Pauling’s Study of Schizophrenia: Pulling Back

ASA leaflet with Pauling’s annotations, circa 1971

[Part 9 of 9]

Throughout his long advocacy of an orthomolecular approach to mental disease, Linus Pauling weathered intense skepticism from his critics and gained support from sources both likely and not. Despite this, Pauling was not always inclined to reciprocate when asked for help by certain of his allies. One notable instance of Pauling “pulling back” concerned a request by the American Schizophrenia Association and its desire to fundraise on behalf of orthomolecular medicine.

The American Schizophrenia Association (ASA), which was initially called the American Schizophrenia Foundation and later renamed the Huxley Institute, was founded in the 1960s by Pauling’s close colleagues, Humphry Osmond and Abram Hoffer. Hoffer and Osmond served on the board as Vice-President and President respectively for a number of years, and as a favor to his friends, Pauling joined the board as well.

By 1971, the ASA was in need of funds. In an effort to raise more capital and grow the organization’s membership, ASA chairman Donald Webster began organizing a direct mail campaign. Believing Pauling to be the most “well known and respected” person on the board, Webster asked Pauling to offer his signature at the bottom of the campaign’s centerpiece letter.

Webster’s draft, however, raised some red flags. For one, Pauling felt as though the style and voice of the letter was too dissimilar from his own. He was likewise concerned about attaching his name to an offering that might be scientifically inaccurate or misleading. And he was irked by a recent experience with Executive Director Mel Mendelssohn, who had written in a publicity flyer that Pauling was “one of the few men ever to have won two Nobel Prizes.” Famously the only person to have received two unshared Nobel Prizes, Pauling took the time to write to Mendelssohn and express his feeling that this “carelessness needs to be pointed out” before coolly requesting that Mendelssohn tell him “who the other men are” who had also won two Nobel Prizes.

For all of these reasons, Pauling believed that it would be “unsatisfactory” for him to sign. As he explained in his reply to Webster, “I have taken action of this sort a few times in the past, and have also regretted it a few times.”


Webster, for his part, seemed to initially understand Pauling’s hesitation, but nonetheless was persistent. He responded by first acknowledging that “style is a highly personal” characteristic “which cannot be duplicated by another writer” and then emphasizing that his initial pass was just a draft “composed for its idea value.” Clearly Webster still felt as though the ASA’s best option for fundraising was to lean on Pauling’s celebrity.

These tactics did not convince Pauling to agree to sign the letter, but did compel him to offer a new rationale for his decision. This time around, Pauling offered that he could not participate in the letter project because of the time commitment it would require and because he was “so burdened with work […] editing the contributions to the new book Orthomolecular Psychiatry.”

Though twice spurned, Webster continued the conversation and eventually Pauling agreed to have his name used for the fundraising campaign. But this acquiescence did not allay Pauling’s concerns about the veracity of the letter’s claims. For example, a suggestion that a $25 donation could “provide a kit for diagnosing schizophrenia” seemed too high. Pauling wanted to know how expensive the kits actually were, and asked the ASA to verify the cost. About a month later he received his answer — the kits did not actually cost $25, but that total would, among other things, cover the ASA’s costs of sending samples out for laboratory testing.

Pauling was bothered by what he saw as a misrepresentation of costs and also by the ASA’s failure to divulge that they were not analyzing samples in-house. For these reasons, he once again soured on the idea of signing the letter, and wrote to the organization to retract the use of his name from the campaign. Ironically, amidst this all, the ASA sent Ava Helen Pauling a solicitation letter mentioning the $25 schizophrenia kit.


Once he had decided to sever ties with the direct mail initiative, Pauling took pains to point out all the other errors that he had found in the ASA’s letter. One passage claimed that “fifty dollars distributes a research study to ten clinics.” From experience, Pauling knew that this claim was inaccurate, noting that “this seems to me to be about ten times what it should cost to distribute reprints of a paper, even including the cost of reprints.”

By October 1971, Pauling had decided that he wanted to detangle his research from ASA support, writing in a curt letter to the board that he “would prefer not to report on the work that [I] am doing at the present time.” Though he did not elaborate much on his reasons, nor comment on the conflict about the fundraising campaign, the message was clear: the time had come for Pauling to pull back from the ASA.

Pauling’s Study of Schizophrenia: Clashes with Jean Mayer

Jean Mayer. Credit: Tufts University

[Part 8 of 9]

“I am afraid you and Jean Mayer will have to lock horns. Read the attached clipping. He is doing you a lot of harm.”

-Richard Stanton, publisher of Executive Health, to Pauling, 1976.

One of the most vocal critics of Linus Pauling’s orthomolecular approach to the treatment of schizophrenia was a popular and respected nutritionist by the name of Jean Mayer. The battle between the two, which mostly played out in public forums, was pitched and sometimes ugly.

Born in France in 1920, Jean Mayer received degrees from the University of Paris in 1939. After graduation, and with the outbreak of World War II, Mayer joined the French army and served as a second lieutenant. He was captured by German forces in 1940 but managed to escape. He then fought with the Free French and Allied forces in parts of Italy and Northern Africa; for his bravery he was awarded fourteen medals, including the Croix de Guerre, which is one of France’s highest military honors.

After the war, Mayer moved to the United States, serving as a Rockefeller Foundation fellow from 1946-1948. During this period, he also met and married an American, Elizabeth Van Huysen. He received his Ph.D. in chemistry from Yale in 1950, and went on to a faculty career at Harvard, where he remained for twenty-five years. In 1975 he left Harvard to become president of Tufts University, remaining in that post for sixteen years. He died of a heart attack in 1993.


Mayer spent much of his career focusing on nutrition, and eventually became quite well-known for this work. Perhaps most notably, Mayer correctly identified a biological link between blood glucose levels and feelings of hunger. From there, Mayer helped to popularize the idea that obesity was a “disease of civilization” caused by a variety of factors such as smoking, drinking alcohol, eating a poor diet, and failing to get enough exercise. As his profile rose, Mayer helped found the National Council on Hunger and Malnutrition, and also served as an advisor to presidents Nixon, Ford, and Carter, helping to initiate federal food assistance programs during this time.

Mayer was also deeply concerned about the intersection between malnutrition and human suffering worldwide. When the Biafran War erupted in Nigeria in 1969 for example, Mayer traveled to Africa to try and assess the needs of the starving. The report that he authored convinced President Nixon to increase food aid to the war-torn region. During later periods of regional famine, Mayer was often among the first experts called upon to assess the needs of hungry people.

Given his background, it is not surprising that Mayer took an interest in Pauling’s orthomolecular research. And the more he learned, the more he came to disagree with the approach, finding it ineffective and ultimately harmful. As he began to air his disagreements with the work, a feud emerged between the two high-profile scientists, one that would last for the better part of two decades.


Although Mayer and Pauling’s public disagreement was long-standing, the crux of the issue never really changed: Mayer did not think orthomolecular therapy worked and Pauling was certain that it did. As such, their discourse tended to revolve around efforts by Pauling to disprove what he believed to be blatant misrepresentations by Mayer.

One noteworthy exchange began with Mayer publicizing a report suggesting that orthomolecular treatment of schizophrenia increased the suicide rate of those treated. Mayer was quite well-known when he began pushing this report, and Pauling knew that its conclusions would be treated as gospel by many. As such, Pauling knew that he would need to both correct what he saw as misrepresentations and also redirect public opinion in favor of trusting orthomolecular methods.

In the opinion piece that he wrote as a rebuttal, Pauling pointed out that the report’s claim had been based on a single case study. This lone outlier, in Pauling’s view, “ha[d] very little value” and should certainly not be used to draw any broader conclusions. From there, Pauling publicly urged Mayer to avoid basing his criticisms on others’ research, but to instead assess the efficacy and safety of the research that Pauling and his colleagues had done, which included numerous double-blind studies — a far cry from the single case that Mayer had leaned on. Indeed, Pauling was keen to address the suicide issue head-on, and pressed Mayer to examine the data in one double-blind study where four placebo patients had tragically taken their own lives, with nothing of the sort being recorded for the orthomolecular patients. Pauling wrote that this data “has some significance” and could not ethically be ignored by critics like Mayer.

Mayer did not retreat in his response, illustrating his position in a letter sent to Pauling. The letter contained an anecdote in which Mayer wrote of a friend’s son who had developed suicidal schizophrenia. After an initial period of hospitalization,

his father heard of treatment of schizophrenia by large doses of vitamins, to which [Pauling’s name] was associated, removed his son from close supervision, and sent him to be treated with vitamins[…] Two weeks later the young man hanged himself.

Though a stark and compelling story, the anecdote failed in the same way as the single-case report that Mayer had previously amplified. Though Pauling had no reason to dispute the truth of what Mayer had conveyed, he again expressed fundamental disagreement with Mayer’s use of a solitary account in his campaign to discredit orthomolecular therapies.

Amidst the public back and forth, Pauling invited Mayer to attend an orthomolecular symposium being hosted at Stanford University in the summer of 1972. The invitation included offer of a $250 honorarium, plus all expenses paid. Notably, Pauling did not ask that Mayer speak at the event, instead suggesting that he participate as an attendee “and take part in the discussions.” Mayer declined the invitation, citing plans to be out of the country at the time, “probably in France.”


By the mid-1970s, Mayer’s profile had grown with the public largely through his syndicated newspaper column, in which he would often respond to subscriber-generated questions concerning health. In other instances, Mayer used the space write longer form pieces on topics that he thought relevant and useful to his readership, which sometimes meant a renewal of attacks on orthomolecular therapy.

In one such instance – an April 1975 column that appeared in the Los Angeles Times and elsewhere – Mayer criticized the notion that vitamins could be used to treat schizophrenia, citing as support the growing number of mainstream researchers who argued that orthomolecular therapy had “been thoroughly disproved.” (In this, Mayer was presumably leaning on a report authored by a National Institute of Mental Health task force that had come out against orthomolecular treatments.) In other pieces, Mayer reiterated his belief that the lack of substantial changes in positive and consistent outcomes for schizophrenia patients being treated with megavitamin doses was enough to disprove even the most ardent supporters of orthomolecular therapy.

Though the volleys would continue, there did emerge a brief moment in 1983 when Mayer and Pauling joined together in supporting the ailing Soviet scientist, Andrei Sakharov. Despite their differences, Mayer and Pauling were acutely sympathetic to the perceived cruelty that Sakharov was enduring while in exile in the city of Gorky. (modern day Nizhny Novgorod). And when a new Soviet leader, Yuri Andropov, rose to power after the death of Leonid Brezhnev, many scientists, including Mayer and Pauling, embraced the opportunity to lobby for Sakharov’s release. The tone of Pauling and Mayer’s correspondence shifts during this period, as the two scientists wrote to one another to coordinate and support this work.


The cordiality was short lived however and, pretty quickly, interactions became even more vitriolic. By 1985, Mayer was a decade into his tenure as president of Tufts University, and in this capacity was able to significantly influence the school’s Diet and Nutrition newsletter. On multiple occasions, Mayer used the publication as a personal soapbox to once again discredit Pauling and his approach to schizophrenia treatment. The January 1985 issue, for instance, featured a series of articles to this effect, an effort that Pauling found to be not only inaccurate, but also petty. In a letter to Mayer, Pauling made his feelings clear:

I am disappointed[…] I think that this is the largest collection of false and misleading statements about vitamin C that I have seen so far. Every bit of contrary evidence, no matter how feeble, that has been dug up or invented in the past seems to be mentioned here.

Mayer’s response was to further the criticism, with the next issue of the newsletter making mention that “no well-designed study has ever shown that vitamins at any level cure more psychiatric problems, including schizophrenia.” In response, Pauling wrote again to Mayer that “the statements about vitamins in relation to schizophrenia are completely wrong” and that “The impression that I have is that you are part of the group that makes little effort to discover the truth about nutrition.” Given that Mayer’s entire scientific career had been based on his expertise and devotion to the field of nutrition, Pauling’s words might be interpreted as having been particularly biting.

Though the two continued to battle in public from time to time, their conflict gradually fell from view. Regardless, the two never did arrive at any agreement on the validity of orthomolecular therapy, their feud only concluding with Mayer’s death on New Year’s Day, 1993.

Pauling’s Study of Schizophrenia: A Hearing Before the Connecticut State Senate

Linus Pauling, 1977.

[Part 7 of 9]

As we have seen, a primary objective of Linus Pauling’s work on schizophrenia was to establish the therapy as legitimate and to push it closer toward the mainstream. One opportunity to do so came about in 1977, when the Connecticut state legislature introduced to its docket two bills related to orthomolecular therapy. The legislation, which would add orthomolecular approaches to the roster of standard treatments offered to patients with mental illnesses, marked a unique opportunity for Pauling and others to prod orthomolecular treatments into the mental health mainstream.


On February 17, 1977, Pauling and five other prominent mental health researchers and practitioners, testified before the Public Health and Safety Committee at the Connecticut State Senate, providing their views on two bills that had been proposed: “Bill 5465: An Act to Provide Orthomolecular Therapy to Mental Patients;” and “Bill 5635: An Act Concerning Orthomolecular Therapy.” If passed, these two pieces of legislation would add orthomolecular medicine to the standard of care provided to patients at all of Connecticut’s state-run mental hospitals.

At the hearing, two factions – one pro and one con – identified themselves rather quickly. Pauling, along with three other people from the pro-orthomolecular camp, offered their testimonies first. And while each person spoke individually, the collective put forth a common core message: that orthomolecular medicine was safe, that the science behind the approach was sound, and that those in opposition were often unfair in their criticism.

In addition to Pauling, three others spoke in support of the bills: Bernard Rimland, Michael Lesser, and Carlton Fredericks. Rimland was a well-known psychologist from San Diego whose main area of research was autism. Lesser was a psychiatrist and president of the California Orthomolecular Society; he also served as the director of the U.S. Navy Drug Rehabilitation Program at the time of the testimony. Fredericks was a public health educator and host of a syndicated radio show where he discussed nutrition education. Two years prior to the hearing, Fredericks had been elected president of the International Academy of Preventative Medicine; he was also a founding member of the Academy of Medical Preventics.

Bernard Rimland. Credit: International Society for Orthomolecular Medicine

Among the first points that the speakers pressed was the basic idea that, as Rimland noted, “the use of vitamins and minerals in the treatment of mental disorders is by far the safest, most promising new treatment available.” Lesser reinforced this sentiment in adding that, “no one has ever successfully committed suicide using a vitamin substance.” Pauling also spoke to the issue, suggesting that “these vitamins – niacin and ascorbic acid, and the other B vitamins, pyridoxine – certainly do not have toxic side-effects, even when taken in large quantities.”

From there the speakers turned their attention to what they viewed to be invalid or undue criticism offered by a community of naysayers. Lesser pointed out that much of the negative press surrounding orthomolecular medicine had been drawn from inaccurate sources. Among these were the findings of an American Psychiatric Association task force that had relied on “classical drug research techniques” that, in Lesser’s view, “must be rejected as invalid.” Bernard Rimland added that

there is an extremely strong opposition on the part of major functions, or major persons of the medical profession, against any kind of nutritional approach toward the treatment or prevention of disease. And I think that the committee ought to be aware that when they have other people testifying, there’s going to be what I regard as a very irrational opposition; irrational and uninformed opposition to this form of treatment.

Carlton Fredericks seconded this idea, theorizing that “if we had a proposal to bring a new tranquilizer into your state institutions, there would be no problem, there would be no hearing and there would be no debate, despite the fact that tranquilizers can cause irreversible brain damage, despite the fact that they are at best palliative.” Fredericks further pointed out that when Pauling

addressed a subsection of the American Psychiatric Association in the 1960s on the subject of orthomolecular psychiatry, he was booed after he made his remarks. I cite this reluctantly but to separate the point that irrational opposition is more likely to be encountered than anything rational.

As they concluded their remarks, the speakers worked to emphasize the soundness of the science behind orthomolecular medicine. Following comments from Lesser on the seeming demonstration of “great long-term effectiveness” for the orthomolecular approach, Pauling made use of his deep understanding of the past work to argue that orthomolecular techniques had, in fact, been used for a long time. “While advances in medicine are notoriously slow,” he offered, “the cultural lag in this particular case is very aggravated, because contrary to what you have heard, orthomolecular psychiatry is not new. The Russians were using a B Complex vitamin in schizophrenia in 1943; it’s in their literature.”


After the proponents had given their testimony, the opposition had a chance to speak. During the hearing, just two people spoke against the bills, but their point of view was bolstered by several letters of opposition submitted before the hearing, most of them written by organizational representatives. These letters then became a part of the official hearing record, available for use by Senators to help them make their decision. One example letter was written by Richard Kramer, chair of the Connecticut Committee on Mental Health at the Connecticut State Medical Society. In it, he made clear that neither he nor his organization were in favor of the bills passing. In his own letter, the president of the Connecticut Hospital Association, Herbert A. Anderson, also indicated that he, along with “the great majority of psychiatrists do not support” the bills.

The two speakers who offered in-person opposition testimony were Howard Zonana, an associate professor of Psychiatry at Yale University, and Bruce Bower, an internist who worked for Hartford County Medical. Both men offered a similar, bifurcated message: 1) that orthomolecular therapy was dangerous; and 2) that the bills, if passed, would force physicians to kowtow to patients’ whims, even if their treatment requests were medically unethical or contraindicated.

In seeking to define orthomolecular medicine as unsafe, Bower argued that,

controversy surrounds this area because of the lack of objective scientific data demonstrating benefit [and] because of the intense anecdotal, but highly emotional basis of its popular appeal. Minimized in this furor are the well-defined results of the hazards of this form of treatment. For example, liver damage has been documented with megavitamin therapy employing nicotinic acid or vitamin B-6. Vitamin D causes elevation of blood calcium, elevation of blood pressure, kidney stones and kidney failure.

Zonana echoed Bower’s sentiments and added that vitamin B-3’s “toxic effects include jaundice, abnormal liver function, increased uric acid levels, hypotension and dermatological conditions.”

From there, the duo painted a portrait of conflicted doctor-patient interactions. If passed, the two claimed, the bills would force mental health practitioners to act unethically, by legally mandating them to use orthomolecular medicine even if it was contraindicated. “There is a dangerous precedent,” Bower argued, “which would be introduced into the practice of medicine through any statutory requirement that a physician provide orthomolecular therapy upon the demand of the patient.”

Bower further expounded that, “to give an untrained patient the legal ability to require the doctor to give ortho-molecular therapy when, in the physician’s professional judgment, it is not called for, creates a potentially counterproductive intervention in the medical management of the patient and other unnecessary point of friction in the delicate balance between the patient and the physician.” Zonana reinforced this point, stating his belief “that there is a difference in a patient electing a treatment with informed consent and a treatment being mandated for a population.”


Though both the pro and con sides of the hearing were invited to deliver prepared testimonies, Zonana and Bower were offered more time to share their remarks and, importantly, the presiding Senators asked questions of Zonana and Bower, but not of the Pauling group. The tenor and scope of these questions revealed that the Senators were in support of the Bower-Zonana position.

Bower was the first speaker to be questioned. When asked to provide sources for his claims that megavitamins are dangerous, he immediately had a source and a citation ready, noting that it had been retrieved from the “standard pharmaceutical text […] the bible.” Later, another Senator simply asked Bower to comment about vitamins, essentially offering an open invitation to continue speaking without constraint.

A different Senator asked Bower to elaborate on his fear that the bills might force “across the board decisions,” including a mandate that physicians prescribe orthomolecular treatments. In his response, Bower stated that not only was he fearful of potential ethical issues, he was also concerned that the legislation would create an environment where necessary testing and procedures would be ignored in order to comply with a legal mandate to pursue orthomolecular therapies. Bower also suggested that baseline tests for vitamin levels “themselves are controversial,” which could lead to mismanagement of dosing and further damage to the patient.

Senators approached Zonana in a similar manner and asked him similar types of questions. One of the final questions offered was, “do you, yourself, know of any miraculous cures” such as those touted by “these megavitamins or orthomolecular treatment?”

Zonana’s response? A terse and short, no. And the fate of the bills? Perhaps unsurprisingly, they did not become law.

Pauling’s Study of Schizophrenia: The Media

[Part 6 of 9]

Even in the starchiest Establishment criticism, there lurk phrases or hints that just maybe Linus and his buddies have something – if only they would get their ducks of scientific proof in line. Lest the future catch a critic out, no one wants to say Pauling is dead flat wrong.

-Barbara Yuncker, New York Post, October 25, 1974

As with the scientific community, Pauling’s work on schizophrenia experienced a mixed reception in the media, with some commenters offering acclaim and others classifying the approach as inappropriate or even harmful. Perhaps unsurprisingly, Pauling found much of the negative press to be a misrepresentation of his or his colleagues’ work, and he did not shy away from fighting back, both in public and in private. In doing so he was seeking, of course, to maintain and uphold his image as a legitimate scientific researcher, but also to guard against the derailment of a therapy that he felt had great potential for improving the lives of many patients suffering from a terrible affliction.

One notable entanglement with a publication came in 1975 and centered around a Medical World News article titled, “Megavitamins and Mental Disease: Useful Therapy or Wishful Thinking?” Pauling found many of its claims to be wildly inaccurate and wrote to the publication’s editor, Howard Cohn, to express his objections. One of Pauling’s biggest complaints was the article’s assertion that, in a two-year double-blind study conducted by Rutgers University psychologist Richard Wittenborn, schizophrenia patients treated with niacin had experienced an “alarming side effect.” In actual fact, the observed side effect was nothing more than a mild skin rash that quickly dissipated.

For Pauling, this willingness to sensationalize “probably misled some [readers] into accepting a wrong conclusion about the toxicity of niacin.” In addition, “there is no certainty that even this benign and transient effect is a side effect of niacin [because no other] psychiatrists who have given megadoses of niacin to thousands of patients over very long periods of time” had reported a similar finding. In his letter to Cohn, Pauling asked that Medical World News publish his objections as well as a retraction. The editor responded that he was unable to publish Pauling’s defense, “owing to inevitable space limitations.”

Pauling remained intent on correcting misrepresentations of orthomolecular therapy in the media, and was also keen on collecting reports that pointed out the inefficiencies of more traditional schizophrenia therapies. For example, Pauling saved and highlighted a June 27, 1979 San Francisco Chronicle piece titled, “Shock Therapy – Not as Bad as it Sounds?” Despite its title, the article’s author notes that shock therapy is oftentimes not effective, and that as many as thirty percent of treated patients “are just not having any response.” Pauling believed that his approach might offer a solution for those thirty percent, as well as many others who responded more favorably to a therapy that, regardless of its benefit, still posed the threat of multiple side effects.


There were, however, moments where the press responded more favorably to Pauling’s perspective. In 1968, shortly after Pauling published his first article on the subject, the San Diego Union reported that “one of the country’s ablest chemists” had put forth an idea that was “quite promising.” As time moved forward and criticisms began to emerged, other newspapers offered more cautiously positive assessments. In one instance, published in April 1973, a San Jose Mercury staff writer noted Pauling’s belief that the controversy surrounding his schizophrenia work would lead to “more thorough clinical tests which…will confirm [his] claims.”

Supporters also took to the papers to press their case. One reader, Rae Irene Plick, wrote to the editor of the New Jersey Star-Ledger to express dissatisfaction with recent negative coverage of Pauling’s work. Plick made clear that she had personally benefited from megadosing therapy and, as a result, knew firsthand how effective it could be. “[F]or those of us whose families have experienced success with megavitamin therapy,” she wrote, “we can only shake our heads sadly to think of all the patients who are being deprived of this modality of treatment by so-called traditional psychiatrists.”

A higher-profile writer who likewise offered support was Barbara Yuncker, an award-winning science journalist and editor. In an October 1974 New York Post piece titled “Schizophrenia: New Treatment,” Yuncker praised Pauling’s efforts. Though acknowledging that “megavitamin therapy … has never moved into the mainstream of mental illness therapy” the concept was almost two decades old and “has been adopted by a few doctors and some patients and their families with a fervor akin to that of Bible Belt Fundamentalists.” Yuncker was clear that all credit for this rise in popularity – even modest though it may be – should rest solely with Pauling and his “unquenchable gadfly energy.” Yuncker further noted that

the critics may – and do – call orthomolecular medicine offbeat, far-out, insufficiently proven experimentally, questionable in some of its methodology – in short, a bit wacky. But they can’t – and don’t – call it quackery.

The “they,” in this case, was the “Establishment,” which was firmly against Pauling. More specifically, Yuncker pointed out that federal bodies were discouraging the use of megavitamins and that the American Psychiatric Association had formally decried Pauling’s approach. But for Yuncker, what mattered most was that the research was based in legitimate science and often seemed to be effective. These were reasons enough to keep the conversation about orthomolecular psychiatry alive.

Pauling’s Study of Schizophrenia: Support

[Ed Note: The Pauling Blog becomes a teenager this week! On March 4, 2008 we introduced ourselves to the world with our first post. Thirteen years later, we’re thrilled to be publishing post 5 of 9 in our series on schizophrenia, and post number 810 overall. Our continuing thanks to the many readers who have helped make this such a rewarding experience for the duration.]

As we have seen, Linus Pauling’s work on the use of orthomolecular therapies as a treatment for schizophrenia never attracted anything like widespread acceptance from mainstream psychiatric and psychological professional organizations. But despite this, Pauling’s ideas did attract attention and respect from other corners of the mental health profession, both individuals and groups.


In addition to Abram Hoffer and Humphry Osmond, another early proponent of the orthomolecular approach to schizophrenia was Harry Vanderkamp, who worked for the Veterans Administration Hospital in Battle Creek, Michigan. Notably, in 1966 Vanderkamp published an article in the journal Neuropsychiatry titled, “A Biochemical Abnormality in Schizophrenia involving Ascorbic Acid.” The paper, which Pauling noted and which actually preceded his own first publication on the topic by about two years, echoed the basics of Pauling’s core thesis; that schizophrenia could be successfully treated through megavitamin dosing. In the article, Vanderkamp specifically argued that schizophrenia patients could “metabolize ten times as much [vitamin C]” as those without schizophrenia and that, as such, one might reasonably draw a connection between schizophrenia diagnosis and low levels of vitamin C.

The ideas of Vanderkamp and others informed Pauling’s first formal paper on the subject, “Orthomolecular Psychiatry: Varying the Concentrations of Substances Normally Present in the Human Body May Control Mental Disease.” The article appeared in the April 1968 issue of Science, and attracted a great deal of interest. One particular outcome was a series of invitations to speak on the topic at Tulane University, which invited Pauling to address the school’s entire medical school in May 1970 and again in March 1971. Pauling was chosen for this honor by unanimous decision of the school’s faculty and students, and in both instances the title of his lecture was simply, “Orthomolecular Medicine.” The same was true for a spring 1971 lecture at the University of New Brunswick, as well as four other major talks delivered between 1968-1972.


Pauling also found traction with the American Schizophrenia Foundation following the 1968 publication. Shortly after it appeared, the organization (which later changed its name to the American Schizophrenia Association), offered Pauling space in its newsletter to expand upon his academic work and defend his ideas as necessary. Pauling took advantage of this offer and in the October 1968 issue wrote that megadosing was safe and effective, and that any “psychiatrist who refused to try the methods of orthomolecular psychiatry, in addition to the usual methods, is failing in his duty as a physician.”

Two-and-a-half years later, despite the negative press that Pauling was receiving, the ASA granted Pauling an undisclosed monetary award and provided an additional $1,000 to Stanford University – where Pauling was working at the time – to support continued research on the orthomolecular approach to schizophrenia. Later that same month, the association’s journal, which had been titled Schizophrenia, changed its name to the Journal of Orthomolecular Medicine. At the time of the change, the journal was being edited by Abram Hoffer, who wrote to Pauling that the new name “more accurately reflects the spectrum of [the publication’s] concern.”

Other academic support for Pauling came from the Journal of Autism and Childhood Schizophrenia. Founded in 1971, the journal’s first editor was Leo Kanner, a leading figure in child psychiatry. From the start, Kanner wanted Pauling to serve on the journal’s board as a contributing editor. Pauling accepted this offer and remained a member of the board until 1979, when the mission of the publication changed. But during those years of association, Kanner stressed that Pauling’s role as a contributing editor boosted the publication’s name recognition and, importantly, its credibility. Pauling seemed to enjoy the connection as well, joking at one point that, “Years ago I was a member of the Editorial Board of J.A.C.S. It was, however, the Journal of the American Chemical Society.”


In 1973, when negative press surrounding megadosing crested in the wake of the American Psychiatric Association’s damning task force report, a second round of support for Pauling and orthomolecular medicine emerged in response. In private correspondence, colleagues like J.B. Drori, Chairman of the Committee of Education at John Muir Memorial Hospital, wrote that despite the fact that Pauling’s ideas “have not been widely accepted,” they still “seem to make a lot of sense to me.” Likewise Dr. C. David Geer, chair of the New Jersey Schizophrenia Foundation, who publicly lauded Pauling’s work, noting to a reporter that his own research on megadosing had come to pass as a result of the momentum that Pauling had brought to the field.

And Pauling naturally retained the support of his friends. High among them was Humphry Osmond, who often rallied around Pauling and offered public praise. So too Abram Hoffer who, in a piece detailing historical advances in schizophrenia treatment, wrote of the late 1960s that “Dr. Linus Pauling’s concept of orthomolecular psychiatry seemed most appropriate at the time and still does.” For Hoffer, Pauling was clearly “a major historical root” for the field.

Hoffer and Pauling’s professional connection eventually evolved into a tight friendship. In 1986, for example, Hoffer was invited to celebrate the launch of an endowed orthomolecular chair at Ben Gurion University in Israel. In agreeing to do so, Hoffer further suggested that Pauling’s presence would be a “a major attraction” and “a marvelous opportunity to promote [his] books.” (and thus the benefits of orthomolecular medicine). Hoffer, who often referred to Pauling simply as “Linus” in their correspondence, ultimately covered the full cost of Pauling’s trip to Israel.

On another occasion, Hoffer arranged for a “Linus Pauling Reception Dinner,” which was held to raise funds for the Canadian Schizophrenia Foundation, with Pauling set to receive half of the proceeds. At a rate of $25 per person and $45 per couple, Pauling’s share of the gate was $4,275.46. This model of generating support and raising money for orthomolecular causes was so successful that the foundation set up another lecture series for Pauling in 1992. Even though Pauling announced that he had cancer in February of that year, he was determined to attend the event to support Hoffer and to help raise funds for an organization that he believed in.

Pauling’s Study of Schizophrenia: Pushback

[Wishing an early happy birthday to Linus Pauling, who would have turned 120 years old this coming Sunday. To celebrate, we continue our survey of his work on schizophrenia; this is part 4 of 9.]

I feel that the use of substances normally present in the human body for improving health of human beings, and especially their mental health, has been unjustifiably ignored by the medical profession for some thirty or thirty-five years now, and that the possibilities of improvement in the health of the American people and of other people in the world by improved nutrition are truly great.

-Linus Pauling, speech to the American Schizophrenia Association, July 1971.

Though lauded in smaller circles, Linus Pauling’s work on the orthomolecular treatment of schizophrenia failed to earn the support of the mainstream psychiatric community. Members of the American Psychiatric Association (APA) and the National Institute of Mental Health (NIMH) for example, tended to marginalize Pauling’s ideas as existing on the fringe, and certain of their objections were quite critical.

Pauling’s disagreements with the psychiatric mainstream dated back several years. In one instance, at the 1956 annual meeting of the American Psychiatric Association in Chicago, Tulane University psychiatrist and researcher Robert Heath put forth an argument that schizophrenia was caused by misshapen protein molecules. For an “electrified audience of 4,000,” Heath’s ideas were viewed as extremely promising, particularly because of their implications for targeted treatment. Pauling though, was wary of the findings, and went to the media to caution that the results not be interpreted “too broadly.”


As time moved forward, one of the entities with whom Pauling most found himself at odds was the NIMH. Though Pauling had received grant funding from the NIMH, for many within the organization, his work had never delivered concrete or compelling evidence supporting the orthomolecular approach to schizophrenia. Many at the Institute also disagreed with the theoretical arguments underlying Pauling’s work.

These criticisms of Pauling’s ideas were voiced amidst a broader acknowledgement of the urgent need for more effective schizophrenia treatment options. By 1970, the situation had become so dire that the NIMH commissioned a special team to write a report on the subject. In it, the authors warned that schizophrenia diagnoses were increasing, with “more than 200,000 Americans…hospitalized” and an additional 2-6% of the U.S. population believed to have suffered at least one schizophrenic episode. These staggering numbers were estimated to be costing the country some “$14 billion [approximately $92 billion in 2020] annually.” The authors further warned that the magnitude of the actual problem was almost certainly even larger still, noting that “chronic institutionalization throughout the individuals’ most productive years…in terms of personal suffering and loss of productivity, are devastating.”

For these researchers then, the current state of schizophrenia in the United States was frightening; the costs to treat were high and the number of people suffering from the illness was growing at an alarming rate. Moreover, the current standard of care for schizophrenia – hospitalization and tranquilizers, namely – did little to alleviate these problems. Schizophrenia seemed to be a disease brimming with unanswered questions and hampered by partial solutions.

But even given this context, the NIMH report offered little enthusiasm for Pauling’s approach. Though the authors acknowledged that he had “made a major methodological contribution by developing new automated techniques for screening large numbers of samples of urine and other body fluids for screening abnormalities of vitamins and other essential nuritivites,” Pauling’s hypothesis was deemed “extremely proactive” and the “interpretations of [his] findings must wait further work.”


The controversy surrounding megadosing did not end with the NIMH report; the American Psychiatric Association (APA) had its own hesitations about Pauling’s findings and initiated its own study to try and replicate them.

The head of the APA study group was Dr. Morris Lipton, founding director of the Biological Sciences Research Center at the University of North Carolina School of Medicine and, at the time, deputy editor of the American Journal of Psychiatry. In the estimation of Pauling’s colleague Bernard Rimland, Lipton was also the “psychiatric establishment’s most vociferous and outspoken opponent to the megavitamin treatment.” For Rimland this was obviously problematic, because it meant that Lipton was far from impartial and that any assertions made by the task force would be colored by his point of view.

In mid-1973, after four years of data collection, the six-person task force published its results, which the APA itself characterized as a “broadside assault on megavitamin and orthomodular therapy in treatment of schizophrenia.” In their report, the task force noted in particular that they had found it difficult to “replicate studies” because of a perceived lack of sophistication underlying orthomolecular-based experiments. In this vein, megadosing studies had too often been tarnished by subjectivity and, for the task force, their results were “found wanting.”

In the estimation of the task force, the whole notion of “orthomolecular psychiatry” was “a misnomer,” the report’s authors adding that “there is nothing orthomolecular about” the way Pauling and his colleagues had been treating patients. The task force also made clear that prominent psychiatrists in the field agreed with their assessments and did not believe in vitamin megadosing.


The APA results were unveiled in July 1973 at the Kittay Scientific Foundation’s first international symposium, and unfortunately for Pauling and his supporters, the task force report was not the only negative press to emerge from the gathering. One of the conference presenters was John R. Wittenborn, the director of the Inter-Disciplinary Research Center at Rutgers University, who shared the results of an 18-month study that he had conducted on eighty-six patients with schizophrenia. Wittenborn’s project involved dosing a portion of the patient group with megavitamins while witholding them from a second control subset, and like the APA study, the work was done independently of Pauling. As with the task force, Wittenborn had found little to support Pauling’s research, noting that, after all factors had been controlled for, there were “no significant differences” in outcome for the study group versus the control group. In fact, the experimental patients – those who were given the vitamins – “may have been a bit worse off.”

Others at the symposium found Pauling’s work to be doubtful from a theoretical standpoint. One participant, Yale geneticist Leon Rosenberg, acknowledged that some diseases could be cured through megadosing, but that schizophrenia was not one of them. In cases where vitamins could cure disease, Rosenberg argued, there had always been a “very clear correlation between the particular biochemical defect and the rationale for the vitamin.” But in the case of schizophrenia, “no evidence exists” that there is a particular biochemical defect.

Ultimately, the Kittay symposium gave license to other scientists to express their disagreement with Pauling’s orthomolecular work. Dr. Michael Mendelson, director of the New Jersey Psychiatric Neuropsychiatric Institute, summed up the view of many in stating, “I believe in anything that is effective,” but “in my opinion megavitamins have not proven themselves.”

Pauling’s Study of Schizophrenia: A Program of Work

[Part 3 of 9]

I feel, accordingly, that it is the duty of every psychiatrist to add megavitamin therapy, orthomolecular methods, to his armamentarium, and to make use of these vitamins, to try them out in proper amounts, not just by doubling the recommended daily allowance, but in the proper amounts as discussed by Dr. Hoffer and others here as having been found to be effective for many patients.

-Linus Pauling, speech to the American Schizophrenia Association, July 1971

Upon learning about the potential that vitamin megadosing might have for improving the lives of people suffering from schizophrenia, Linus Pauling quickly began thinking about a new research program. This process was only accelerated by his interactions with Irwin Stone, who introduced vitamin C as a potential tool for attacking mental disease, among other health maladies. One piece that Pauling still needed however, was a more complete understanding of how best to run the types of experimental trials that he had in mind. To bridge this gap, Pauling once again turned to the literature, reading everything that he could find that was even remotely related to orthomolecular protocols.

One interesting resource that Pauling consulted amidst his information gathering process was the Veteran’s Administration. Specifically, in June 1967 Pauling asked the VA’s chief of psychobiology research, Arthur Cherkin, to provide a digest of all research that had been done by the federal agency on the correlation between mental disorders with nutrition, protein deficiencies, and vitamin deficiencies. Cherkin was happy to help, supplying Pauling with notes on some 500 different studies that involved these topics.

A few months later, Pauling also reached out to Humphry Osmond to ask if he knew of any “psychiatrists, especially in California, who are sympathetic to the use of nicotinic acid, nicotinamide, and ascorbic acid in the treatment of schizophrenia.” What seems to be clear in these exchanges is that even though Pauling had read reports about the design and effectiveness of other trials, he was still pondering how best to organize his own experimental approach.


By December 1967, Pauling was feeling more ready to begin his research. His careful reading of the literature had convinced him that schizophrenia could be caused by a nutritional imbalance of nutrients, and that orthomolecular therapy could be of great benefit. He also had a good idea about the analytical tool that would drive his experiments.

From the beginning, Pauling worked closely with his University of California – San Diego colleague (and former Caltech student) Art Robinson. Together they collaborated with County University Hospital in San Diego to conduct human trial nutrient tests on patients with schizophrenia. The study initially tested the trial group’s capacity to absorb vitamin C, and was later repeated to analyze absorption of vitamins B3, B6, and B12. Importantly, as he had done in the 1940s, Pauling once again relied upon urinalysis to compile his data. In the County University Hospital trials, subjects’ urine was collected and analyzed both before and after dosing with vitamin C, which was ingested in the form of orange juice.

Art Robinson, 1974.

Though the urinalysis approach had proven unsuccessful in the 1940s work, Pauling was inspired to try it again as a result of his more contemporary reading. In one particularly relevant research notebook entry, dated July 25, 1967, Pauling analyzed a 1966 paper in which author H. VanderKamp reported on his use of urine sampling to investigate ascorbic acid and thorazine treatments for schizophrenia patients. The idea was clearly enticing for Pauling, who wrote in his journal that day, “Could a urine test be useful in diagnosis?” The answer proved to be yes, and by the time Pauling was running his human subjects trials in San Diego, he had fine tuned his approach. To test the amount of vitamin C present in a urine sample, Pauling and Robinson would use gas chromatography to detect the presence and quantities of aromatic compounds that are created when vitamin C reacts with alcohols.

The initial trials showed promise, with “all patients elevat[ing] to normal levels [of vitamin C] after eight days” of treatment. This finding aligned with Pauling’s hypothesis that vitamin C levels in schizophrenics were too low, and that through supplementation they would be able to reach “normal” levels in a relatively short period of time.


Pauling and Robinson’s first data set was exciting enough that they decided to apply for funding to expand the scale of their project. In mid-1968, the duo submitted a grant proposal titled “Orthomolecular Psychiatry – Diagnosis and Therapy” to the National Institutes of Health, requesting $336,945 (roughly $2.7 million in 2020 dollars) to support work conducted from January 1, 1969 to December 31, 1973.

The proposal outlined a plan that would follow the same general procedure as before, centering around the administration of “oral doses of substances and then to analyze samples of urine” using “chemical, microbiological, spectrophotometric, and gas chromatographic methods.” The substances that Pauling and Robinson planned to test were “ascorbic acid [vitamin C], nicotinamide [B3], pantothenic acid [B5], cyanocobalamin [B12], and pyridoxine [B6].” However, unlike the previous study, this project would also make use of controls – people who did not have schizophrenia – including “nurses, physicians, students, [and] faculty members.”

In justifying the proposal, Pauling admitted to grand ambitions, stating that

We are not attempting to carry out a definitive test of a well-defined hypothesis, but rather to discover something about mental disease. I hope that it will turn out that what we are doing now is analogous to what my coworkers and I did between 1945, when I had an idea about the nature of sickle-cell anemia, and 1949, when Drs. Itano, Singer, and Wells and I published our paper, “Sickle Cell Anemia, a Molecular Disease.”


The study was funded, and also happened to coincide with a period of rapid change for Pauling, whose institutional home shifted from UCSD to Stanford to the Institute for Orthomolecular Medicine (co-founded by Pauling and Robinson) during the lifetime of the grant. Despite all these transitions, Pauling published a number of papers as a result of the grant, all of which emphasized a positive relationship between vitamin megadosing and improved health for schizophrenia patients. As its profile rose, the work also began to attract interest from additional funding sources including, as communicated in a 1978 letter from Art Robinson, “the Multiple Sclerosis Society, the Educational Foundation of America, the National Cancer Institute, and the National Institute of General Medical Sciences.”

As the program moved forward, Pauling continued to devote time and energy to perfecting experimental design and minimizing side effects for trial participants. In his correspondence with Humphry Osmond for example, regular attention is given to defining proper dosages and best practices for maximum absorption. Taking supplements with Coca-Cola was, for instance, ill-advised, and so too with caffeinated coffee. Concerns were also raised about the sugar content in fruit juices, and eventually pure glucose was used to sweeten the vitamin C trial drinks. Likewise, milk was not recommended for any person of African or Asian descent, and at least two or three grams of bran were to be given to all patients per day “to help avoid the use of laxatives” often needed by those taking high doses of antipsychotic drugs.


One major trial that involved Pauling and Robinson as collaborators was titled “Urine Biochemistry in Schizophrenia and the Effects of Vitamin Loading,” and was carried out at the Agnews state mental hospital in Santa Clara, California. Pauling and Robinson were primarily asked to take charge of analyzing urine samples collected from the 200 schizophrenic patients recruited into the study, but the importance of Pauling’s past work clearly permeated the new trial. In the study’s introduction, lead researcher Maurice Rappaport pointed out that

Pauling, on the basis of previous research, has reached the conclusion that there are differences in the metabolism of ascorbic acid, nicotinic acid and pyridoxine between those who are in good mental health and those who are in poor mental health. Specifically he reports that among the mentally ill as compared to the mentally well, ‘there is a much larger group of people with unusually high requirements for one or another of these three vitamins.’

The sum result was

a theory of mental ill health based upon the fact that a man’s normal diet does not always supply the amount of essential nutrilites necessary to establish an optimal molecular environment for his mind. Further, [Pauling] has suggested that there are biochemical variations in some men which cause their requirements for essential nutrilites to be so unusual that the failure of their diet to satisfy these requirements results in mental illness.

Clearly Pauling’s work had made a significant impact in a short period of time. But, as we shall see, signs of trouble were soon to appear.

Pauling’s Study of Schizophrenia: A New Model Vitamin

Irwin Stone. (Image by Oscar Falconi)

[Part 2 of 9]

“I have decided, on the basis of the evidence presented by Irwin Stone, that there is very strong evidence now, that most human beings are suffering from hypoascorbemia, a mild sort of deficiency of ascorbic acid in the blood; perhaps it is wrong for me to call it a mild sort. The point that I call to your attention is that I believe that for all or almost all human beings, the amount of vitamin C that is contained in the food is less that the optimum amount, and that the state of health of almost all human beings is not so good as it would be if they were to ingest a larger amount.”

-Linus Pauling, speech to the American Schizophrenia Association, July 1971.

Linus Pauling’s chance encounter with the work of Abram Hoffer and Humphry Osmond convinced him that metabolic diseases could be treated by megadosing with certain vitamins; a practice that he labeled “orthomolecular medicine.” As Pauling’s interest in the topic grew, he sought out as much of the existing scientific literature as he could find, and quickly began to see a pattern.

As early as the 1940s, there seemed to be evidence of a positive correlation between increased niacin intake and improvement of certain psychoses in patients. The literature also supported Hoffer and Osmond’s finding that vitamin megadosing was not likely to cause significant side effects. On the contrary, many of the era’s commonly prescribed anti-psychotic drugs often caused severe side effects, sometimes even at low doses. The benefit of this new alternative was made clear by Osmond in a 1970 letter to Pauling, in which he noted that

[we are] dealing with a set of highly physiologically active substances [such as niacin] which do not, however, seem to produce the sort of danger which one finds in most physiologically active substances.

Though Pauling was convinced that orthomolecular therapy was effective, his continuing review of the literature cast doubt on whether or not niacin was, in fact, the most effective vitamin to use in treating patients with psychoses, such as schizophrenia. Though niacin was clearly safe, certain investigators had reported marginal success rates with their patients. Enough data of this sort had been reported to lead Pauling away from niacin and in the direction of a new vitamin. It was here that Irwin Stone entered his life.


In March 1966, Pauling traveled to New York to accept an award from the Carl Neuberg Society for International Scientific Relations. In his speech, Pauling – then sixty-five years old – expressed hope that he might live for another twenty years, so that he might witness the scientific advances that he believed to be forthcoming. Irwin Stone, a biochemist who worked mostly in the brewing industry, was in the audience that evening, and he felt as though he could virtually guarantee another twenty years or more for Pauling.

In a letter that he wrote after the speech, Stone told Pauling about research that he had been conducting on the health effects of vitamin C, stressing that he had been megadosing with the vitamin for the past few years and was healthier than ever as a result. In relaying this, Stone acknowledged that the story seemed implausible and admitted that he had remained a bit skeptical himself until he was involved in a car accident. Buoyed by his high dose vitamin C regimen, Stone recovered from the incident far faster than he or his doctors believed possible, and from then on he had been convinced. In Stone’s view, vitamin C would easily buy Pauling another twenty years, and maybe up to fifty!

When Stone sent his letter, he could not have known that Pauling was hatching his own interest in orthomolecular medicine; Pauling’s first paper on the subject did not appear until a year later. As such, Pauling knew that Stone’s testimony was not informed or biased by previous knowledge of his work. The letter did, however, add to Pauling’s growing belief in power of high dose supplementation in the treatment of disease. Likewise, Pauling had also been given a new model that he might explore for mental illness in lieu of the niacin trials conducted by Hoffer, Osmond and others. The next step then, was to see how effective megadoses of vitamin C might be for patients suffering from schizophrenia.

Pauling’s Study of Schizophrenia: Origins from Hoffer and Osmond

Abram Hoffer and Linus Pauling at the symposium, “Adjuvant Nutrition in Cancer Treatment,” Tulsa, Oklahoma, November 1992.

[Part 1 of 9]

“If there is evidence, for example, that an increased intake of ascorbic acid decreases the amount of illness with the common cold and other diseases, and the evidence is in fact strong, it is not improper to recommend that parents give vitamin C to their children, to see if it leads to an improvement in their health. In the same way orthomolecular (megavitamin) treatment of schizophrenia, in addition to the conventional methods of treatment, is justified by the facts that a good number of psychiatrists have reported it to be of value and there is little danger in serious side effects from the vitamins.”

-Linus Pauling for the Journal of Autism and Childhood Schizophrenia, November 1974    

Orthomolecular Medicine, loosely defined as the pursuit of optimal health through the intake of the “right molecules” in the “right amounts,” is the discipline that defined Linus Pauling’s work for the last three decades of his life. The undertaking marked a dramatic shift away from the research that Pauling had pursued previously; work that garnered him a reputation as one of the leading scientists of the twentieth century. The shift was made all the more dramatic by the level of commitment that Pauling made to pursuing this new area of study: not only did he write multiple books on the topic, he also co-founded an institute to explore new ideas on orthomolecular medicine.

Today, the bulk of Pauling’s research output on orthomolecular topics centers on the use of vitamin C to treat the common cold and cancer. Less known is the fact that Pauling’s initial foray into orthomolecular topics focused on the treatment of schizophrenia.


One might propose that Pauling first became interested in orthomolecular treatments for mental disorders as the result of happenstance and boredom. In 1965 Pauling visited a psychiatrist friend in Carmel, California for a party. When his interest in socializing began to wane, Pauling wandered the house and picked up a book that seemed interesting, Niacin Therapy in Psychiatry, by the Canadian scientist, Abram Hoffer. As Pauling would soon learn, the book focused on treating schizophrenia with vitamins, specifically niacin. This idea was new to Pauling and provoked considerable interest.

Humphry Osmond, 1972

In his book, Hoffer detailed the experimental work that he and a colleague, Humphry Osmond, had conducted to demonstrate the positive impact that high levels of niacin – one of the B vitamins – made on the mental functioning of patients with schizophrenia. In these trials, Hoffer and Osmond had treated their patients with megadoses of niacin and other vitamins that were routinely more than a thousand times higher than the recommended daily allowance. The duo reported that, through years of megadosing, their patients never experienced negative side effects and often found relief from their illness. In effect, Osmond and Hoffer had seemed to find an effective treatment for schizophrenia that bore few to no side-effects. This accidental book that Pauling picked up would help start him down a path to studying the orthomolecular treatment of mental illness.  


Even though Pauling had found Hoffer and Osmond’s book interesting, he did not initially understood how his own scientific background could be applied towards orthomolecular approaches. But a bit of further reflection on work that he had done decades earlier helped to clarify the connection and prompt a new round of investigations.

In the 1940s, Pauling had tried to see if he could diagnose phenylketonuria (PKU) through a simple urine test. PKU is a birth defect that diminishes one’s ability to properly break down amino acids. If left untreated, the resulting build-up of amino acids can lead to mental disabilities, seizures, and even death. Pauling thought that it might be possible to diagnose PKU patients by conducting laboratory analyses of enzymes that were naturally excreted through urine. Though this specific project ultimately proved unsuccessful, Pauling believed that his failures were not due to problems with the theory, but instead could be sourced to inferior technologies of the era that were not sensitive enough to make a proper analysis. Years later, when reading about Hoffer and Osmond, Pauling realized that he could apply urinalysis to their work.

For PKU patients suffering from an enzyme imbalance, health could be restored by ingesting doses of supplemental enzymes. Pauling extended this model to Osmond and Hoffer’s results, suggesting that niacin succeeded in reducing patients’ symptoms precisely because schizophrenics were suffering from an imbalance of enzymes; megadosing was a means of restoring balance in their brains.

In a 1967 paper, Pauling made it public that he had been working and ruminating on the concept of megadosing. He used the same publication to define this specific type of orthomolecular therapy as, “the treatment of mental disease by the provision of the optimum molecular environment for the mind, especially the optimum concentration of substances normally present in the human body.” He would go on to posit that “The functioning of the brain and nervous tissue is more sensitively dependent on the rate of chemical reactions than the functioning of other organs and tissues.” As such, “I believe that mental disease is for the most part caused by abnormal reaction rates, as determined by genetic constitution and diet, and by abnormal molecular concentrations of essential substances.”


Pauling’s realization that his past urinalysis work could connect with orthomolecular therapy was just one reason why he became involved in the research. Pauling was also driven by a fundamental belief that the human need for certain vitamins, such as vitamin C, was an evolutionary phenomenon. According to Pauling,

the process of evolution does not necessarily result in the normal provision of optimum molecular concentrations. Let us use ascorbic acid [vitamin C] as an example. Of the mammals that have been studied in this respect, the only species that have lost the power to synthesize ascorbic acid and that accordingly require it in the diet [in addition to humans] are many other primates (rhesus monkey, Formosan long-tail monkey, and ring-tail or brown capuchin monkey), the guinea pig, and an Indian fruit-eating bat.

By extension, this evolutionary precedent might also imply that, even though certain enzymes are essential, they are still not readily produced in the quantities that we need. Pauling postulated from there that mental imbalances, sometimes manifesting in illnesses such as schizophrenia, could be a result of inherited enzyme imbalances.

Pauling also knew that deficiency diseases such as scurvy (which results from a deficiency in vitamin C) and pellagra (which results from a deficiency in niacin) can both manifest as mental illnesses. People with scurvy often suffer from mood changes and depression, and people with pellagra are sometimes beset by hallucinations or dementia. This correlation between mental illness and nutritional deficiency was echoed by Abram Hoffer, who wrote that, “if niacin was removed entirely from food, everyone would become psychotic in one year.”


Eventually, numerous other maladies would fall under Pauling’s definition of an orthomolecular disease. Diabetes, for instance, was the result of an insulin imbalance and its treatment entailed the injection of insulin, therefore it was an orthomolecular disease. Goiters too were seen as an orthomolecular disease because they occur as a result of iodine imbalance and were treated with iodine dosing. Even cavities could be viewed through an orthomolecular lens, given their prevention with supplemental fluoride. Possibilities of this sort fascinated Pauling and would consume much of his time in the years to come.

Sickle Cell Research to the Present and the Future

Three-dimensional rendering of sickle cell anemia blood cells. Credit: National Institutes of Health.

By Dr. Marcus Calkins, Part 3 of 3

Forty years after Linus Pauling and his lab demonstrated the molecular basis for Sickle cell disease and James Watson speculated that upregulation of fetal hemoglobin may protect from the disease, methods to control fetal hemoglobin specifically in red blood cells began to be developed. The molecular biology revolution of the late 20th century had produced extensive knowledge about the molecular systems that drive fetal hemoglobin production, but harnessing that intricate knowledge has taken another thirty years.

Hematopoietic Stem Cells (1990s)

Since the advent of radioactivity research, it has been well-established that red blood cells have a short lifespan of only about 115 days and are continually produced from precursors in the bone marrow. In order to replace defective blood cells in an individual, a protocol for whole-body irradiation and allogenic bone marrow transplant was pioneered by a group of doctors in Seattle in the 1970s, as a treatment for cancer patients.

However, the ability to specifically isolate and identify hematopoietic stem cells from patients was only developed in the 1990s. At that time, nuclear dye exclusion and flow cytometry characteristics were used to isolate the stem cells, but since then, a variety of cell surface markers have been identified, and protocols to isolate, expand and differentiate hematopoietic stem cells have become standardized. In addition, scientists have learned to modify the hematopoietic stem cells at a genetic level, creating the possibility that stem cells may be extracted, genetically modified ex vivo, and then used to reconstitute the bone marrow of patients with blood diseases.

For patients with Sickle cell disease, it may therefore be possible to extract hematopoietic stem cells and inactivate the BCL11A gene, which normally suppresses fetal hemoglobin. The red blood cell progeny of these altered stem cells would then produce fetal hemoglobin that could mask the effects of the disease-causing mutation in the β-globin gene. Afterward, the modified stem cells could be transplanted back into the same patients from which they were isolated, providing the person with a continual supply of red blood cells that expresses fetal hemoglobin and are resistant to sickling.

Gene Therapy and Genome Editors (2000s-2010s)

The final component of a therapy for Sickle cell disease has recently been realized, as it is now feasible to efficiently inactivate BCL11A in isolated hematopoietic stem cells. In the last two decades, several systems of modifying the genome (gene editors) have been developed. Although the first editors to be produced may still find clinical use, CRISPR has quickly overtaken previous technologies to become the most widely applied and well-known gene editing platform.

In the late 1990s, researchers invented two key methods of using proteins to make targeted edits to the genome. These early gene editor proteins are called TALENs and Zinc fingers, both of which are being tested in clinical trials today. Each of these editors is able to target highly specific DNA sequences and make an incision in the DNA helix at a predictable site. Once the DNA strand is incised, error-prone DNA repair processes are activated to fix the incision, often resulting in random base insertions, deletions and changes. In this way, the genetic code is disrupted in some cells, and these random disruptions often serve to inactivate the targeted gene. If those cells with an inactivated gene can be identified and expanded, whole populations of cells with the genetic alteration can be established.

The comparative difficulty of using TALENs and Zinc finger proteins instead of CRISPR is that targeting a particular site in the genome often requires a major technical effort. Since the proteins themselves target the DNA sequence of interest, each target sequence must have its own specialized editor. The introduction of CRISPR/Cas9 in the early 2010s allowed researchers to target various DNA sequences much more easily. This system uses a short guide RNA molecule for DNA targeting, so the same protein can be used to cut any genomic site. Since generating these guide RNAs is a relatively simple procedure, the amount of effort required to design and execute genome edits is greatly reduced.

Theoretically, TALENs, Zinc fingers and CRISPR could all be used to inactivate BCL11A in hematopoietic stem cells. However, design of an appropriate TALEN or Zinc finger might require relatively large investments of money and time.  On the other hand, CRISPR promises to be a more cost-effective and faster approach to editing the genome. In academic studies, CRISPR is already widely used and far more common than the other editing technologies for making genetic modifications to laboratory model organisms. However, with human patients, safety and efficacy greatly outweigh effort and cost. Time will tell which gene-editing platform proves to be most cost-effective, efficient and safest for clinical use.

A New Clinical Reality (2020s)

With these new tools at hand, Watson’s dream of increasing fetal hemoglobin in Sickle cell disease patients is finally within sight. At least two major collaborations to perform ex vivo gene therapy for Sickle cell disease have been initiated since 2018. Both use gene editors to inactivate the BCL11A gene and promote fetal hemoglobin expression in red blood cells.

One collaboration between Bioverativ and Sangamo is testing a protocol for gene editing with a Zinc finger. The estimated completion date for this trial is 2022. Another collaboration that has received a great deal of attention, and was recently published in the New England Journal of Medicine, involves CRISPR Therapeutics and Vertex Pharmaceuticals. This trial is among the first to attempt CRISPR in a clinical setting, and the results are highly anticipated by the research and medical communities, not only for their impact on Sickle cell disease, but also as a bellwether for the use of CRISPR in medical practice. So far the results of the trial are encouraging. As of December 2020, the first two patients to receive therapy were reportedly doing well and were free from symptoms more than one year after receiving the treatment. While this news is exciting, there is still much work to be done before the technique can be applied to a wider population.

It has taken many years and many twists, but the visions of the 1950s are finally beginning to be realized, bringing us to the cusp of an exciting new dawn in medicine. The slow march toward a cure for Sickle cell disease clearly demonstrates that through patience and continued investment in scientific discovery, we can continue to achieve the dreams of our predecessors and plant new seeds for future generations to reap the harvest.