gums.
Alice was prescribed 150 mg of vitamin B3—in the form of niacinamide—to be taken every three hours for six doses daily (900 mg/day).
Three weeks later at Alice's next exam, much of her joint swelling had resolved, although she was still experiencing some pain and stiffness. She had better balance when she walked, and she sat more erectly than on her first visit. Her joints' range of motion had also improved measurably.
Nearly three months after starting the vitamin, the range of motion in her joints had improved again, though her ankles were still swollen. The sedimentation rate index of her blood—a measure of inflammation—had decreased from 1.80 mm/min to 1.00 mm/min, and she was taking only one aspirin a day for her pain. In her doctor's words, "She seemed to be more alert mentally and more vigorous physically."
Alice continued to improve at subsequent check-ups, and a little over a year after she started taking vitamin B3, she had no signs of joint pain or swelling and was finally able to walk upstairs normally again. Entirely free from bone and joint pain, Alice had not taken any aspirin for about 8 months.
Her sedimentation rate index had improved to 0.56 mm/min. The muscle strength in her hand (grip strength, measured in pounds per square inch) had improved from an initial measurement of 20 to 50 in her right hand, and from 12 to 46 in her left hand—putting her back into the normal range for women her age. She had no evidence of liver enlargement or swelling of the liver on palpation.
"In addition to the objective improvement in all of her joints and in her general health, there was a striking decrease in her apparent age," her doctor observed. "With considerable satisfaction, she reported a renewed interest in being with people, and in entertaining guests," he noted. "She looked younger than when first seen, appearing to be closer to 60 than 80 years of age."
Alice's case is one of hundreds recounted in William Kaufman's 1949 paper, "The Common Form of Joint Dysfunction" which describes, sometimes in exhaustive detail, his experience using niacinamide, a form of vitamin B3, to treat arthritis.
Kaufman was an American medical doctor and physiology researcher who took a special interest in vitamin therapy in the 1940s and '50s. His preoccupation with something as simple as vitamin B3 to treat a condition as disabling as arthritis may seem simplistic to modern doctors, but from the perspective of his era, it makes perfect sense.
Kaufman had grown up during the now-forgotten plague of deadly pellagra—considered the greatest epidemic of nutritional deficiency in American history. Pellagra was a frightening new disease at the time, which affected twice as many women as men.
The condition was diagnosed by the "four Ds": 1) dermatitis, a scaly rash that often appeared like a collar on the victim's neck and extremities, 2) dementia, involving frightening mental and emotional outbursts and irrationality, 3) diarrhea and other gastrointestinal complaints and finally 4) death.
Other symptoms (observed later in X-ray studies) included extensive osteoporosis, mineral depletion and tooth decay in more than half of the patients studied, as well as a swollen tongue. In most cases, dental decay was associated with "severe gingival retraction, sepsis, exposure of cementum, and loosening of teeth."1
Pellagra expanded so rapidly in the US during the early 1900s that many doctors believed it was some sort of infectious epidemic. Between 1906 and 1940, more than 3 million Americans had the disease, and at least 100,000 of them died.2
By 1926, Dr Joseph Goldberger, assigned to study pellagra by the US Surgeon General, demonstrated that the disease was linked to a grain-based diet deprived of meat, fish, eggs and milk. Old ways of preparing grain had been abandoned for new processing, and this had stripped the grains of nutrients, causing the deficiency disease to suddenly materialize. By introducing fresh meat, milk and even brewer's yeast into the diet, Goldberger demonstrated that the disease could be reversed and prevented.
The B3-arthritis connection: William Kaufman, MD, PhD
Dr Kaufman was an early pioneer in the use of high-dose vitamin therapy to treat disease. His once-forgotten discovery that vitamin B3, in the form of niacinamide, can reverse signs of osteo- and rheumatoid arthritis, first proposed in the 1940s, is now gaining traction as new research has confirmed and extended his findings.
In 1937, Conrad Elvehjem, a biochemistry professor at the University of Wisconsin-Madison, discovered that the vitamin niacin (also called vitamin B3) cured black tongue in dogs—the canine equivalent of human pellagra. The next year, doctors Tom Spies, Marion Blankenhorn and Clark Cooper were named TIME magazine's "Men of the Year" for their research establishing that niacin also cured pellagra in humans.
It was the same year that Kaufman graduated from the University of Michigan Medical School after also completing his doctorate in physiology. Kaufman was witness to one of the most dramatic public health initiatives in history over the next few years, as the dreaded pellagra was nearly wiped off the US map.
After 1942, when niacin was added to flour and average consumption rose from 11 mg to 17 mg daily, the disease was considered pretty much eradicated, and it has since become forgotten medical history.
It was fresh in Kaufman's mind, however, during a time when doctors considered nutritional deficiency as a cause of disease, and vitamin therapy was award-winning and mainstream, not pushed to the fringe as dangerous quackery.
Besides the spectacular reversal of the pellagra epidemic with vitamin B3, not 10 years earlier Dutch physician Christiaan Eijkman and English biochemist Sir Frederick Hopkins were awarded the Nobel Prize for Physiology or Medicine for their discoveries linking beriberi disease to a deficiency in vitamin B1, also known as thiamine. Beriberi is another condition with diffuse symptoms, from swelling of the limbs to heart failure and confusion, that was dramatically cured by infusion of a single vitamin.
Kaufman wondered if many of the symptoms he saw in patients in his practice were just milder versions of similar deficiencies—perhaps they were metabolic disorders in people who for genetic or other reasons required far more of the vitamins for optimal functioning.
He began using niacinamide in large doses to treat his private patients in 1941, before compulsory enrichment of refined cereal products with vitamins and iron began in the US in 1943.
In a 1943 monograph, he stated that when niacinamide was administered orally to 30 patients with obvious arthritis in divided doses amounting to 400 to 1,000 mg per day, it had a number of benefits including increased joint mobility and decreased stiffness, swelling, deformity and pain.
He was not alone in beginning to experiment with vitamins as medicine, as other doctors were reporting similar success using niacin to treat patients with a variety of conditions.
In Canada, psychiatrist Abram Hoffer suspected a common cause of the dementia that occurred in pellagra and the cases of schizophrenia he was seeing. He reported that 80 percent of schizophrenic patients he treated with high-dose vitamin B3 in the form of niacin showed marked improvement.3
Internist William Parsons and others at the Mayo Clinic, following Hoffer's suggestion, conducted trials beginning in 1955 showing that niacin significantly improved the lipid profiles of cardiac patients, lowering "bad" LDL cholesterol and serum triglycerides while raising "good" HDL cholesterol.4 Niacin—known as the "flushing" form of vitamin B3 due to its side-effect of red, warm and sometimes itchy skin (see box, page 65)—went on to be widely used for decades as the only cholesterol-lowering remedy available.
In 1959, Hoffer tried to shine a light on Kaufman's work, publishing his own experience with six patients who had seen remarkable joint improvement while taking vitamin B3 (either niacin/nicotinic acid or niacinamide).5
One case was a 68-year-old woman who had experienced prolonged stress due to the severe and lingering illness of her husband. She had begun to age very rapidly and complained of severe pain in both arms, failing vision in one eye, insomnia and pain and restricted movement in her hands, which were becoming deformed with arthritic nodes on all fingers.
She started taking 1,000 mg of niacin per day in two divided doses, and after about three months she experienced a marked improvement both mentally and physically.
Her arm pain vanished, along with the distortion in her wrists and nodes on her fingers (though she reported that the nodes had swelled slightly first before disappearing one by one). "Her hands became normally mobile," Hoffer observed.
He also noted that her skin looked more youthful. "For the remainder of the year and over the next two years, she continued to be subjected to severe stress and during that interval suffered the loss of her husband, some difficulty with the estate, etc. She has remained mentally and physically normal," Hoffer said.
Another of his cases was a previously healthy boy who had developed pain and stiffness in his knees at age 14 in 1952. In the summer of 1953, he was hospitalized and given physiotherapy and aspirin. He improved considerably at first, but by the fall of that year, his condition worsened again. In the fall of 1954, he was in bed for five weeks with severe pain in his hips, back and the joints of his foot.
In December 1954, the boy was started on 2,000 mg of nicotinic acid (niacin) per day divided into two doses, along with 100 mg of ascorbic acid (vitamin C) per day in addition to aspirin. Five days later, he returned to school somewhat improved. "He has continued to improve since that time," Hoffer reported.
Within six months, his feet, which had swollen to a size E width, were reduced to a size C. His fingers were less swollen and more mobile. He had quartered his daily aspirin dose by 1956.
By 1957, his condition had continued to improve, though he still had pain in his back, which remained slightly stiff. He reduced his niacin dose to 1,000 mg per day but reported that whenever he took less, he felt a return of joint stiffness. His sedimentation rate measure of inflammation had normalized. "His scholastic career continues uninterrupted, but medication [vitamin B3] cannot be stopped," Hoffer wrote.
Hoffer added that Kaufman had observed hundreds of similar cases in which, "without exception, those patients who took adequate amounts of niacinamide continuously, experienced clinically significant, measurable improvement in joint mobility and joint function and often such additional benefits as improvement in muscle strength and working capacity, decreased fatigability, improved sense of equilibrium, and relief of certain mental syndromes, including depression."
Joint deformities often lessened in severity or disappeared with niacinamide treatment in cases of what would be diagnosed today as osteo- or rheumatoid arthritis, according to Kaufman's reports.
Elevated sedimentation rates tended to normalize, but the benefits of therapy continued only so long as the vitamin was taken. "Perhaps these massive quantities of vitamin force some improvement in intracellular oxidative respiration," Hoffer speculated, but as a psychiatrist with experience using vitamin B3, he said, he only wanted to confirm Kaufman's findings and ask that rheumatologists do their own study.
It would be decades before that study was undertaken. In 1996, researchers at the US National Institutes of Health (NIH) tested the vitamin on 72 patients who'd had osteoarthritis for at least five years and were all taking nonsteroidal anti-inflammatory drugs (NSAIDs) daily for pain. They were randomly divided into two groups—one receiving six 150 mg doses of niacinamide throughout the day (for a total of 3,000 mg/day) and the other given identical placebo pills. Neither the patients nor doctors doling out the pills knew who was receiving the treatment vs. the control.
The results were a clear confirmation of Kaufman and Hoffer's earlier reports. Arthritis patients taking niacinamide experienced an overall improvement of 29 percent during the 12-week study compared to those taking the placebo, whose condition worsened by 10 percent.
Pain levels did not change, but those on niacinamide reduced their NSAID intake by 13 percent. Niacinamide reduced sedimentation rates by 22 percent and increased joint mobility by 4.5° over controls.
Side-effects were more common in the niacinamide group (40 percent vs 27 percent) but considered minor, with gastrointestinal upset being the most common. Most of these issues were managed by taking the vitamin with food. One patient was hospitalized for gastric bleeding, but she was in the placebo group and had developed an ulcer from her NSAID use.
The niacinamide patients' blood levels of glucose, uric acid, cholesterol and other markers did not change significantly during the trial. One marker—serum glutamic oxaloacetic transaminase (SGOT), a measure of liver function—was slightly elevated in the niacinamide treatment group, but not to a concerning level in any patient.
The researchers, led by W. B. Jonas, cautioned that SGOT levels should be followed in patients taking niacinamide, but concluded that "niacinamide may have a role in the treatment of osteoarthritis" because it "improved the global impact of osteoarthritis, improved joint flexibility, reduced inflammation, and allowed for reduction in standard anti-inflammatory medications when compared to placebo. More extensive evaluation of niacinamide in arthritis is warranted."6
Jonas surmised in his paper that large amounts of niacinamide might work by increasing levels of niacinamide adenine dinucleotide (NAD), an essential coenzyme for more than 200 reactions in the body, including energy production in mitochondria—the powerhouses of cells that decline in function as we age and are exposed to metabolic stress. Niacinamide's boost of NAD would provide energy and materials important for cartilage repair, he thought.
Arthritis patients are still treated with medicines that are known to have limited control of symptoms and to carry a host of serious and even deadly dangers. Doctors' most frequent response to arthritis, prescribed to half of all elderly patients with osteoarthritis, is NSAIDs like Aleve, Motrin and Advil.
In 2015 the US Food and Drug Administration (FDA) upgraded its warnings on these drugs, which have been known to elevate the risk of heart attack and stroke, and said that the risk is present after just two weeks of first use of the drugs even in patients with no history of cardiovascular disease.
The higher the dose and the longer the use of NSAIDs, the greater the risk.1 NSAIDs are also linked to gastrointestinal ulcers, which claim 7,000 to 10,000 victims each year, as well as acute kidney injury.2
Doctors also prescribe opioid painkillers to patients with arthritis, but these drugs have caused the greatest addiction and overdose crisis in medical history, as well as having the lesser-known risks of increased pain, liver damage, infertility, insomnia, constipation and nausea.3
Arthritis sufferers are also frequently treated with prescription corticosteroid drugs, which are a fast and effective way to control inflammation, but with a price: side-effects range from potentially life-threatening adrenal suppression, which leaves adrenal glands sluggish and unable to properly respond to illness or injury, to dangerous spikes in blood sugar, bone loss, weight gain and conditions such as diabetes and eye damage that may be permanent.4
B3's relative dangers
Vitamin B3 is not entirely risk-free. One 2017 case study describes a 22-year-old athlete who took 20 grams of niacin in one dose—high by even Kaufman and Hoffer's enthusiastic standards—and developed acute liver toxicity requiring an emergency liver transplant.1
A 1992 review of the literature on liver toxicity from niacin reported adverse reactions in six patients resulting from the exclusive use of high-dose unmodified niacin (also called nicotinic acid, the "flushing" version of vitamin B3 known for causing recipients' skin to become warm and red), and in two patients from the exclusive use of time-release preparations.
Another 10 patients developed adverse liver reactions after abruptly changing from flushing to time-release preparations. Signs of liver toxicity developed in less than seven days in four of these patients. All of these cases were reversed when niacin was stopped.2
A more recent case study describes a 74-year-old woman who was using 500 mg of flushing niacin three times per day that was changed suddenly to extended-release form. This is thought to be the first case of death due to the resulting liver toxicity.3
Niacinamide is not associated with the same level of liver toxicity risk as niacin. In 1955, Kaufman wrote that niacinamide (alone or combined with other vitamins), in his "thousand patient-years of use," had caused no adverse side-effects.4
The 1996 NIH study suggests that liver damage is something to watch out for, and the higher the dose, the higher the risk.5 Though toxicity is exceedingly rare, especially in comparison to drugs commonly used to treat arthritis, it is important to have a doctor oversee high-dose vitamin B3 use and to be on the alert for symptoms of liver damage, which include nausea and vomiting, skin and eyes that appear yellowish (jaundice), abdominal pain and swelling, swelling in the legs and ankles, dark urine and loss of appetite.
An avalanche of subsequent research seems to be confirming Jonas's idea. Studies have begun to focus on how supplementing vitamin B3 precursors to NAD—niacin, niacinamide and, of special new interest, nicotinamide riboside (NR)—increases NAD production, triggering a host of wide-ranging longevity benefits at the cellular level.
A 2018 Nature paper reported that NR supplementation was safe and increased NAD by 60 percent in healthy, middle-aged people.7
NR has become a trendy supplement as a result, but the discovery has also renewed interest in the effects of the much cheaper and easily supplemented NAD precursor, niacinamide. A 2019 review of niacinamide's diverse functions describes it as anti-inflammatory, with antidepressant and anti-anxiety effects.
Niacinamide has been shown to protect the skin from UV light and skin cancer, to improve acne and other skin conditions and to ward off vision and hearing loss. It also has brain-protective properties, including against neurodegenerative diseases like Alzheimer's and Parkinson's.8
How much to take: Kaufman's protocol
Kaufman only prescribed niacinamide in frequent, smaller divided doses totaling 900 mg to 4,000 mg per day, and he considered more frequent 250 mg doses to be 40 to 50 percent more effective than 500 mg doses for arthritis.
He preferred thin gelatin capsules (over thick ones) for delivery and generally expected it to take about three months from the patient starting niacinamide to see a measurable improvement in arthritis.
Surprisingly, there has been no follow-up by the NIH or others on Jonas' promising findings. For the nearly quarter-century since then, arthritis has been the leading cause of work disability in the US. The Centers for Disease Control and Prevention (CDC) reports that arthritis affected 54.4 million Americans in 2015, and the rate is predicted to soar.
By 2040, the agency estimates that 78 million adults (more than a quarter of the entire adult population of the US) will have doctor-diagnosed arthritis.9
"These estimates may be conservative," the CDC states, "as they do not account for the current trends in obesity, which may contribute to future cases of osteoarthritis." Like pellagra, arthritis strikes women disproportionately, with nearly two-thirds of those diagnosed being female.
How and why did a public health agency—and researchers worldwide—ignore a study that showed the potential of a relatively safe vitamin to give a substantial improvement in arthritis symptoms after just three months of use?
For Andrew Saul, coauthor with Abram Hoffer of the book, Niacin: The Real Story (Basic Health Publications, Inc., 2015), the reason is two-fold. First, the history of niacin deficiency is forgotten not just by the public. "Most medical doctors have never studied nutrition any more than superficially," he explains.
"Second, there is no money in cheap nutrient therapy. With niacinamide, you can treat a patient for a month for less cost than a single day on many patented drugs. No pharmaceutical company is going to encourage use of an economical, non-prescription solution to a lucrative problem."
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