Orthomolecular Psychiatry: What Would Abram Hoffer Do?

13 Pages·2014·0.18 MB·English

54 Educational Article Volume 29, Number 2, 2014 JOM
Orthomolecular Psychiatry:
What Would Abram Hoffer Do?
L. John Hoffer, MD, PhD1,2,3,4
1 Project Director, Lady Davis Institute for Medical Research
2 Senior Physician, Divisions of Internal Medicine and Endocrinology, Jewish General Hospital
3Professor, Faculty of Medicine, McGill University
4 Associate Professor, School of Dietetics and Human Nutrition, McGill University
Abstract
This article provides a practical explanation of orthomolecular psychiatry as practiced by
my father, Abram Hoffer, a research psychiatrist and biochemist who dedicated his life to finding a
cure for schizophrenia. Even after his death in 2009, Hoffer remains an icon for many people suf-
fering from schizophrenia. The article summarizes the formal clinical trials published by Hoffer’s
research group in the 1950s and 1960s, and the evolution of his clinical practice after he retired from
academic psychiatry in 1967. Its content is based on Hoffer’s many publications and conversations I
had with him over those many years. Given our close relationship, it’s unavoidably biased. Explicitly
included are my own interpretations, updates, qualifications and disagreements, as framed by my
career as an academic internist and clinical investigator. Key historical and other references are cited
at the end of an article that was published in this journal in 2010 but which, unfortunately, lacks
the in-text reference numbers.1 Interested readers may contact me for a properly annotated version.
They may also consult an article published by Jonathan Prousky with similar intent to this one but a
slightly different slant; it is available on the internet.2
What is Orthomolecular Psychiatry?
therapy. Regrettably, Wikipedia probably
According to Wikipedia (accessed May has it right that in recent years, some peo-
26, 2014, and slightly paraphrased), Or- ple have come to use “orthomolecular” as a
thomolecular psychiatry is based on the assertion scientific-sounding synonym for “natural
that there is an optimum nutritional environ- product therapy.” In my opinion, the prac-
ment in the body. It uses unorthodox forms of tice of regarding any dietary substance used
individualized testing and diagnosis to attempt therapeutically as “orthomolecular therapy”
to establish an etiology for each patient’s specific obscures it in ambiguity.
symptoms, and claims to tailor the treatment The famous chemist Linus Pauling
accordingly using a combination of nutrients, coined the term “orthomolecular” in a review
dietary changes and medications. In the 1950s, article published in Science in 1968. (Paul-
Abram Hoffer was the first major practitioner. ing also coined “molecular biology.”) Pauling
A number of descriptions of the prin- and Hoffer viewed orthomolecular psychia-
ciples of orthomolecular psychiatry are try as a conceptual paradigm for generating
available on the web page of the founda- testable hypotheses for treating psychiatric
tion that publishes this journal (http://www. disorders. The notion was to explore the
orthomed.org/). Despite their important clinical implications of modifying the con-
conceptual content, these documents don’t centrations of molecules that naturally occur
actually provide much in the way of practi- in the body (through diet or biosynthesis)
cal detail about orthomolecular psychiatric and hence for which regulated metabolic
Orthomolecular Psychiatry: What Would Abram Hoffer Do? 55
pathways exist, so as to leverage or restore Hoffer always combined high-dose vitamin
balance in these pathways. Three decades C with niacin and later added other B vita-
later, the renowned American biochemist mins, especially pyridoxine (vitamin B ) and
6
Bruce N. Ames provided strong conceptual later yet, folic acid. He advocated a low car-
support for this paradigm by demonstrat- bohydrate “junk food-free” or “paleolithic”
ing how common polymorphisms in the diet, and later became convinced that certain
genes can influence metabolic flux, and how foods and food additives could have impor-
metabolic flux may be modulated by altering tant adverse cognitive effects in specific psy-
coenzyme concentrations; the concept ap- chotic patients.
plied particularly well to the B vitamins.3-6 Hoffer was among the first North
As another example, the relatively common American psychiatrists to realize that
MTHFR C677T variant of methylenetet- schizophrenia is caused by disordered brain
rahydrofolate reductase, which increases the chemistry, a radical view in the late 1950s.
risk of defective one-carbon metabolism in He and his close colleague, Humphry Os-
people with borderline folic acid deficiency, is mond, considered that about one third of
strongly associated with mental diseases such people with acute schizophrenia may recover
as schizophrenia, thus suggesting a role for spontaneously, and they came to regard their
appropriate folic acid nutriture in their pre- approach of optimized nutrition, lifestyle
vention and treatment.7 Yet another example and certain vitamin supplements as enhanc-
is the recent discovery that an important ing natural recovery. Patients immediately
proportion of patients with mild versions of understood the difference between symptom
phenylketonuria, a disease of phenylalanine suppression and recovery. I suspect that the
toxicity due to deficient activity of phenyla- hope and motivation this attitude inspired in
lanine hydroxylase, respond very well to ex- patients may have contributed to some of his
tremely large doses of biopterin, a necessary recovery successes. Recovered patients often
vitamin cofactor for the enzyme.8 reported the life-enhancing effect of simply
Orthomolecular psychiatry’s purpose is being asked what they planned to do with
hypothesis generation, based on a sophis- their lives after they recovered.
ticated understanding of biology, nutrition Recovery from schizophrenia is not
and brain function. It is not enough to come mentioned in modern psychiatry textbooks
up with a good idea, not even a brilliant one, nor taught to psychiatry residents, despite
however. Hypotheses generated within the the overwhelming evidence for it in the
paradigm have to be put to the clinical test. psychiatric literature. The notion of recov-
ery seemingly contradicts popular theories
Hoffer’s Orthomolecular Psychiatry
about schizophrenia as a neurodevelopmen-
The clinical hypothesis Hoffer and his tal disease. More importantly, it creates a
research colleagues tested in the 1950s and serious practical dilemma. One of the great
1960s–and which captured the attention of practical challenges of modern schizophre-
Linus Pauling–involved the use of large doses nia care is convincing patients to keep taking
of the B-vitamin, niacin, as a novel treatment their medication. People who suffer more
for acute schizophrenia. Their randomized frequent relapses have a worse long-term
clinical trials suggested that the addition of prognosis (the extent to which this phenom-
high-dose niacin (nicotinic acid) to the best enon reflects cause or effect is not so clear).
available therapy (barbiturates and electro- Psychiatrists want to feel comfortable insist-
convulsive therapy) improved the remission ing that their patients stay on antipsychotic
rate of people with acute schizophrenia and medication for life, despite the risk of serious
reduced their risk of relapse.9 They published side effects and toxicity, and it is much easier
only one short-duration clinical trial of nia- to do so when they are convinced that doing
cin therapy in chronic schizophrenia, with so is indisputably in their patients’ interest.
disappointing results. In clinical practice, But the data indicate otherwise. Prospective
56 Journal of Orthomolecular Medicine Vol 29, No 2, 2014
studies of stopping medication provide hints that impairs cognitive function? The diet
as to which patients are most likely to relapse of many schizophrenic patients is vitamin-
and which more likely to remain well,10,11 deficient,18-21 and certain subclinical vitamin
but the predictors are far from foolproof. deficiencies (especially vitamin C, thiamine,
To complicate matters, it is unclear which folic acid and cobalamin) are known to ad-
patients relapse because their underlying versely affect mood or cognition.

disease has flared up or because their brains
What are the Megavitamins?
have become habituated to their antipsy-
chotic drug.12-14 If it were publicly acknowl- Abram Hoffer and Humphry Osmond
edged that a certain proportion of patients essentially stumbled upon the niacin treat-
who are in remission can indeed go off drugs ment for acute schizophrenia. Hoffer’s doc-
without relapsing, how much harder would it toral research at the University of Minnesota
become to convince people who really need dealt with the B vitamins. He was aware that
them to continue taking them? It’s a com- the niacin deficiency disease, pellagra, some-
plicated business, but the evidence is what it times manifests as a psychiatric disorder that
is: some patients will not relapse, presumably occasionally requires large doses of niacin
and especially when the drug is tapered off to reverse. He read case reports of the ef-
very slowly to avoid rebound psychosis.12,13 fective use of large doses of niacin to treat
What does all this mean biologically? Hoffer certain organic brain disorders. Why not try
believed that natural recovery from schizo- it in acute schizophrenia? At the time they
phrenia is of central biological importance were entertaining this idea, Hoffer and Os-
and highly relevant to clinical practice. mond were working on the theory that the
As his views matured, Hoffer came accumulation of a putative, highly reactive
to regard the human brain as functioning oxidative metabolite of adrenaline, adre-
both within a social system and a biologi- nochrome, could trigger a neurotoxic reac-
cal one, namely, the physical body. Both sys- tion manifesting as schizophrenia. Despite
tems need respect and looking after. In this recently published claims to the contrary,22
regard his views don’t seem to differ much it is now established that adrenochrome is
from those of Loren Mosher, chief of the synthesized within the human body and
Center for Studies of Schizophrenia at the that its administration to humans causes a
United States National Institute of Men- temporary psychotic state.23-25 What is not
tal Health between 1969 and 1980 (see so clear is how this metabolite of adrenaline
http://www.moshersoteria.com) and one of could get into the cortex or subcortex of the
Hoffer’s great scientific enemies. Hoffer ad- brain, when the only nerve terminals known
vocated social support, shelter, respect, sup- to release adrenaline are located in the brain-
portive psychotherapy, rest, exercise, healthy stem. Perhaps, as Smythies has surmised, as
diet, and avoidance of alcohol, cigarettes and yet unidentified reactive metabolites of the
other recreational drugs. Compare this ap- closely related and widely distributed neu-
proach with the Mosher-inspired “recovery” rotransmitter, noradrenaline, could have
model of schizophrenia.15-17 The chief dif- neurotoxic effects similar to those of adre-
ference may be that, unlike Mosher, Hoffer nochrome.23 Hoffer and Osmond wondered
paid careful and explicit attention to life- whether large doses of niacin (which is me-
style and nutrition. Hoffer would disapprove tabolized in part by methylation) could limit
of the way current schizophrenia recovery the availability of methyl groups necessary
paradigms ignore the critical role of physi- to convert noradrenaline to adrenaline (it’s
cal well-being and sound nutrition in opti- now clear that such a mechanism is highly
mum cognitive function. Why, Hoffer would unlikely) or, perhaps, that it boosted or sus-
ask, wouldn’t these essential contributors to tained neuronal concentrations of the cel-
overall good health be at least as important lular protective coenzyme, NAD.26 They
for people who are struggling with a disease further reasoned that large doses of the
Orthomolecular Psychiatry: What Would Abram Hoffer Do? 57
antioxidant vitamin C might prevent adre- covered by health insurance plans, and is
nochrome from accumulating in the blood inexpensive in any case. Niacin’s important
and brain. Simultaneously addressing these nuisance side effect is transient skin flushing
different potential mechanisms, they treated and itching. Skin vasodilation, redness (flush)
a number of acutely schizophrenic patients and itching are separate phenomena mediat-
with the combination high-dose nicotinic ed by the release of different prostaglandins
acid and vitamin C with astonishingly ben- from different skin cells.27 The flush/itching
eficial results. (No doubt these favorable episode subsides after 30 to 45 minutes, and
responses were easily detected because the diminishes greatly in intensity (and usually
antipsychotic drugs were not available at the disappears) after a few days of continuing
time they carried out these trials. The antip- niacin administration (a phenomenon called
sychotic drugs suppress psychosis due to a tachyphylaxis). Flush/itching is maximal at
number of causes and are now the standard the 500 mg dose. It does not worsen with in-
of care in this situation.) creasing doses. Sometimes mild flush/itch-
Here is a summary of Hoffer and Os- ing occurs unpredictably. People with a fair
mond’s megavitamin therapy for acute or rosy complexion (“blushers”) flush and
schizophrenia. itch more intensely than people with a swar-
1. Nicotinic acid (commonly known as nia- thier complexion. If a few doses are missed
cin) is widely available in 500 mg tablets. the flush/itching recurs upon restarting it.
Start with 500 mg niacin daily after a meal Two points should be emphasized about this
for a few days, then gradually increase the side effect. The first is that it is a nuisance,
dose at seven day intervals, over four to six innocent of danger, for the vast majority of
weeks, to reach the target dose of 1 gram patients, and it is completely reversible. The
three times per day. second is that there are effective strategies
2. Vitamin C, one gram three times daily for mitigating the side effect while waiting a
right from the start. few days for tolerance to develop (see Table
3. Pyridoxine 250 mg per day. Later, Hoffer 1, below).
often prescribed a B-50 complex tablet twice Early in his research Hoffer discov-
per day instead. ered that a large proportion of people with
schizophrenia do not flush after niacin ad-
Details of Niacin (nicotinic acid) Therapy
ministration, a phenomenon that has since
Niacin effectively lowers serum triglyc- been widely confirmed and is under active
eride and LDL (“bad”) cholesterol levels investigation using a standardized niacin-
while increasing HDL (“good”) cholesterol. impregnated skin patch which induces a
Niacin is available without prescription, is localized area of reddening in most normal
Table 1. How to Mitigate an Episode of Niacin-induced Flush/itch
Take niacin with or after food, with a glass of cold water. Do not take niacin on an
empty stomach. These actions prevent rapid gastric absorption and greatly reduce
the intensity of the flush/itching.
Take 80 mg of aspirin (or 325 mg if the lower dose doesn’t work) half an hour before
the morning dose of niacin. Have a good reason for taking niacin and a positive atti-
tude about its potential neuroprotective and healing effect. The flush can be regarded
favorably, as a sign it is “working.” Enjoy the pleasant, relaxing post-flush sensation.
58 Journal of Orthomolecular Medicine Vol 29, No 2, 2014
people, but a lesser or absent response in psychosis. Many people with a psychiatric
people with schizophrenia. The no-niacin- disorder overuse alcohol, and even ordinary
flush phenomenon may be the only con- alcohol consumption will transiently elevate
firmed biological marker we currently have liver transaminases. In our current obesity
for “schizophrenia.” The mechanism is under epidemic (including obesity induced by an-
investigation. Many tissues, including cer- tipsychotic drugs), fat accumulation in the
tain skin cells, fat cells, and neurons, have liver can induce non-alcoholic steatohepati-
been found to express “niacin” receptors. tis (NASH) that is manifested by elevated
There is some suggestion that the expression serum liver enzymes.
(or regulation) of these receptors is abnormal The niacin dose is increased gradually
in predictable areas of the brain of schizo- to prevent liver enzyme elevation. Very oc-
phrenic people but not people with other casionally a patient’s serum liver enzyme
forms of mental illness.1 level will rise, but as long as the increase is to
It is essential to fully explain the niacin less than three times the upper normal limit
flush/itch phenomenon, its transience, and and the patient feels well, niacin can be con-
how to mitigate it, to anyone contemplating tinued with continued monitoring; in most
niacin therapy. Systematic studies show that cases the enzyme level will return to normal
most uninformed patients do not tolerate on its own. Clinical liver toxicity is very rare
this side effect28,29 whereas most appropri- with ordinary niacin.32
Hyperacidity
ately informed and counseled ones tolerate Niacin stimulates stom-
it well.30 ach hydrochloric acid secretion, presumably
If there was insufficient or no response by activating or sensitizing gastric H2 recep-
after three or four months, Hoffer would in- tors. The resulting hyperacidity can be trou-
crease the niacin dose up to about six grams bling for many patients, and this is another
per day (sometimes higher). He claimed to important reason for taking the vitamin after
get responses at the higher doses that were meals. If necessary, the H2-blocking drugs
not obtained at lower doses. But he never ranitidine or famotidine can be used tempo-
published these data except anecdotally. rarily, or long-term.
Hyperuricemia
Niacin very slightly in-
Niacin Toxicity
creases serum uric acid concentrations (it
Properly informed and appropriately competes with urate for secretion by the re-
motivated people tolerate high-dose niacin nal tubules). Patients at high risk could ex-
without problem, but anyone who prescribes perience an attack of gout.30
niacin has to be aware both of its innocent
Nicotinamide as an Alternative to
side effects and its rare potential for adverse
Niacin
effects and toxicity. Several recent reviews are
available and should be consulted.30-33 Here Some people simply will not tolerate
is a summary of the important features. niacin due to the intensity of flush/itching
Liver toxicity
As with all lipid-lowering (I have even rarely seen urticaria). People
agents (such as the now very widely pre- with aspirin-exacerbated respiratory disease
scribed statins) it is obligatory to measure (a triad of aspirin allergy, nasal polyps and
serum liver enzyme levels prior to com- asthma) can develop severe nasal conges-
mencing niacin therapy and repeat them af- tion and headache after niacin. When niacin
ter about six or eight weeks of therapy. (The proved to be unacceptable, Hoffer prescribed
risk of liver function abnormalities is greater nicotinamide, a different form of vitamin B
3
when niacin and a statin are prescribed in that does not cause flush/itching (and does
combination.) Any liver function abnormal- not improve the serum lipid profile). The
ities found to be present at baseline require clinical trial evidence that nicotinamide is
a diagnosis. For example, Wilson’s disease beneficial in acute schizophrenia is weaker
causes hepatitis, but its first symptom can be than for niacin, consisting as it does of a sin-
Orthomolecular Psychiatry: What Would Abram Hoffer Do? 59
gle double-blind clinical trial that indicated toxicity, it is prudent simply to prescribe two
equal superiority of niacin and nicotinamide B-50 complex vitamin formulations, each of
over placebo. The maximum daily dose of which contains 50 mg of most of the B vi-
nicotinamide is 3 g, because, unlike niacin, tamins, including pyridoxine (but not more
larger doses can cause nausea and liver tox- than 1 mg folic acid).
icity. There is current interest in the use of
Vitamin C
nicotinamide as a neuroprotective agent. Its
safety and lack of side effects are well docu- Hoffer and Osmond prescribed 1 g vita-
mented.34 min C three times per day. I am unconvinced
that this much is necessary – perhaps 500
Slow Release Niacin
mg twice a day would be as effective – but
Hoffer occasionally prescribed extended it is safe, except possibly for people with a
release niacin (so called “no-flush” niacin), documented history of oxalate kidney stone.
but I recommend against it. First, some of Nevertheless, since their clinical experience
the products on the market may not be reli- was based on this regimen, I continue to rec-
ably absorbed from the gastrointestinal tract, ommend it. Vitamin C has two advantages.
or, if absorbed, release their niacin. One com- First, it reliably lowers uric acid concentra-
monly used extended release product, inosi- tions35 and hence could mitigate a potential
tol hexanicotinate, appears to be absorbed side effect of niacin. Secondly, there is prom-
but has questionable efficacy. Second, unlike ising evidence that vitamin C protects the
ordinary niacin, slow release products may stomach from the adverse effects of aspirin
induce liver toxicity. Readers may consult and presumably other NSAIDS.36
recent reviews.30,32,33 Niaspan is a well-stud-
Tailor Therapy, but Don’t Make it Too
ied, safe, formally approved extended release
Complicated
product available on prescription in Canada
and the United States for the indication of Wikipedia is correct that Hoffer indi-
lipid lowering. The maximum recommended vidualized therapy. Patients who tolerated 3 g
dose is two grams at bedtime. Higher doses niacin per day but failed to respond might
are not necessarily dangerous, but they have be prescribed 6 g per day and, rarely, even
not been verified to be safe, and prescribing more. In addition, he emphasized sound
them would be off-label. general nutrition individualized for each
patient. Patients with iron deficiency would
Other B Vitamins
have their iron deficiency corrected, for ex-
Hoffer prescribed pyridoxine (vitamin ample. Once the fish oils came on the scene
B ) partly because many enzyme activities he did not hesitate to prescribe eicosapen-
6
can be increased with pharmacologic dos- taenoic acid (EPA) in a dose of 2 g per day
es of this B-vitamin enzyme cofactor, but taken together with a fat-containing meal
mostly because colleagues anecdotally re- to enable absorption. Given the abundance
ported good clinical results (often together of vitamin D receptors in the human brain,
with zinc). I never saw a suitable presenta- he would not hesitate to prescribe vitamin
tion of the evidence supporting its use. Dos- D (or sunlight) to a patient with vitamin
es greater than 250 mg/day are not recom- D insufficiency. (Vitamin D deficiency has
mended because of rare reports of sensory been linked to depression, but I have not
neuropathy after long-term use, although seen evidence that it triggers or exacerbates
typically in doses closer to 2 g/day. People psychotic disorders.) Intriguing preliminary
with the serious metabolic disease, homo- but rigorous and biologically plausible data
cystinuria, commonly take very large doses suggest a benefit of the antioxidant supple-
of pyridoxine with great benefit and no re- ment N-acetylcysteine, both in schizophre-
ported toxicity. On balance, given the uncer- nia and in obsessive-compulsive states like
tainty of benefit and the small but real risk of hair-plucking.37-40
60 Journal of Orthomolecular Medicine Vol 29, No 2, 2014
It is biologically and clinically plausible for this dilemma, but common sense sug-
to recommend natural vitamin E 400 IU gests making the prescription as simple and
twice daily (with food to enable absorption) replicable as possible. Prescribe what Hoffer
to prevent tardive dyskinesia. There is strong prescribed and see what happens. The pa-
but inconclusive evidence that high-dose vi- tient has to understand the program and its
tamin E mitigates existing tardive dyskine- implications, want to go for it, and be able to
sia.41 Why not, then, prescribe the vitamin to follow through with it. Be on the lookout for
prevent this devastating toxic effect of antip- what seems to help the most. It’s uncertain,
sychotic drugs from developing in the first meticulous work, with no guarantee of suc-
place? Vitamin E may have a role in mitigat- cess. The only way to sustain such an effort
ing NASH.42 is to care about the patient and sustain unbi-
Food intolerances
There is evidence ased intellectual curiosity.
that people with coeliac disease, which is
Therapeutic Goals
caused by an intestinal allergy to gluten, are
at increased risk of schizophrenia.43,44 Glu- After the antipsychotic drugs became
ten can cause extra-intestinal manifestations available Hoffer used them, but judiciously.
in the skin or brain in people with coeliac He aimed for the lowest effective dose (“as
disease.45-47 Medical understanding of the little as possible, as much as necessary”)
spectrum of gluten intolerance has entered while colleagues opted for the highest tol-
an era of great uncertainty and shifting erated dose to minimize the risk of relapse.
terminology48,49 that goes beyond the scope The following treatment philosophy would
of this article. Suffice it so say that there is be in line with Hoffer’s approach:
now good evidence that adverse reactions to The patient should be in the best condition
gluten are not limited to people with proven on the lowest effective dose of appropriate an-
coeliac disease.48,50 A trial gluten-free diet tipsychotic medication.
is therefore reasonable in people with sug- Orthomolecular psychiatry is neither
gestive symptoms even when their total proven nor refuted, so practice evidence-
IgA level is normal and their IgA antitissue based medicine. In the situation when the
transglutaminase antibody titre is low. Con- balance among benefit, risk and disadvan-
trary to what most general physicians realize, tage cannot be confidently estimated, the
there is very good evidence that certain food rules of evidence-based medical practice re-
additives or ingredients can adversely affect quire the therapist to explain the uncertainty,
behavior in children with or without a be- the potential benefits and risks of the pro-
havioral disorder.51 No systematic evidence, posed treatment and ensure that the decision
one way or the other, has been published in as to whether to proceed, or not proceed, is
adults. consistent with the patient’s attitudes and
How much tailoring is too much? Much preferences.52,53 In light of the well-docu-
is speculated, more is unknown, and little is mented inadequacies of standard antipsy-
clear. There is an understandable tendency chotic drug therapy54,55 and the lack of evi-
to load the patient up with as many good- dence that polypharmacy is any better,56 the
ies as possible. I recently saw a patient with balance of uncertain benefit versus minimal
schizophrenia who, after paying thousands risk could well tip in favour of orthomo-
of dollars for specialized blood and hair lecular therapy for certain, suitably assessed,
tests, was prescribed a protein-rich diet, a informed and motivated patients. Indeed,
gluten-elimination diet and a large number proceeding with the lifestyle approach alone
of supplements including niacinamide, zinc, can only benefit patients, including patients
copper, slippery elm, lipoic acid, EPA, iron, with antipsychotic drug-induced obesity
and vitamin C. The program didn’t work for and hyperlipidemia. Rational orthomolecu-
this particular patient because it was simply lar psychiatric practice, as described here, is
overwhelming. I don’t have an easy answer consistent with the principles of evidence-
Orthomolecular Psychiatry: What Would Abram Hoffer Do? 61
based medicine.39 Which Patients Respond and How Fast?
Allow at least three months for a ben- The existing clinical trial evidence sug-
eficial effect to occur before increasing the gests that niacin improves acute schizophre-
niacin dose or abandoning it, and be willing nia (i.e. less than two years chronicity). The
to wait much longer than this for patients negative clinical trials that Wikipedia refers
with chronic schizophrenia. to as refuting niacin therapy were carried out
If the patient is in complete remission, in chronic schizophrenic patients, the major-
do they really want to embark on what is ity of them institutionalized and deteriorat-
a complex and demanding change in their ed. Hoffer told me he sometimes saw rapid
lifestyle? The answer is likely to be “no” and dramatic improvements in patients with
for many people. Are social support struc- acute schizophrenia but sometimes had to
tures in place? The patient should be able wait months to see the benefit. Generally, he
to articulate persuasively why they want told me, patients with chronic schizophrenia
to go proceed with the program. The or- improved only very slowly or not at all. But
thomolecular therapist’s responsibility is he never gave up on any patient.
to make sure the program is well explained How could I forget Luella R, a young
and understood, and that it is feasible, safe woman with chronic refractory schizophre-
and inexpensive for this particular patient. nia who helped look after my brother, sister
Decisions about tapering the antipsychot- and me when we were small children! My
ic drug are between the patient and their father describes her (giving her the pseud-
psychiatrist. Dose tapering should never onym Mary Jones) in one of his last books.59
commence before at least six months on Luella would have spent her entire life in the
the full lifestyle and vitamin regimen. The back ward of a chronic psychiatric hospital
aim of therapy is remission on the lowest had Hoffer not brought her to live in our
necessary dose of antipsychotic medica- house, in a therapeutic milieu. She slowly
tion. Hoffer defined success as complete but entirely recovered in this environment,
remission on the smallest necessary dose of but only after she was treated with niacin.
antipsychotic drug. For some patients, that
Did Hoffer’s Patients Have Schizo-
dose may be zero.
phrenia?
If the patient has residual positive symp-
toms attributable to their disease, it makes Hoffer’s therapies focused on using niacin,
sense to monitor them (intensity and fre- among other nutrients, to treat what he diag-
quency) as signals of whether the lifestyle/ nosed as acute schizophrenia based on an unac-
diet/vitamin approach is actually helping. cepted test. In 1973, a task force of the American
The therapist should objectively record the Psychiatric Association examined niacin mono-
patient’s symptom status. Hoffer, an experi- therapy of patient populations with chronic
enced psychiatrist, always based his decisions schizophrenia and bipolar disorder and rejected
on clinical judgment, but he also used, and the practice along with the reliability of Hoffer’s
advocated, the Hoffer Osmond Diagnostic diagnostic approach. (Wikipedia)
(HOD) test, a self-report card-sorting test It has been claimed–as recently as a
that was later succeeded by a more sophis- year after Hoffer’s death22–that the recover-
ticated test called the Experiential World ies and sustained remissions reported in his
Inventory.57,58 Both tests survey the patient’s randomized clinical trials are bogus because
perceptions and thought processes. The the patients enrolled in them didn’t have
practical limitation of both tests is that they schizophrenia, but rather a variety of other
are not standardized, validated, nor widely conditions he and Osmond falsely identified
used. I recommend adding or substituting as schizophrenia using the HOD test. This
standard, widely used symptom scales whose is simply untrue. Hoffer always used stan-
results will be understood and credited by dard clinical diagnostic methods to diag-
conventional psychiatrists. nose schizophrenia. He advocated using the
62 Journal of Orthomolecular Medicine Vol 29, No 2, 2014
HOD test to follow its clinical progress. The mented with 3 g per day of niacin.63 Study
patients in their formal clinical trials were participants were enrolled at the time of
not enrolled by Hoffer or Osmond, but rath- admission to the Male Admission Ward of
er by other collaborating psychiatrists, many the New Jersey State Hospital at Marlboro
of them skeptical, using standard diagnostic with a diagnosis of an episode of schizo-
methods.60 phrenia, and closely followed on treatment
This is not to claim that in later years for two years. As with most trials in schizo-
Hoffer refused to treat patients suffer- phrenia, the dropout rate was very high (only
ing from psychotic disorders that might or 75 of the 140 patients originally enrolled
might not later turn out to be schizophre- completed the protocol, making intention-
nia. He tried to help every patient. He would to-treat analysis impossible) and baseline
normally diagnose schizophrenia in a patient randomization was imperfect. The patients
who manifested delusions, hallucinations, assigned to supplemental niacin were sig-
disorganized or blocked thinking, and nega- nificantly more chronic (an average of 4.8
tive symptoms such as inertia, lack of enjoy- years had transpired since their first serious
ment, and lack of social interest. psychotic episode, whereas only 3.0 years
had transpired in the control group). Basing
Does Orthomolecular Psychiatry Work?
his results on the outcome of the 86 patients
In 1973, a task force of the American Psy- who remained in the study for at least 18
chiatric Association examined niacin mono- months, Wittenborn found that psychiatric
therapy of patient populations with chronic rating scales, social adjustment, self-report,
schizophrenia and bipolar disorder and rejected and medication data were similar in both
the practice. (Wikipedia) treatment groups. While cautioning that the
Regrettably, the APA’s 1973 Task Force data analysis was continuing, Wittenborn
Report 7, Multivitamin and Orthomolecu- concluded that his study had failed to show
lar Therapy in Psychiatry, is no longer avail- that niacin was a useful add-on therapy for
able.61 Task Force Report 7 contains some this kind of schizophrenic patient.63 The fol-
cogent criticisms, but it is seriously marred lowing year Wittenborn published his final
and to a considerable extent discredited by analysis. It indicated that people whose in-
its unashamedly hostile, scornful bias. The terpersonal relationships had been relatively
Task Force Report correctly concluded that normal prior to developing schizophrenia
there was no good published evidence that responded well to niacin, whereas people in
high-dose niacin is useful in chronic schizo- the control group with the same pre-morbid
phrenia, but failed to concede the evidence characteristics did not improve.64 Such peo-
pertaining to niacin treatment of acute ple accounted for one-third of the patients
schizophrenia. More evidence is certainly in the study. Acknowledging the post-hoc
necessary, but the barriers to obtaining are nature of his analysis, Wittenborn recom-
insurmountably high at the present time.1 mended that a new clinical trial be carried
A particularly important problem in schizo- out to explore the important implications of
phrenia is heterogeneity.62 Schizophrenia his findings. His recommendation was ig-
may represent a nonspecific cognitive dys- nored. His second article is never cited.
function with more than one cause.
How Can We Find Out Which Patients
A most interesting clinical trial of niacin
Will Respond To Orthomolecular
therapy was published in 1973 by a respected
Therapy?
psychopharmacologist and clinical trial spe-
cialist, J.R. Wittenborn. This United States The amount and kind of randomized
National Institutes of Health-funded trial clinical trial evidence that orthomolecular
compared the clinical effects of standard an- psychiatry reliably benefits most patients
tipsychotic therapy with intensive social with acute schizophrenia is, at the present
support versus the same therapy supple- time, insufficient to justify its routine pre-
Orthomolecular Psychiatry: What Would Abram Hoffer Do? 63
scription. The likelihood of obtaining the completely normal on niacin. During our
kind of clinical trial evidence necessary ei- conversation he remarked that when he had
ther to establish or refute it is almost zero, at to write essays for school he would stop tak-
least for the foreseeable future. Randomized ing the niacin for a few days because the
clinical trials, even of single drugs, are very loosening of associations that followed soon
difficult to carry out in schizophrenia. The after improved his creative writing. I found
kinds of clinical trials necessary to properly this unembellished narrative, from a down-
evaluate orthomolecular therapy would be to-earth, intelligent young man, electrifying.
much more difficult to fund and carry out It was authentic. Admittedly, it was merely
even if funded.1 Prompt and easy detection the fragment of an anecdote. It might just
of a favorable response to orthomolecular have been a “placebo effect.”
therapy will be confounded by the symp-
Conclusions
tomatic effectiveness of the antipsychotic
drugs, which are, as they should be, the stan- The people most likely to benefit from
dard of care. (Imagine trying to test a poten- orthomolecular psychiatric therapy have acute
tially curative treatment for chronic head- schizophrenia, and among them, those who
ache in people who continue taking large have a history of a good pre-morbid psycho-
and risky doses of aspirin with moderate logical adjustment. These are the very people
symptom control.) The validation or refuta- most likely to experience a natural recovery.
tion of Hoffer’s orthomolecular therapy will This is not to say that people with chronic
eventually come in the form of fundamental schizophrenia cannot benefit, but acceptable
breakthroughs in our understanding of the evidence is lacking. Hoffer’s experience was
biology of schizophrenia. In the meantime, that improvements can take a long time to
is there anything that can be done clinically? come about. Depending on the patient’s sit-
What comes to mind, and is available to any uation, attitudes and preferences, one would
suitably trained and motivated therapist, is use the basic regimen of niacin, vitamin C,
careful clinical observation and the prepara- and B complex 50, normal vitamin D status,
tion and publication of high quality, sophis- a junk-free diet, avoidance of stimulants and
ticated case reports. Even more important drugs, and cognitive therapy, personal respect,
would be consecutive case series to eliminate and the lowest effective dose of antipsychotic
selection bias. Well presented case reports drug. When feasible, a plausible interpreta-
are anecdotes, but that doesn’t make them tion of the evidence suggests that 400 or 800
unimportant if something can be learned IU vitamin E (with food to enable absorp-
from them.65,66 Evidence-based medicine is tion) is a prudent measure that might prevent
well served by clinical evidence from uncon- tardive dyskinesia. An additional promising
trolled observations when the effect is large, possibility is N-acetylcysteine in a dose of 1
unmistakable and well-documented.67 Dra- g twice daily. Orthomolecular therapy is off-
matic narratives of recovery, including re- label, so the patient must be fully informed
covery from schizophrenia,16,65,66,68,69 are ap- about the uncertainty of the evidence sup-
propriate and can be influential. I hope that porting it. Baseline disease status should be
well-documented and well-told case reports measured at baseline and during therapy. The
could be published in this journal. symptom rating scales drug companies are
Writing these lines, I remember an in- required to use to obtain regulatory approval
terview I had many years ago with a young for their products have questionable rel-
man diagnosed with schizophrenia. I was evance to real-life experience. More impor-
home from university for the summer, and tant are the patient’s evaluation and objective
my father asked me to go through some of information of how they are doing. Hoffer’s
his clinical charts, contact the patient, and criteria for success were normal perception
get longer term follow up information. This and thought, normal social relationships, full
young man, now a high school senior, was employment, and paying income tax.