People with schizophrenia may have a greater tendency to be deficient in folic acid, than the general population¹³ and they may show improvement when given supplements. A preliminary trial found that, among schizophrenic patients with folic acid deficiency, those given folic acid supplements had more improvement, and shorter hospital stays than those not given supplements.¹⁴ In a double-blind trial, a very high amount of folic acid (15 mg daily) was given to schizophrenic patients being treated with psychiatric medications who had low or borderline folic acid levels. The patients receiving the folic acid supplements had significant improvement, which became more significant over the six-month course of the trial.¹⁵ The symptoms of folic acid deficiency can be similar to those of schizophrenia, and two cases of wrong “schizophrenia” diagnoses have been reported.^{16 , 17} In one of these cases, an initial supplement of 20 mg daily of folic acid and a maintenance supplemental intake of 10 mg daily, led to resolution of symptoms.¹⁸

In another double-blind study, daily supplementation with folic acid (2 mg), vitamin B6 (25 mg), and vitamin B12 (400 mcg) for three months improved symptoms of schizophrenia compared with a placebo.¹⁹ All of the participants in this study had elevated blood levels of homocysteine, which can be decreased by taking these three B vitamins. Based on this study, it would seem reasonable to measure homocysteine levels in people with schizophrenia and, if they are elevated, to supplement with folic acid, vitamin B6, and vitamin B12.

There have been several reports of glycine reducing the symptoms of people with schizophrenia who were unresponsive to drug therapy.²⁰ Large amounts of glycine (0.8 gram per 2.2 pounds of body weight per day) have been shown to reduce negative symptoms of schizophrenia and improve psychiatric rating scores in one preliminary trial;²¹ however, these results have not been repeated in later trials using similar (very high) amounts.^{22 , 23} Earlier double-blind trials found significant improvements in depression and mental symptoms in people with schizophrenia who took glycine for six weeks.^{24 , 25} Most trials demonstrated a moderate improvement in schizophrenia symptoms in those taking glycine supplements.²⁶ Long-term supplementation with high amounts of glycine may be toxic to nerve tissue, however. Some preliminary successes have been reported using smaller amounts of glycine, such as 10 grams per day.²⁷ Long-term studies on the safety of glycine therapy are needed.

There are two different classes of essential fatty acids: omega-6 fatty acids and omega-3 fatty acids. There is considerable evidence these fatty acids are deficient, or are not used properly, in people with schizophrenia.^{28 , 29 , 30 , 31 , 32 , 33} Some investigators suggest this altered fatty acid metabolism may be involved in the increased need for niacin seen in some schizophrenic patients.³⁴ A case has been reported in which a man with schizophrenia had dramatic and sustained improvement while being supplemented with 2 grams daily of omega-3 fatty acids.³⁵ In a preliminary trial, schizophrenic patients receiving omega-3 fatty acids showed improvement in symptoms, as well as a reduction in adverse effects from their anti-psychotic medications.³⁶ Another study found that people with schizophrenia had lower blood levels of both omega-3 and omega-6 fatty acids, compared with non-schizophrenic people, even though both groups were consuming similar amounts of these fatty acids.³⁷ In a separate preliminary study, higher intake of omega-3 fatty acids was associated with less severe disease, and supplementation with 10 grams of concentrated fish oil, a source of omega-3 fatty acids, led to significant improvement in symptoms over a six-week period.³⁸ In addition, a double-blind trial found that supplementing with 1.2 g per day of omega-3 fatty acids from fish oil prevented the development of psychosis in adolescents and young adults who were at very high risk of developing a psychotic disorder.³⁹

In a double-blind trial that included 87 patients with chronic schizophrenia or a related illness (schizoaffective disorder), supplementation with 3 grams per day of eicosapentaenoic acid (one of the omega-3 fatty acids found in fish oil) was ineffective.⁴⁰ The patients in this negative study were older and had been ill for longer, compared with patients in earlier studies who improved with omega-3 fatty acid supplementation.

Several clinical trials have examined the effects of supplementation with essential fatty acids in people with schizophrenia, with inconsistent results.^{41 , 42 , 43 , 44} While the results of trials using omega-3 fatty acids are promising, further double-blind trials are needed to establish whether fatty acid supplementation is an effective therapy for schizophrenia. Trials of omega-6 fatty acids (like GLA from borage oil) have yielded predominantly negative results.⁴⁵

People with schizophrenia may have a greater tendency to be deficient in folic acid, than the general population⁴⁶ and they may show improvement when given supplements. A preliminary trial found that, among schizophrenic patients with folic acid deficiency, those given folic acid supplements had more improvement, and shorter hospital stays than those not given supplements.⁴⁷ In a double-blind trial, a very high amount of folic acid (15 mg daily) was given to schizophrenic patients being treated with psychiatric medications who had low or borderline folic acid levels. The patients receiving the folic acid supplements had significant improvement, which became more significant over the six-month course of the trial.⁴⁸ The symptoms of folic acid deficiency can be similar to those of schizophrenia, and two cases of wrong “schizophrenia” diagnoses have been reported.^{49 , 50} In one of these cases, an initial supplement of 20 mg daily of folic acid and a maintenance supplemental intake of 10 mg daily, led to resolution of symptoms.⁵¹

In another double-blind study, daily supplementation with folic acid (2 mg), vitamin B6 (25 mg), and vitamin B12 (400 mcg) for three months improved symptoms of schizophrenia compared with a placebo.⁵² All of the participants in this study had elevated blood levels of homocysteine, which can be decreased by taking these three B vitamins. Based on this study, it would seem reasonable to measure homocysteine levels in people with schizophrenia and, if they are elevated, to supplement with folic acid, vitamin B6, and vitamin B12.

The results of one double-blind trial indicate that melatonin supplementation improves sleep quality in people with schizophrenia.⁶¹ In one study, all patients with a diagnosis of schizophrenia were found to have low melatonin output. Replacement of melatonin with 2 mg of a controlled-release supplement per day for three weeks improved sleep duration and quality compared to placebo. When patients receiving placebo were crossed over to the melatonin group, they too experienced improved sleep quality.

The term “orthomolecular psychiatry” was coined by Linus Pauling in 1968 to refer to the treatment of psychiatric illnesses with substances (such as vitamins) that are normally present in the body. In orthomolecular psychiatry, high amounts of vitamins are sometimes used, not to correct a deficiency per se, but to create a more optimal biochemical environment. The mainstay of the orthomolecular approach to schizophrenia is niacin or niacinamide (vitamin B3) in high amounts. In early double-blind trials, 3 grams of niacin daily resulted in a doubling of the recovery rate, a 50% reduction in hospitalization rates, and a dramatic reduction in suicide rates.⁶² In a preliminary trial, some schizophrenic patients continued a course of vitamins (4 to 10 grams of niacin or niacinamide, 4 grams of vitamin C, and 50 mg or more of vitamin B6) after being discharged from the hospital, while another group of patients discontinued the vitamins upon discharge. Both groups continued to take their psychiatric medications. Those who continued to take the vitamins had a 50% lower re-admission rate compared with those who did not.⁶³ Several later double-blind trials, including trials undertaken by the Canadian Mental Health Association, have been unable to reproduce these positive results.^{64 , 65} Early supporters of niacin therapy contend that many of these trials were poorly designed.⁶⁶ One clinical trial reported no greater improvement in a group of schizophrenic patients given 6 grams of niacin than in others given 3 mg of niacin; all patients were also being treated with psychiatric medications.⁶⁷

There are potential side-effects of niacin therapy, including an uncomfortable flushing sensation, dermatitis (skin inflammation), heartburn, aggravation of peptic ulcers, increased blood sugar, increased panic and anxiety, and elevation of liver enzymes, which may indicate damage to liver cells. A positive side effect of niacin therapy is reduction of cholesterol levels. Some of these effects, such as flushing, gastric upset, and reduction of serum cholesterol, do not occur with the use of niacinamide.⁶⁸ Because of the seriousness of some of these side effects, high amounts of niacin should not be used without the supervision of a healthcare practitioner.

Vitamin B6 has been used in combination with niacin in the orthomolecular approach to schizophrenia. Pioneers of orthomolecular medicine reported benefits from this combination. However, although two placebo-controlled trials found significant improvement when schizophrenic patients were given either 3 grams of niacin or 75 mg of pyridoxine along with their psychiatric medications, this improvement was lost when the two vitamins were combined.^{69, 70} In a double-blind trial, schizophrenic patients were given either a vitamin program based on their individual laboratory tests or a placebo (25 mg of vitamin C) in addition to their psychiatric medications. The vitamin program included large amounts of various B vitamins, as well as vitamin C and vitamin E. After five months, the number of patients who improved was not different in the vitamin group compared with the placebo group.⁷¹

Clinical trials of the effects of vitamin B6 have yielded differing results. The results of supplementation with 100 mg daily in one schizophrenic patient included dramatic reduction in side effects from medication, as well as reduction in schizophrenic symptoms.⁷² In a preliminary trial, 60 mg per day of vitamin B6 resulted in symptomatic improvement in only 5% of schizophrenic patients after four weeks.⁷³ Another preliminary trial, however, found that a higher amount of vitamin B6—50 mg three times daily given for eight to twelve weeks—in addition to psychiatric medications, did bring about significant improvements in schizophrenic patients. These patients experienced a better sense of well-being, increased motivation, and greater interest in their “personal habits and their environment.”⁷⁴

The term “orthomolecular psychiatry” was coined by Linus Pauling in 1968 to refer to the treatment of psychiatric illnesses with substances (such as vitamins) that are normally present in the body. In orthomolecular psychiatry, high amounts of vitamins are sometimes used, not to correct a deficiency per se, but to create a more optimal biochemical environment. The mainstay of the orthomolecular approach to schizophrenia is niacin or niacinamide (vitamin B3) in high amounts. In early double-blind trials, 3 grams of niacin daily resulted in a doubling of the recovery rate, a 50% reduction in hospitalization rates, and a dramatic reduction in suicide rates.⁷⁵ In a preliminary trial, some schizophrenic patients continued a course of vitamins (4 to 10 grams of niacin or niacinamide, 4 grams of vitamin C, and 50 mg or more of vitamin B6) after being discharged from the hospital, while another group of patients discontinued the vitamins upon discharge. Both groups continued to take their psychiatric medications. Those who continued to take the vitamins had a 50% lower re-admission rate compared with those who did not.⁷⁶ Several later double-blind trials, including trials undertaken by the Canadian Mental Health Association, have been unable to reproduce these positive results.^{77 , 78} Early supporters of niacin therapy contend that many of these trials were poorly designed.⁷⁹ One clinical trial reported no greater improvement in a group of schizophrenic patients given 6 grams of niacin than in others given 3 mg of niacin; all patients were also being treated with psychiatric medications.⁸⁰

There are potential side-effects of niacin therapy, including an uncomfortable flushing sensation, dermatitis (skin inflammation), heartburn, aggravation of peptic ulcers, increased blood sugar, increased panic and anxiety, and elevation of liver enzymes, which may indicate damage to liver cells. A positive side effect of niacin therapy is reduction of cholesterol levels. Some of these effects, such as flushing, gastric upset, and reduction of serum cholesterol, do not occur with the use of niacinamide.⁸¹ Because of the seriousness of some of these side effects, high amounts of niacin should not be used without the supervision of a healthcare practitioner.

Vitamin B6 has been used in combination with niacin in the orthomolecular approach to schizophrenia. Pioneers of orthomolecular medicine reported benefits from this combination. However, although two placebo-controlled trials found significant improvement when schizophrenic patients were given either 3 grams of niacin or 75 mg of pyridoxine along with their psychiatric medications, this improvement was lost when the two vitamins were combined.^{82, 83} In a double-blind trial, schizophrenic patients were given either a vitamin program based on their individual laboratory tests or a placebo (25 mg of vitamin C) in addition to their psychiatric medications. The vitamin program included large amounts of various B vitamins, as well as vitamin C and vitamin E. After five months, the number of patients who improved was not different in the vitamin group compared with the placebo group.⁸⁴

Clinical trials of the effects of vitamin B6 have yielded differing results. The results of supplementation with 100 mg daily in one schizophrenic patient included dramatic reduction in side effects from medication, as well as reduction in schizophrenic symptoms.⁸⁵ In a preliminary trial, 60 mg per day of vitamin B6 resulted in symptomatic improvement in only 5% of schizophrenic patients after four weeks.⁸⁶ Another preliminary trial, however, found that a higher amount of vitamin B6—50 mg three times daily given for eight to twelve weeks—in addition to psychiatric medications, did bring about significant improvements in schizophrenic patients. These patients experienced a better sense of well-being, increased motivation, and greater interest in their “personal habits and their environment.”⁸⁷

L-tryptophan is the amino acid precursor of serotonin, a neurotransmitter (chemical messenger in the brain). There is evidence that L-tryptophan levels in schizophrenic people are lower than in non-schizophrenics⁸⁸ and the way the body uses L-tryptophan is altered in people with schizophrenia.^{89 , 90} In a preliminary trial, patients with schizophrenia were given 2–8 grams of L-tryptophan and 100 mg of vitamin B6 daily. This resulted in decreased agitation and less fear and anxiety, but these improvements were not as great as those achieved with psychiatric medications.⁹¹ It is not clear whether the benefits seen in this trial were due to vitamin B6, L-tryptophan, or a combination of the two. No other clinical trials using L-tryptophan have been published. L-tryptophan is currently available by prescription only.

Up to 6 grams daily of vitamin C has been reported to be beneficial for people with schizophrenia;^{92 , 93} in one case the addition of 400 IU daily of vitamin E enhanced this benefit.⁹⁴ A small preliminary trial using 8 grams daily of vitamin C showed decreases in hallucinations, suspiciousness, and unusual and disorganized thoughts in 77% of schizophrenic patients.⁹⁵ In all reported cases, patients were also being treated with sychiatric medications. Some early studies found no difference between blood and urine vitamin C levels in schizophrenics and non-schizophrenics, either before or after supplementation.^{96 , 97 , 98} However, later studies found that blood and urine levels of vitamin C were lower in schizophrenics than in non-schizophrenics before and after a single 1,000 mg “load” of vitamin C was taken. After four weeks of daily supplementation with 1,000 mg of vitamin C, blood levels became the same, but urinary levels remained lower in the schizophrenic group, leading the researchers to conclude that the amount of vitamin C required by people with schizophrenia may be greater than that of the general population.^{99 , 100}

Vitamin B12 deficiency can cause symptoms that are similar to those of schizophrenia and one case has been reported in which such symptoms cleared after supplementation with vitamin B12.¹⁰¹ Some studies have reported finding lower levels of vitamin B12 in people with schizophrenia than in the general population,¹⁰² but others have found no difference.¹⁰³ No trials of vitamin B12 supplementation in schizophrenic patients have been published.