Wednesday, April 04, 2018

Niacin For Depression: Does Vitamin B3 Improve Mood?

Niacin For Depression: Does Vitamin B3 Improve Mood?

Stumble
SHARES46
Niacin (vitamin B3) is a colorless hydrophilic organic compound classified as an essential dietary nutrient among humans.  Foods highest in niacin include: organ meat (liver, heart, kidneys), chicken, beef, fish, venison, and whole grains.  For human adults, the daily recommended allowance of niacin falls within the range of 12 mg to 16 mg per day, with slightly greater intake (up to 18 mg per day) recommended for pregnant women.
The chemist Hugo Weidel is credited as being first to ever describe niacin in the late 1800s and biochemist Casimir Funk is thought to have been first to extract niacin.  It wasn’t until the late 1930s that biochemist Conrad Elvehjem was able to specifically identify niacin after extracting it from the liver.  Upon identifying niacin, Elvehjem appropriately referred to it as “pellagra-preventing factor” due to the fact that it protected against onset of the debilitating condition known as pellagra, characterized by symptoms of dementia, dermatitis, and diarrhea.
When ingested, niacin and its nicotinamide derivative are converted to NAD (nicotinamide adenine dinucleotide), which can undergo enzymatic phosphorylation (via NAD+ kinase) to form NADP (nicotinamide adenine dinucleotide phosphate).  It is estimated that upwards of 400 enzymes in the body necessitate NAD and NADP to accept or donate electrons in redox reactions.  Research suggests that NAD is implicated primarily in reactions that generate energy from catabolism of carbs, proteins, and fats – whereas NADP is more involved in anabolic processes such as synthesis of fatty acids and cholesterol.
Medically, niacin is considered effective and recommended for the treatment of high cholesterol (hypercholesterolemia) and high lipids (hyperlipidemia).  That said, many question whether supplemental niacin may be useful as an intervention for other medical conditions, including major depression.  As of current, little research has been conducted to investigate the therapeutic potential of niacin as an antidepressant, however, some are anecdotally convinced of its effectiveness.

How Niacin May Treat Depression (Mechanisms of Action)

It is possible that niacin might be an effective standalone and/or adjunct treatment for depression in a subset of individuals, however, since it hasn’t been well-researched for this purpose, its hypothetical mechanism of antidepressant action remains unclear.  Most would agree with the idea that niacin supplementation would attenuate symptoms of depression among individuals with an underlying deficiency (e.g. those with pellagra).  That said, mega-dosing with niacin supplements without a deficiency seems to affect neurological and biological function in ways that could improve mood.
For example, niacin supplementation is understood to affect: BDNF (brain-derived neurotrophic factor), cholesterol, hormones, neuroinflammation, and serotonin.  Some research suggests that niacin is capable of protecting brain cells from damage and/or death, as well as that it may reduce oxidative stress.  It is unknown as to whether one particular mechanism of niacin’s action may be more important than others in a possible antidepressant effect, however, it is possible that each mechanism hypothesized mechanism contributes to a varying extent and may be dose-dependent.
Anti-inflammatory effect: A means by which niacin supplementation may combat symptoms of depression is via reducing neuroinflammation.  As of 2016, researchers agree that many cases of major depression are a direct consequence of ongoing neuroinflammation.  In depressed individuals, circulating concentrations of inflammatory biomarkers within the CNS (central nervous system) usually appear elevated.
Predictably, many interventions that reduce neuroinflammation tend to facilitate antidepressant effects.  For example, preliminary research indicates that administration of anti-inflammatory drugs may treat depression principally by decreasing abnormally high levels of systemic inflammation.  Furthermore, treatment with first-line antidepressant medications generally reduces neuroinflammation.
Report this ad
Among individuals with excessive concentrations of inflammatory mediators such as cytokines, it is thought that these mediators send signals to the brain that disrupt homeostatic neurological function.  Specifically, cytokines are understood to deleteriously modulate the release, uptake, and production of neurotransmitters – making it easy to understand how neuroinflammation could lead to a monoaminergic imbalance and corresponding depressed mood.  Research by Offermanns and Schwaninger (2015) shows that nicotinic acid (niacin) is capable of ameliorating neuroinflammation by activating HCA(2).
It seems as though neurons affected by inflammation express HCA2, a receptor for nicotinic acid, beta-hydroxybutyrate (a neuroprotective ketone body), and DMF (dimethyl-fumarate).  When HCA2 is activated after one of the aforestated compounds binds to it, neuroinflammation decreases.  Intriguingly, each of these interventions have shown therapeutic promise for the treatment of multiple sclerosis (MS) and neurorehabilitation following a stroke – largely attributed to the HCA2-induced neuroinflammation reduction.
Researchers Wakade and Chong (2014) documented that niacin supplementation might reduce inflammation through action on GPR109A, a niacin receptor.  Agonists of GPR109A have been shown to exert anti-inflammatory effects throughout the skin, gut, and retina – and similar effects are speculated to occur in the brain.  Some suspect that niacin supplementation could also reduce neuroinflammation through its activation of the GPER (G protein-coupled estrogen receptor).
Note: It should be noted that Niacin Receptor 1 (NIACR1), GPR109A, and HCA2 all refer to the same receptor.
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/26260453
  • Source: https://www.ncbi.nlm.nih.gov/pubmed/25766751
  • Source: https://www.ncbi.nlm.nih.gov/pubmed/25455298
Report this ad
BDNF increases: Among the most convincing mechanisms by which niacin may treat depression is through its ability to increase BDNF (brain-derived neurotrophic factor) and corresponding expression of TrkB (tropomyosin receptor kinase B).  An onslaught of recent research emphasizes correlations between abnormally low BDNF concentrations and major depressive disorder in humans and animal models.  Furthermore, suboptimal concentrations of BNDF are associated with elevated stress, cognitive dysfunction, and neurodevelopmental deficits.
BDNF functions by acting on neurons to promote neuronal survival and stimulates the growth of new neurons (via neurogenesis) plus new synapses (via synaptogenesis).  Though many neurotrophic factors are necessary for the induction of neurogenesis, BDNF is regarded as being the most important.  Normative levels of BDNF in the hippocampus, cortex, and basal forebrain are associated with the ability to learn, form new memories, higher stress threshold, as well as enhanced mood.
Despite low levels of BDNF in persons with major depressive disorder, BDNF can be increased with antidepressant medications.  After 4 to 8 weeks of antidepressant treatment, individuals with major depression exhibit substantial increases in BDNF.  This finding has lead researchers to speculate that BDNF may be among the most important mechanisms of antidepressant action.
The delayed increase in BDNF after 4 to 8 weeks of treatment may also explain why antidepressants take so long to work or “kick-in” (it’s because BDNF requires weeks for upregulation).  An upregulation in BDNF after treatment with antidepressants is thought to restore neuronal plasticity, ultimately altering activity in neuronal networks and helping an individual recover from his/her depressed mood.  For example, a study by Shirayama, Chen, Nakagawa, et al. (2002) infused BDNF into the dentate gyrus of the hippocampus and noted pronounced antidepressant effects in animal models (based on learned helplessness and forced swim tests) within 3 days.
Report this ad
Other research by Castrén and Rantamäki (2010) showed that antidepressant interventions such as drugs or ECT (electroconvulsive therapy) increase BDNF and TrkB expression.  Castrén and Rantamäki suspected that BDNF is a mediator of neuroplasticity, and that increasing it likely rewires dysfunctional neural networks to enhance a person’s ability to cope with environmental stressors, thereby improving mood.  Upregulating BDNF in those with deficient levels is also thought to increase activity in monoaminergic systems such as serotonin and norepinephrine.
While most would agree that increasing BDNF concentrations is favorable, the favorable effects of BDNF are region-specific.  For example, prominent BDNF expression in the hippocampus is associated with an antidepressant effect whereas BDNF expression in the prefrontal cortex is associated with stress/depression.  Administration of supplemental niacin is understood to therapeutically increase BDNF in rats after an ischemic attack.
A study by Xu, Chopp, Zacharek, et al. (2010) involved subjecting rats to a middle cerebral artery occlusion.  Next, they administered extended-release niacin (40 mg/kg) to some of the rats, whereas the others received no treatment.  The niacin was administered for 14 consecutive days after the ischemic attack and changes in neural biomarkers were monitored throughout the experiment.
Results indicated that niacin treatment (40 mg/kg) and HDL cholesterol increased BDNF (plus TrkB expression) and neurite outgrowth compared to controls.  Researchers concluded that niacin administration promotes synaptic plasticity and growth of axons, in part by BDNF and TrkB.  Since this study was conducted in rats with a specific brain injury, it is unknown whether similar niacin supplementation-induced BDNF/TrkB expression would occur in humans with major depression.  That said, if niacin supplementation is able to enhance hippocampal BDNF/TrkB expression, there’s reason to hypothesize that attenuates depression.
Report this ad
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/11943826
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/20186711
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/20671245
Cholesterol modulation: Niacin supplementation is a medically-supported intervention for the management of hypercholesterolemia, a condition characterized by abnormally high levels of cholesterol in the bloodstream that may lead to onset of aortic aneurysm, heart attacks, peripheral artery disease, and/or stroke.  Given the association between cholesterol abnormalities and depression, it is reasonable to theorize that niacin-induced modulation of cholesterol may yield downstream antidepressant effects.  A study by Partonen, Haukka, Virtamo, et al. (1999) provided evidence that low serum total cholesterol is directly correlated with major depression and suicide risk.
In the study, a total of 29,133 men ages 50 to 69 provided blood samples over a duration of 5 to 8 years.  All blood samples were assessed for serum total and HDL (high-density lipoprotein) cholesterol concentrations.  The mood of each participant was documented using depression self-reports and hospital records, whereas suicide data was gathered from death certificates of deceased participants.
Analysis of the data revealed that low serum total cholesterol (TC) was predictive of depressed mood and suicide.  More recently, a meta-analysis by Wu, Ding, Wu, et al. (2016) assessed 65 epidemiological studies to investigate the relationship between serum lipids and suicidality.  The meta-analysis encompassed 510,392 participants, and discovered that serum total cholesterol (TC), LDL-C, triglycerides (TG) were significantly lower among suicidal individuals than non-suicidal depressed counterparts.
Additionally, the meta-analysis showed that compared to healthy euthymic controls, suicidal individuals exhibited lower serum concentrations of HDL-C, LDL-C, and TC.  Overall, results of the meta-analysis revealed an inverse association between serum lipid levels and suicidality.  A study by Aksay, Bumb, Janke, et al. (2016) was among the first to document that successfully treating depression [with ECT] appears to significantly increase serum concentrations of lipids.
Report this ad
In the study, researchers monitored serum lipids and mood of 27 patients with major depression prior to treatment with ECT, as well as post-ECT.  Those who derived significant antidepressant effects from ECT exhibited significant increases in HDL, LDL, and Apolipoprotein A1 compared to baseline.  Since this was a small-scale study and participants were taking psychiatric medications prior to ECT, it is unclear as to whether cholesterol changes were predictive of its antidepressant efficacy.
Nonetheless, it seemed as though successful responses to ECT were associated with noticeable alterations in serum lipids.  From this information, we could theorize that modulation of cholesterol may affect a person’s brain function and mood.  Knowing that niacin supplementation has a significant influence on serum lipids, it isn’t a stretch to consider that it may modify neurological function to improve depressive symptoms in a subset of patients to enhance mood.
Niacin is understood to increase HDL (“good”) cholesterol though several mechanisms including: downregulating of CETP (cholesterol ester transfer protein) gene activity, affecting the beta chain of ATP synthase, and modifying the production of apolipoprotein A1 to inhibit hepatic HDL uptake.  Although niacin increases HDL cholesterol, it is understood to decrease other lipids including: LDL (“bad”) cholesterol, VLDL, IDL, lipoprotein A.  It reduces levels of the aforestated lipids by: inhibiting enzymatic activity of DGAT2 implicated in triglyceride synthesis, binding to receptor HCAR2 (to reduce lipolysis and FFA flux to the liver to synthesize triglycerides), and increasing catabolism of apolipoprotein B.
Though some might suspect that niacin-induced reduction in lipids (e.g. LDL, VLDL, IDL, and lipoprotein A) would exacerbate depressive symptoms, there’s reason to believe that standalone increases in HDL may facilitate an antidepressant effect.  A study by Maes, Smith, Christophe, et al. (1997) showed that men with major depression and suicidal tendencies exhibit significantly lower serum concentrations of HDL cholesterol than those without depression.  They concluded that low HDL-C was an insightful biomarker for distinguishing depressed from non-depressed persons.
Report this ad
More research by Lehto, Hintikka, Niskanen, et al. (2008) analyzed serum lipid levels in 63 patients with a 7-year history of major depression and compared those to 61 euthymic (non-depressed) controls.  Results showcased significantly lower HDL-C concentrations among individuals with depression compared to the euthymic controls.  Even after adjusting for potential confounds such as educational attainment, marital status, alcohol consumption, smoking habits, and body weight – the correlation remained significant.
Yet another study highlighting the relationship between HDL-C and depression was conducted by Teofilo, Farias, Pinto, et al. (2014).  In this study, researchers analyzed HDL cholesterol levels during pregnant mothers and documented their mood based on scores from the Edinburgh Postnatal Depression Scale.  After adjusting for possible confounding factors (socioeconomic status, demographic, behavior, etc.), researchers noted that severity of depressive symptoms was associated with significantly lower HDL-C.
The abundance of research documenting low HDL cholesterol among those with depression has lead to the finding that low HDL is associated with blunted cortisol responses, as well as altered serotonergic transmission – especially among those with the 5-HTTLPR polymorphism.  Some theorize that low HDL may decrease G-protein coupling and binding of 5-HT to 5-HT1A receptors, as well as decrease density of 5-HT1A receptor sites.  Though these speculations are not well-substantiated in humans, it is possible that the niacin-induced upregulation in HDL alleviates depression [in some individuals] through modification of serotonergic transmission.
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/9111854
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/18583011
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25163727
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/10645328
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/26505144
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/26426831
Report this ad
Correcting niacin deficiency: There are many causes of niacin deficiency (i.e. pellagra) including: insufficient dietary intake, poor bioavailability of niacin (from un-limed grains), alcohol abuse, inability to absorb tryptophan, metabolic disorders, and/or chemotherapy treatment.  Though the overarching symptoms of niacin deficiency are diarrhea, dermatitis, and dementia – many other neuropsychiatric symptoms can occur.  In fact, an extremely common neuropsychiatric symptom among those with niacin deficiency is severe depression.
Depression among persons with pellagra could be related to low serotoninsynthesis stemming from a reduction in tryptophan availability within the brain, as well as 5-ALA and kynurenic acid concentrations.  It is known that nicotinic acid happens to influence the synthesis of respiratory enzymes and indirectly affects serotonin synthesis, plus nicotinic acid is derived from tryptophan, an amino acid precursor to serotonin (5-HT).  Many have speculated that niacin deficiency-induced depression is related to abnormally low serotonin synthesis as well as dysregulation within other neurotransmitter systems.
Should an individual experience depression from an underlying niacin deficiency, administering supplemental niacin is likely to normalize serotonin synthesis and function of other neurotransmitter systems.  Upon the reversal of niacin deficiency-related neurotransmitter system dysregulation, such as through dietary or supplemental ingestion of niacin, a person’s mood is likely to recover from a depressed state.  Moreover, the attenuation of neurological symptoms (e.g. brain fog and/or cognitive dysfunction) with niacin supplementation, may also contribute to mood enhancement.
Homocysteine regulation: Though not frequently discussed, another potential mechanism by which niacin might improve mood is through modulation of homocysteine.  It is well-documented that homocysteine abnormalities tend to occur among individuals with major depression, which in many persons might be related to overmethylation or undermethylation (stemming from genetic polymorphisms).  Individuals with genetically-mediated disturbances in their methylation cycle may end up with elevated homocysteine levels that cause neuropsychiatric symptoms such as depression, as well as other serious medical conditions.
Folstein, Liu, Peter, et al. (2007) proposed a homocysteine hypothesis of depression in which high homocysteine concentrations lead to neurotransmitter deficits and vascular disease to cause depressive symptoms.  While not every person with depression is guaranteed to exhibit a high level of homocysteine, many studies support the idea that homocysteine concentrations are elevated among depressed individuals compared to non-depressed controls.  An effective way to decrease homocysteine concentrations is to increase dietary intake of folate.
Sufficient folate is necessary for the methylation of homocysteine to methionine, and studies show that plasma homocysteine concentrations can be reduced by up to 25% with optimal folate intake.  That said, it appears as though adequate concentrations of niacin are important for the conversion of folate to its tetrahydrofolate derivative.  The tetrahydrofolate derivative is able to reduce homocysteine and is essential (along with vitamin B12) for the biosynthesis of tetrahydrobiopterin, a cofactor which crosses the blood-brain-barrier (BBB) and affects concentrations of serotonin, melatonin, dopamine, norepinephrine, epinephrine, and nitric oxide in the brain.
It should be noted that niacin supplementation will not always lower homocysteine.  In fact, research suggests that supplemental niacin can induce elevated homocysteine in some individuals.  For this reason, it may be that niacin supplementation (at individually-calibrated doses) favorably regulates homocysteine levels among those with specific methylation abnormalities.
Report this ad
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/17541043
Oxidative stress reduction: It’s possible that some of niacin’s mood enhancing effect might be related to decreasing oxidative stress.  A considerable amount of research suggests that excessive oxidative stress likely plays a (minor-to-moderate) role in onset and perpetuation of depressive disorders.  For example, a meta-analysis by Liu, Zhong, Liao, et al. (2015) discovered that free radical and oxidative damage concentrations were significantly greater in depressed patients compared to controls.
It was also noted that serum antioxidant levels and total antioxidant capacity (TAC) were significantly lower among those with depression compared to controls.  Interestingly, after treatment with an antidepressant medication, oxidative stress markers seemed to decrease.  Logically, it was hypothesized by researchers that certain antioxidants may prove efficacious as standalone and/or adjunct interventions for the alleviation of depression.
A separate meta-analysis by Jiménez-Fernández, Gurpegui, Díaz-Atienza, et al. (2015) provides evidence that oxidative stress appears to play a role in the etiology of depression and that action of antidepressants may involve attenuation of oxidative stress and/or upregulation in antioxidant status.  Since administration of niacin appears to reduce oxidative stress, its ability to do so may facilitate varying degrees of mood enhancement.  Research by Ganji, Kashyap, and Kamanna (2015) noted that niacin substantially reduced reactive oxygen species (ROS) production by inhibiting NADPH oxidase activation.
A study by Hamoud, Kaplan, and Meilin (2013) discovered that administration of niacin supplements for a 12-week duration significantly decreased oxidative stress.  The reduction in oxidative stress was evidenced by lower thiobarbituric acid reactive substances, lipid peroxides, and paraoxonase activity compared to pre-treatment.  Among depressed patients with heightened oxidative stress, niacin supplementation may be useful – especially if the oxidative stress co-occurs with cholesterol abnormalities.
Report this ad
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/26445247
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/26579881
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/26024755
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/22990043
Neurotransmitter modulation: A deficiency in niacin is known to deleteriously alter the production, release, and uptake of neurotransmitters throughout the brain.  The neurons of individuals that aren’t getting enough niacin (such as in pellagra) won’t function properly to secrete critical monoamines like dopamine, norepinephrine, and serotonin – leading to neurological impairment.  A myriad of neurological symptoms emerge among those with niacin deficits including: brain fog, cognitive dysfunction, dementia, and serious changes in mood.
Even if an individual isn’t suffering from pellagra, a subclinical niacin deficiency may be enough to disrupt neurotransmission and cause depression.  Furthermore, there’s reason to suspect that some individuals might benefit from maintaining supraphysiological levels of niacin via supplementation.  Among those with genetic polymorphisms that alter methylation status (e.g. overmethylation vs. undermethylation), more niacin may be necessary to convert folate to tetrahydrofolate for homocysteine reduction and the formation of tetrahydrobiopterin.
Though not much research has been conducted to determine how supraphysiological niacin concentrations might affect mood, there’s reason to believe that they could facilitate an antidepressant response in some individuals.  The way specific doses of niacin affect neurotransmitter levels haven’t been well researched in humans.  That said, it is logical to suspect that higher doses exert more pronounced effects than lower ones and that modulation of neurotransmitters as a result of niacin supplementation may be contingent upon individualized genetics (especially related to methylation) and neurotransmitter needs (in terms of specific dysfunction that’s causing depression).
Report this ad
Dopamine:  Research by Wakade and Chong (2014) proposed that niacin supplementation may be useful for persons with Parkinson’s disease in part by increasing dopamine synthesis in various parts of the brain such as the striatum by supplying NADPH.  Based on speculation that niacin might increase dopaminethrough supply of NADPH, it is reasonable to hypothesize that this may reverse low dopamine signaling in cases of depression.
Drugs acting on dopaminergic systems (e.g. Adderall for depression) seem to be highly effective for a subset of people with major depression.  Though niacin doesn’t function as a dopamine reuptake inhibitor nor releaser, its ability to counteract suboptimal dopamine concentrations in certain regions of the brain (with NADPH) may play a role in mood enhancement.
  • Source: https://www.ncbi.nlm.nih.gov/pubmed/25455298).
Histamine: Research by Tian, Li, Ma, et al. (2013) mentions that methylation is necessary for the degradation of neurotransmitters, including histamine.  Researchers documented the fact that niacin intake is understood to affect the methylation cycle, neurotransmitter degradation, and ultimately concentrations of histamine.  For this reason, they conducted a study to determine how significantly nicotinamide supplementation (100 mg) would affect plasma levels of histamine post-administration.
They discovered that plasma levels of histamine were significantly elevated after the nicotinamide (100 mg) dose.  It was concluded that niacin can disturb concentrations of neurotransmitters, likely by affecting degradation.  Though researchers imply that elevations in histamine may lead to neuropsychiatric disorders and neurological dysfunction, it is possible that slight increases in histamine may contribute to an antidepressant effect in some individuals.
Report this ad
Histamine signaling in the central nervous system (CNS) is associated with learning, wakefulness, feeding behavior, motivation, and goal-oriented behaviors – mediated by various histamine receptor sites in specific regions of the brain.  If histamine concentrations are suboptimal, it is no surprise to expect that a person might feel drowsy, mentally foggy, and lack motivation; (think of how you feel after taking an antihistamine).  Assuming niacin is increasing central levels of histamine by preventing excessive degradation, this could play a role in facilitating an antidepressant effect.
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/23426511
Nitric oxide: There’s some evidence to suggest that niacin might attenuate overexpression of nitric oxide synthase, which could contribute to its antidepressant effect.  A study by Du, Wang, Liu, and Zhang (2004) discovered that niacin supplementation decreased the expression of nitric oxide synthase in rat lungs exposed to silica.  Though these findings cannot be confirmed in humans and the effect of nitric oxide synthase attenuation occurred in the lungs (as opposed to the CNS), it is possible that similar effects may occur throughout the CNS.
Since many individuals with depression exhibit an overexpression of nitric oxide synthase, it is logical to suspect that administration of a nitric oxide synthase inhibitor may yield antidepressant effects. Not surprising is the finding that inhibition of nitric oxide synthase is associated with prominent antidepressant (plus anxiolytic) effects in animal models.  Researchers know that nitric oxide levels affect uptake and extracellular concentrations of other neurotransmitters including: dopamine, GABA, glutamate, and serotonin.
Various antidepressants have been observed to modulate concentrations of nitric oxide in the hippocampus of the human brain, possibly a means by which they enhance mood.  Knowing that niacin supplementation could attenuate nitric oxide synthase overexpression, this may prove therapeutic as an intervention for depression – especially among individuals for whom nitric oxide is a critical underlying component of their depressed mood.
Report this ad
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/15182488
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/9365231
Norepinephrine / Epinephrine: Many suspect that niacin influences concentrations of norepinephrine and epinephrine, both peripherally and centrally, to alter mood.  Research suggests that a subset of depressed patients exhibit low norepinephrineand altered epinephrine concentrations.  Based on this evidence, some antidepressant drugs (e.g. SNRIs, NRIsNDRIs, etc.) have been engineered to inhibit norepinephrine reuptake, whereby extracellular concentrations of norepinephrine increase, and noradrenergic signaling is enhanced.
Niacin is suspected to modulate norepinephrine and epinephrine significantly, especially when administered at high doses.  This modulatory effect may be enough to enhance a person’s mood and/or contribute to an antidepressant effect.  Though the exact mechanism by which niacin might alter norepinephrine and epinephrine (catecholamine) transmission isn’t elucidated, some believe its effect is mediated by the COMT enzyme.
It is known that nicotinic acid is a cofactor for the COMT enzyme which is implicated in catecholamine metabolism.  When niacin is administered, some theorize that it may limit the amount of norepinephrine that is converted to epinephrine, thereby preventing norepinephrine depletion and epinephrine surges – each of which might cause certain types of depression.  The degree to which niacin affects norepinephrine and epinephrine is likely contingent upon the dosage administered, as well as allelic variation of COMT, nonetheless, this may be a means by which supplementation improves a person’s mood.
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/21918528
Serotonin: Another means by which niacin could enhance a person’s mood is through increasing concentrations of serotonin.  A study by Tian, Li, Ma, et al. (2013) documented that supplementation with nicotinamide (100 mg) inhibited the degradation of monoamines, including serotonin.  The researchers discovered that within just 4 hours of administering the nicotinamide (100 mg) supplement, plasma serotonin concentrations significantly increased.
Report this ad
The increase in serotonin concentrations following supplemental niacin is thought to be a result of reduced serotonin degradation as a result of affecting the methylation cycle.  Though it isn’t known as to whether niacin supplementation increases central concentrations of serotonin by inhibiting its degradation, if it does, this could explain its antidepressant effect.  While serotonin dysfunction is not always implicated in major depression, it is understood that increasing serotonin signaling is often an effective way to improve mood.
Selective-serotonin reuptake inhibitors (SSRIs) are still the most prescribed antidepressant medications.  While niacin does not function by inhibiting the reuptake of serotonin, it could be elevating serotonin concentrations, which might bolster serotonergic signaling.  Moreover, some evidence shows that niacin’s ability to upregulate BNDF induces growth of new serotonin-producing neurons – possibly another mechanism by which it might enhance serotonin to improve mood.
Selective-serotonin reuptake inhibitors (SSRIs) are still the most prescribed antidepressant medications.  While niacin does not function by inhibiting the reuptake of serotonin, it could be elevating serotonin concentrations, which might bolster serotonergic signaling.  Moreover, some evidence shows that niacin’s ability to upregulate BNDF induces growth of new serotonin-producing neurons – possibly another mechanism by which it might enhance serotonin to improve mood.
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/23426511

Other possible mechanisms of niacin’s antidepressant effect…

It is reasonable to suspect that niacin’s ability to reduce inflammation, increase BDNF, modulate neurotransmission, and decrease reactive oxygen species (ROS) may alleviate symptoms of depression.  That said, there may be other mechanisms by which supplementation with niacin affects activity in the brain to treat depression.  Other possible mechanisms of niacin action include: angiogenesis, increasing cyclic ADP-ribose, normalization of mitochondrial function, and modifying myelination processes.
Report this ad
Angiogenesis: Preliminary evidence indicates that niacin is capable of inducing angiogenesis (growth of new blood vessels) to augment recovery following a stroke.  A study by Chen, Cui, Zacharek, et al. (2007) involved subjecting rats to a middle cerebral artery occlusion.  Next, the rats were given niacin (in the form of Niaspan) at doses of 40 mg/kg or 80 mg/kg 24 hours after the stroke and were treated for 14 consecutive days.
As a result of the Niaspan treatment, HDL cholesterol significantly increased, and it was this HDL increase that was culpable for induction of angiogenesis in the post-stroke animal brains.  One means by which angiogenesis was prompted may have been related to upregulation in the expression of VEGF (vascular endothelial growth factor) and modulation of biomarkers such as Ang1, Akt, Tie2, and nitric oxide synthase (NOS).  Though it is quite a stretch to assume that mega-dosing with niacin promotes angiogenesis in the brains of humans with depression, it is a possibility.
If angiogenesis is occurring, research supports that this may induce a profound antidepressant effect.  A report by Newton and Duman (2004) documents that while growth factor-induced neurogenesis may be one mechanism of antidepressant action, growth factor-induced angiogenesis (growth of new vasculature) should also be investigated.  Another report by Yamada (2016) emphasizes that angiogenesis (new blood vessels) is likely important in the recovery from major depressive disorders.
Standardized antidepressant medications such as SSRIs are understood to expedite the process of angiogenesis.  Yamada proposes that deliberate induction of angiogenesis may be capable of curing various cases of refractory depression.  More research is necessary to determine the effect of supplemental niacin on angiogenesis within the human brain.
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/16181076
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/26902903
Report this ad
Cyclic ADP-ribose (cADPR): A paper by Young and Kirkland (2008) documented the role of niacin intake on activation of cyclic ADP (adenosine-5′-diphosphate) enzyme CD38.  It should be noted that the CD38 enzyme is responsible for the manufacturing of cyclic ADP-ribose.  In the paper, it was noted that NAD+ is formed from ingestion of dietary niacin and implicated in the synthesis of cyclic ADP-ribose, a molecule associated with intracellular calcium signaling and known to promote synaptic plasticity within the hippocampus.
The hippocampus is a region of the brain involved in spatial learning, but is also associated with mood and behavior.  It was discovered that when animal models (mice/rats) are given nicotinamide supplements, the supplementation affects NAD+ within the brain, and correspondingly, the cyclic ADP-ribose concentrations.  Furthermore, deficits in niacin are associated with lower NAD+ and cyclic ADP-ribose and impair spatial learning abilities.
It could be postulated that low cyclic ADP-ribose may compromise cognitive performance, ultimately having a negative effect on mood.  Another possibility is that both cognitive performance and mood are deleteriously affected by low levels of cyclic ADP-ribose.  While it’s difficult to know how supraphysiological levels of niacin may alleviate depression, one mechanism might involve upregulating NAD+ and cyclic ADP-ribose in the hippocampus.
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/19079853
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/9354813
DNA repair: Individuals with major depression have been shown to exhibit elevated levels of DNA damage and appear unable to reverse it.  Researchers Czarny, Kwiatkowski, Kacperska, et al. (2015) proposed that a combination of inflammation plus reactive oxygen species (ROS) during times of stress induce DNA damage and compromise DNA repair mechanisms among those with depression.  They conducted a study comparing DNA damage (single-strand and double-strand breaks) in 40 individuals with major depression to that in 46 euthymic controls.
Report this ad
Results indicated that individuals with major depression exhibited significant elevations in DNA breaks and DNA damage, as well as dysfunctional DNA repair systems.  This research showcases the problem of DNA abnormalities among those with major depressive disorders.  Another means by which niacin might counteract symptoms of depression is by forming NAD+, which provides a necessary substrate for activation of the enzyme PARP-1, which is well-documented as enhancing DNA repair processes.
In other words, sufficient niacin through supplementation may be useful for the augmentation DNA repair, ultimately counteracting dysfunctional repair mechanisms seen in persons with depression.  It is also theorized that NAD+ (derived from niacin) can attenuate DNA damage, genotoxicity, and oxidative stress.  Overall, it is not farfetched to believe that upregulated DNA repair from niacin supplementation could play a role in its antidepressant effect.
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25656523
Mitochondrial function: A potential underlying cause of depressive symptoms in a subset of persons is mitochondrial dysfunction.  For example, a report by Bansal and Kuhad (2016) note that dysfunctional mitochondria may lead to: decreased ATP production, impaired Ca2+ signaling within cells, altered concentrations of neurotransmitters, and decreased neuroplasticity.  Evidence suggests that high doses of nicotinamide might prevent mitochondrial dysfunction by protecting against oxidative stress.
If administration of niacin is capable of mitigating or reversing mitochondrial dysfunction among individuals with depression, it’s reasonable to suspect that this may be a mechanism of its antidepressant action.  A study by Jia, Li, Gao, et al. (2008) documented that nicotinamide is associated with neuroprotective effects.  The researchers found that administration of niacin supplements (at high doses) decreased oxidative stress and enhanced mitochondrial function in animal models.
Report this ad
The proposed means by which niacin supplementation enhanced mitochondrial function was via the antioxidant effect of NAD(P)H.  Other research by Depeint, Bruce, Shangari, et al. (2006) suggests that a deficiency in any B-vitamin (including niacin) will impair mitochondrial function because the NADH synthesized from niacin is necessary for oxidative phosphorylation.  Optimizing niacin intake might adjunctively correct preexisting mitochondrial dysfunction to improve mood.
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/18381761
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/16765926
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/26923778
Myelination: Research from Nakashima and Suzue (1982) showed that nicotinic acid supplementation has a profound effect on the brain of developing rats.  In their study, researchers divided rats into 2 groups: one that received nicotinic acid supplements and the other that didn’t.  They then analyzed the brains of the rats given nicotinic acid and compared them to brains of rats devoid of the nicotinic acid supplementation.
Results indicated that myelination in the brains of the nicotinic acid-deficient rats was significantly lower than those given supplemental nicotinic acid.  In particular, the nicotinic acid augmented synthesis of complex lipids in the sheath of nerve fibers.  Though this study involved weanling (young rats), it is possible that supplementation with niacin improves and/or restores myelin plasticity among persons with depression to enhance mood.
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/7161647
Neuroprotection & Neuroregeneration: Niacin appears to protect neurons from inflammatory responses, oxidative stress, and mitochondrial dysfunction.  Supplementation with niacin is also understood to upregulate essential growth factors within the brain to alleviate depressive symptoms including BDNF and VEGF.  The combination of niacin’s activity as a neuroregenerative and neuroprotective agent may also explain its mood enhancing properties.
Report this ad
It is understood that niacin affects activity in the tryptophan-kyneurenic acid pathway through production of NAD.  If levels of NAD are low, a person becomes more vulnerable to incur damage from neurotoxins.  Depleted NAD concentrations also detrimentally affect mitochondria, leading to reduced mitochondrial respiration, lower ATP production, and onset of an energy crisis – which could cause neuronal death.
When niacin is supplemented, mitochondria should get enough NAD for respiration, whereby ATP production can remain high and protect against neuronal death.  Research by Kwon, Suh, Kim, et al. (2013) discovered that niacin suppresses mitogen-activated protein kinase pathway to attenuate brain injury following cardiac events in rats.  Though these findings are unsubstantiated in humans, niacin might also preserve brain function among individuals vulnerable to brain injury (e.g. as a result of medical conditions), thereby protecting against depression.
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/23648567
Note:  Despite the fact that niacin supplementation is associated with increased BNDF, upregulated HDL (“good”) cholesterol, and decreased inflammation – not all the mechanisms by which niacin modulates biological function may be conducive to mood enhancement.  Niacin is understood to reduce serum lipids such as LDL-C, total cholesterol (TC), and triglycerides – which might be unfavorable among those with already-low levels.
Additionally, there appear to be studies suggesting that niacin may lead to insulin resistance over a long-term by downregulating PDE3B (phosphodiesterase 3B).  Moreover, allelic expression of genes implicated in degradation of catecholamines (e.g. COMT) and methylation (e.g. MTHFR), as well as the dosage of niacin administered may influence responsiveness to niacin supplementation as a treatment for depression.

Benefits of Niacin for Depression (Possibilities)

Though the effectiveness of supplemental niacin for depression hasn’t been subject to much research, assuming it works, there are many possible benefits to be attained from utilizing it as an antidepressant.  Arguably the most significant benefit is that it may enhance mood while simultaneously regulating cholesterol (boosting HDL, lowering LDL, etc.), minimizing risk of cardiovascular events, and/or preventing onset of pellagra (associated with niacin deficiency).  Moreover, niacin supplementation is understood to be well-tolerated, safe (at reasonable doses), low-cost, and isn’t known to cause severe withdrawal symptoms upon discontinuation.
Report this ad
  • Adjunctive intervention: Individuals with depression may not want to take niacin as a standalone treatment, however, they may find it useful as an antidepressant augmentation strategy. Administration of niacin along with a neuropsychiatric medication (e.g. SSRI, SNRITCAMAOI) may act synergistically to enhance mood by amplifying antidepressant action of the neuropsychiatric drug and/or by acting upon distinct targets/pathways in the brain associated with mood improvement (that remain unaffected by the neuropsychiatric drug).  Another reason niacin may prove useful as a complementary intervention is based on a hypothesis by Viljoen, Swanepoel, Bipath (2015) suggesting that antidepressant treatment might deplete niacin and NAD stores.  Researchers propose that antidepressant medications might inhibit induction of the enzyme indoleamine 2,3-dioxygenase (IDO) in the kynurenine pathway, leading to increases in serotonin but downstream decreases in niacin/NAD concentrations.  For this reason, it may prove useful to supplement with niacin to prevent an antidepressant-induced deficiency.  (Source: http://www.ncbi.nlm.nih.gov/pubmed/25596911).
  • Anecdotal efficacy: There are many anecdotal reports floating around the internet suggesting that niacin is highly effective for the treatment of depression. Some of these anecdotes mention trying every prescription antidepressant with no favorable effect on mood and/or a worsening of depressive symptoms.  While it is impossible to rule out a placebo effect for those who claim to derive a strong antidepressant effect from niacin, it is reasonable (based on the functions of niacin in the body and brain) to believe that it might be effective as an antidepressant for a subset of users.  Those who are deficient in niacin are most likely to benefit, however, individuals with genetic polymorphisms implicated in methylation cycles and COMT enzyme function may benefit more than the general population.  What’s interesting is that many individuals who noticed mood improvement from niacin did not take it with the intention of treating their depression.  Many individuals started taking niacin for unrelated health conditions (e.g. cholesterol) and were surprised to find that it profoundly affected their mood.
  • Comorbid conditions: If niacin is effective for the treatment of a person’s depression, it may also prove useful for the management of comorbid medical conditions.  Research strongly supports the idea that niacin is useful for the management of hypercholesterolemia, hyperlipidemia, as well as preventing cardiovascular disease.  Preliminary evidence indicates that niacin may also be an effective treatment for neuropsychiatric conditions such as schizophrenia.  Should you have other medical conditions for which niacin’s usage is supported by quality research, you may be able to manage multiple conditions with a single supplement.
  • Few side effects: When ingested at reasonable doses, niacin isn’t associated with significant side effects. Even at fairly high doses such as between 1000 mg and 2000 mg, most individuals are able to tolerate its administration.  The side effects of niacin tend to diminish as the body adapts to its administration over a period of several weeks.  Niacin is unlike most pharmaceutical antidepressants which carry serious unwanted side effects such as weight gain, cognitive dysfunction, and/or sexual dysfunction (Read: “Antidepressant Side Effects“).  Even if side effects occur, most users are able to attenuate them with other agents (e.g. PGD2 antagonists for flushing).
  • Low cost: On average, a bottle of niacin containing 250 extended-release capsules dosed at 500 mg costs less than $15 online. Compared to most prescription antidepressants which may cost several hundred dollars for a 30-day supply, this is a bargain.  Assuming you end up taking 2 capsules per day for a 1000 mg dose, your $15 will have lasted 125 days (just over 4 months).  Even generic antidepressants (e.g. fluoxetine) will cost around $5 for a 30-day supply which ends up being slightly more expensive than niacin.  When considering that you also won’t need to frequently visit your doctor for prescription refill appointments (often costly), the savings are even greater.
  • Minimal interactions: Niacin isn’t known to interact with most prescription drugs and supplements. This means that a majority of medications and/or supplements that a person might be taking to treat a medical condition probably won’t interact with niacin.  That said, always check with your doctor before supplementing with niacin to verify that it’s safe with your current medication and/or supplement regimen.  There are certain medications (e.g. statins) that exert similar effects as niacin and therefore are contraindicated, however, most would agree that niacin has fewer interactions than conventional antidepressants.
  • Non-pharmaceutical: Appealing to many is the fact that niacin is a non-pharmaceutical intervention that might be effective for the management of depression. A subset of people with major depression refuse to take prescription antidepressant medications because they are synthetic (and not 100% natural), whereas others won’t take prescriptions because they are convinced that big pharma is evil.  Another set of individuals may have tested pharmaceutical drugs to treat depression only to find them ineffective with severe side effects.  Those who will never use a pharmaceutical antidepressant might derive some benefit from trying niacin – which may be better than nothing.
  • Zero withdrawal symptoms: Another favorable aspect of using niacin for the management of depression is that it isn’t associated with withdrawal symptoms upon cessation. Most prescription antidepressants are known to cause debilitating, long-lasting withdrawal symptoms when a user stops taking them.  The discontinuation symptoms associated with antidepressants may persist for months, or in some cases even longer (as a result of “Post Acute Withdrawal Syndrome“).  This is because the brain was being supplied with a boost in the signaling of a neurotransmitter system (e.g. serotonin) from a drug, and discontinuing that drug is disastrous not only because the brain became reliant upon its effect – but because the drug created profound neural changes that require a long-term to reverse.  Should you ever end up discontinuing niacin supplementation, there shouldn’t be a major rebound effect because it wouldn’t have been artificially bolstering neurotransmission within one particular system.

Drawbacks of Niacin for Depression (Possibilities)

If you’re thinking of taking niacin for the treatment of depression, it is necessary to understand the potential drawbacks of this approach.  The most notable drawback is that there’s ZERO evidence to suggest that niacin is an effective treatment for depression; it hasn’t been tested in any randomized controlled trials (RCTs).  Other drawbacks include the fact that niacin may be contraindicated in certain users or cause unwanted side effects.
Report this ad
  • Contraindications: Niacin cannot be safely used by everyone because some individuals have medical conditions in which niacin usage is contraindicated. Supplementation with niacin is contraindicated among those with: arterial bleeding, coronary artery disease, elevated serum transaminases, gout, hyperuricemia, hyperglycemia, hypotension, liver impairment, peptic ulcer disease.  It is also known that high doses of niacin can cause birth defects and/or neurodevelopmental impairment of newborns when ingested by pregnant women and are to be avoided.  Keep in mind that the aforementioned list of contraindications may be incomplete and that you should always talk to your doctor to confirm that it’s safe to take niacin given your medical status.
  • Dosing questions: Even if niacin is useful for the treatment of depression, it’s difficult to give a universal recommendation for an effective dosage range. It is known that 2 individuals taking an antidepressant drug may experience different therapeutic effects and/or side effects from totally different doses – one may find that 20 mg works well and is tolerable, whereas another may respond better to 45 mg.  For this reason, it is possible that one person may benefit from just 250 mg niacin per day, whereas another may find that 1000 mg niacin per day is more useful.  An effective dosing range, as well as recommendations based on genes associated with methylation cycles and COMT would be helpful but remains unclear.
  • Efficacy unknown: The effectiveness of niacin as an antidepressant remains unknown. It hasn’t been tested in randomized controlled trials (RCTs) for the treatment of major depression and the strength of evidence to recommend niacin as an antidepressant is nonexistent.  There are some proof-of-concept studies and anecdotal reports claiming that niacin may enhance mood, but these cannot be considered quality data.  Even if niacin were effective as an antidepressant, we wouldn’t know the degree of its efficacy (e.g. modest, moderate, highly) nor how it compares to evidence-based treatments.
  • Interactions: Though niacin may interact with less medications and supplements than most antidepressants, it still may provoke severe interaction effects when administered with various drugs or supplements. Any drugs that are known to modulate lipids and/or cholesterol (e.g. statins) can yield deleterious adverse interactions.  Other substances that could potentially interact with niacin include: Aspirin, Metoprolol, Nexium, Plavix, Tylenol, and Xanax – just to name a few.  Talk to your doctor to confirm that niacin is safe in combination with the current drugs and/or supplements that you’re taking.
  • Side effects: While most side effects associated with niacin are manageable, subside with continued usage, or can be reduced by decreasing the dosage of niacin administered – not everyone finds niacin side effects to be tolerable. The most common niacin side effects include: diarrhea, flushing of the skin (warmth, redness, itchiness, tingling, etc.), headache, muscle pain, nausea, skin rash, and vomiting.  Other side effects may include: blood pressure drops, blood sugar changes, cardiac abnormalities, gastrointestinal dysfunction, insulin resistance, liver impairment, and/or maculopathy.
  • Superior interventions: As of current, there are many antidepressant treatments that should be considered superior to niacin supplementation for the treatment of depression. Niacin supplementation is not supported by scientific studies to treat depression, however, many prescription medications (and even supplements) are reported as safe and effective in scientific studies for the treatment of depression.  For this reason, it would be unwise to try niacin before other evidence-based antidepressant treatments.  Even if you refuse to take an antidepressant medication, there are dietary supplements for depression that are supported by more science than niacin.

Niacin for Depression: Review of Evidence

  • As of current there hasn’t been much research assessing the effectiveness of niacin supplementation as a treatment for major depressive disorder (MDD).  There is some preliminary evidence from older trials indicating that niacin supplementation might reduce depressive symptoms among a subset of patients, however, the quality of evidence is extremely low.  Furthermore, when considering the finding that niacin-induced skin flushing appears inversely correlated with severity of depression (in a subset of persons), and the theory that reduced skin flushing is indicative of increased need for niacin – it is possible that certain individuals might derive varying degrees of antidepressant effects from niacin supplementation.2015Antidepressants may lead to a decrease in niacin and NAD in patients with poor dietary intake.
    One reason that some individuals may want to consider supplementing with niacin while taking pharmaceutical antidepressants is based on a hypothesis by Viljoen, Swanepoel, Bipath (2015) suggesting that pharmaceutical antidepressants could detrimentally affect concentrations of niacin and NAD.  Researchers noted that niacin is a precursor to the coenzymes NAD (nicotinamide adenine dinucleotide) and NADP (Nicotinamide adenine dinucleotide phosphate), each of which are implicated in hundreds of biological reactions.  Particularly, adequate niacin intake ensures that cellular energy production and integrity are being upheld.Niacin deficiencies are associated with onset of the condition pellagra in which individuals experience diarrhea, dermatitis, neurodegeneration, and possibly death.  Despite the fact that a majority of inhabitants of developed countries are consuming enough dietary niacin to avoid a deficiency, the hypothesis by Viljoen, Swanepoel, Bipath mentions that extra niacin intake may be necessary among a subset of individuals taking prescription antidepressants.  This is because antidepressant medications are suspected to inhibit the enzyme IDO (indoleamine 2,3-dioxygenase), and this inhibition is hypothesized to reduce downstream niacin and NAD synthesis.
    For this reason, a subset of individuals may necessitate additional dietary niacin to offset diminished synthesis as a result of their antidepressant treatment.  An obvious way to ensure that persons using antidepressants don’t end up with deficient niacin or NAD is to encourage niacin supplementation.  Supplementation is likely to prevent onset of a niacin and/or NAD deficiency and the corresponding deficiency-induced exacerbation of neuropsychiatric symptoms (e.g. depression).2010Alterations of niacin skin sensitivity in recurrent unipolar depressive disorder.
    A study by Smesny, Baur, Rudolph, et al. (2010) documented that skin flushing after niacin ingestion is likely indicative of the availability of PUFAs (polyunsaturated fatty acids).  Deficits in PUFA concentrations have been discovered among persons with major depression and administration of fish oil for depression (e.g. omega-3 fatty acids) is sometimes an effective treatment (or adjunct).  In this study, researchers attempted to determine whether abnormalities in niacin-induced skin flushing occur among individuals with depression.For the study, researchers recruited 30 patients with major depression (who were taking antidepressants) and compared those 30 individuals to 30 euthymic volunteers.  Skin flushing of all participants was then analyzed over a 15-minute duration after administration of methyl-nicotinate.  Results revealed zero noticeable differences in skin flushing among the individuals with depression and euthymic volunteers.
    That said, sensitivity to niacin was inversely correlated with severity of a person’s depression.  Specifically, the more depressed a person was, the less likely he/she exhibited skin flushing from the niacin administration.  Based on this finding, researchers concluded that a subset of depressed individuals exhibit abnormalities in niacin-induced skin flushing, and theorize that these persons may benefit most from PUFA supplementation.
    • Though not discussed by researchers, the findings of decreased skin flushing may be indicative of an underlying need for additional niacin via diet or supplementation.  Some medical professionals have theorized that individuals with the most blunted niacin-induced skin flushing are likely to derive greatest benefit from its supplementation.  Assuming depressed patients with suboptimal skin flushing responses necessitate additional niacin, supplementation might contribute to modest (or perhaps unpredictably significant) antidepressant effects.
      • 2008The Role of Vitamins and Minerals in Psychiatry
        Cornish and Mehl-Madrona (2008) published a paper discussing the role of vitamins in psychiatry.  It was documented that the effects of niacin appear analogous to those of benzodiazepines and barbiturates (sedative hypnotics) in mouse models.  Furthermore, there’s evidence to suggest that niacin administration induces anticonvulsant, anti-aggression, and muscle relaxant effects.
        Noted by researchers was the fact that, in humans, the daily recommended allowance of niacin is 16 mg for men and 14 mg for women.  Adequate daily intake of niacin ensures that individuals are able to maintain production of coenzymes NAD and NADP, each of which are involved in hundreds of biological processes.  The hypothesis that niacin supplementation may ameliorate CNS dysfunction among persons with neurological disorders was discussed.
        A subset of evidence suggests that niacin supplementation can reduce symptomatic severity of various neuropsychiatric conditions such as schizophrenia, however, this evidence is weak.  Nevertheless, niacin supplementation seems to be tolerable for most users at doses up to 1500 mg per day.  In summary, more research is needed to determine whether niacin and its NAD and NADP coenzymes may counteract CNS abnormalities to treat neuropsychiatric disorders, including major depression.
        In advanced stages of pellagra, a condition caused by niacin deficiency, individuals commonly experience neurodegeneration or dementia.  Morris, Evans, Bienias, et al. (2004) investigated whether variation in a person’s dietary intake of niacin may affect onset of neurodegeneration.  For their study, researchers documented dietary niacin intake in relationship to Alzheimer’s disease and cognitive decline in study encompassing 6,158 elderly adults (ages 65+) between the years 1993 and 2002.
        Dietary intake of niacin was roughly estimated based on data compiled from a food frequency questionnaire given to participants.  A battery of 4 cognitive tests were administered to all participants at intervals of 3-years and 6-years after initiation of the study.  Researchers noted that 3,718 participants completed a minimum of 2 cognitive evaluations to document long-term change in cognitive function (over ~5.5 years).
        From the results gathered, it appears as though niacin is protective against development of Alzheimer’s disease and cognitive decline in the elderly.  In short, the greater the quantity of niacin a person consumed, the less likely they were to develop Alzheimer’s disease or experience a drop-off in cognitive performance.  These findings remained significant even after adjusting for confounding factors such as age, education, race, sex, and ApoE e4.
        Since this study was not a randomized controlled trial and relied on surveys, it’s difficult to know definitively whether increased intake of dietary niacin was the cause of reduced neurodegeneration.  It is also important to emphasize the fact that the study was conducted on elderly participants only (ages 65+) meaning the results may not be applicable to younger adults.  Assuming niacin intake protects against age-related neurodegeneration, we could speculate that it might also protect against age-related onset of major depression.
      • 2004Dietary niacin and the risk of incident Alzheimer’s disease and of cognitive decline.Knowing that neural underpinnings of neurodegeneration can cause and/or overlap with depression (as can the psychological distress implicated in cognitive decline), it is possible that supplementation with niacin might: protect against, slow the onset of, and/or reverse neurodegeneration (and corresponding depression) in a subset of patients.  It is also possible that niacin may exert therapeutic neuroprotective effects in younger populations.  Any protective effect against cognitive decline is likely to have favorable implications for mood.
      • 1979Tryptophan-nicotinamide, imipramine and their combination in depression. A controlled study.
        A trial by Chouinard, Young, Annable, and Sourkes (1979) implemented a double-blind controlled design to test the effectiveness of combined tryptophan-nicotinamide supplementation for the treatment of depression.  For the study, researchers recruited 25 newly-admitted patients with severe depression and assigned them at random to receive either: tryptophan-nicotinamide (combination), imipramine (standalone), OR tryptophan-nicotinamide plus imipramine.  Treatments were received for a duration of 4-weeks and mood of each participant was assessed at baseline and after Week 1, Week 2, Week 3, and Week 4 – using the HDRS, CGI, and BDI.
        A total of 8 participants received the L-tryptophan plus nicotinamide combination at a starting dose of 2 grams L-tryptophan and 0.5 grams nicotinamide for the first week.  Doses were gradually increased to 6 grams of L-tryptophan and 1.5 grams of nicotinamide by the start of Week 3.  Another 8 participants received standalone imipramine (a tricyclic antidepressant) at a dose of 75 mg for the first week of treatment and were gradually titrated up to a 225 mg dose by Week 3.
        The remaining 9 participants received L-tryptophan, nicotinamide, and imipramine at the same doses as the other groups.  Results suggested that all groups exhibited significant antidepressant responses, however, there were no differences between the groups.  When patients with bipolar depression were excluded from the final analysis, the patients receiving all three treatments (L-tryptophan, nicotinamide, and imipramine) experienced greatest improvement in symptoms.This study provides strongest evidence for the idea that L-tryptophan plus niacin can reduce depressive symptoms equally as well as imipramine.  Still, the study was extremely small and conducted over a short-term, making it difficult to rule out a placebo effect.  The trial would’ve benefitted from being conducted over a duration of several months, with more participants, and placebo-only control group.

        It would also be helpful to know whether nicotinamide is necessary to be administered along with L-tryptophan for benefit.  Researchers theorize that nicotinamide inhibits peripheral breakdown of tryptophan, increasing likelihood that the tryptophan survives to alter neural function, however, this theory remains unsubstantiated.  Nonetheless, this provides some modest evidence suggesting that niacin might synergistically improve mood with L-tryptophan.

        1978Role of nicotinic acid and its derivatives in disorders of nervous system function.
        A Russian report by Parkhomets, Kuchmerovskaia, Donchenko, et al. (1978) highlights the fact that nicotinic acid and derivatives are highly important to ensure normative function within the central nervous system.  Researchers document that nicotinamide, nicotinic acid, and the biologically active NAD influence activity in the CNS that may help treat severe neuropsychiatric disorders such as epilepsy and schizophrenia.  This report supports the idea that increasing concentrations of niacin and its coenzyme derivatives may ameliorate dysfunction within the CNS to improve functionality among persons with CNS disorders.  Since CNS abnormalities are implicated in depressive disorders, there’s reason to suspect that ensuring adequate niacin intake through diet (or supplementation) might yield therapeutic effects.
        Cornish and Mehl-Madrona (2008) published a paper discussing the role of vitamins in psychiatry.  It was documented that the effects of niacin appear analogous to those of benzodiazepines and barbiturates (sedative hypnotics) in mouse models.  Furthermore, there’s evidence to suggest that niacin administration induces anticonvulsant, anti-aggression, and muscle relaxant effects.
        Noted by researchers was the fact that, in humans, the daily recommended allowance of niacin is 16 mg for men and 14 mg for women.  Adequate daily intake of niacin ensures that individuals are able to maintain production of coenzymes NAD and NADP, each of which are involved in hundreds of biological processes.  The hypothesis that niacin supplementation may ameliorate CNS dysfunction among persons with neurological disorders was discussed.
        A subset of evidence suggests that niacin supplementation can reduce symptomatic severity of various neuropsychiatric conditions such as schizophrenia, however, this evidence is weak.  Nevertheless, niacin supplementation seems to be tolerable for most users at doses up to 1500 mg per day.  In summary, more research is needed to determine whether niacin and its NAD and NADP coenzymes may counteract CNS abnormalities to treat neuropsychiatric disorders, including major depression.1975: Letter: Treatment of unipolar depression.
        MacSweeney (1975) investigated the efficacy of niacin as an intervention for unipolar depression.  In the investigation, 25 individuals diagnosed with major depression were assigned at random to receive either: electroconvulsive therapy (ECT) OR a combination supplement comprised of L-tryptophan plus niacin.  A total of 13 patients received the ECT unilaterally for a total of 8 sessions, whereas 12 patients received L-tryptophan (3 grams) plus niacin (1 gram) per day.
        The experiment was carried out over a 4-week term and changes in mood of participants were recorded from baseline (pre-trial) through the end of the final week using the BDI (Beck Depression Inventory) self-rating scale.  Specifically, changes in mood were assessed on Day 3, Day 7, Day 10, Day 14, Day 17, Day 21, Day 24, and Day 28.  At baseline, the individuals receiving ECT exhibited an average BDI score of 25.6, whereas the group receiving the L-tryptophan plus niacin exhibited an average BDI score of 24.4.
        Results indicated that by Day 10, those receiving the L-tryptophan plus niacin experienced significant mood improvement compared to the ECT group.  At Day 10, BDI scores of the L-tryptophan plus niacin recipients had dropped to 15.2 (from the 24.4 baseline score) and those receiving ECT experienced a reduction in BDI score to 16.8 (from the 25.6 baseline), but this was not as substantial as the other group.  By Day 21, BDI scores of the L-tryptophan plus niacin recipients had dropped to 3.7 and BDI scores of the ECT group dropped to 8.8.
        After the full 28 days (4-week duration), mood improvement among ECT recipients was indistinguishable from recipients of daily L-tryptophan plus niacin – all study participants experienced significant antidepressant effects.  That said, it appears as though the combination of L-tryptophan plus niacin facilitated a faster onset of antidepressant action compared to ECT (as evidenced by earlier differences in BDI scores).  Overall, this study suggests that both ECT and L-tryptophan plus niacin – are equally effective antidepressant interventions over a 4-week duration.
        While the study was randomized, the study was not controlled (with a placebo intervention), utilized an extremely small sample size (just 25 participants), and was conducted over a short-term (just 4-weeks).  Clearly it is possible that L-tryptophan increases serotonergic production and signaling in the CNS to enhance mood, however, it’s difficult to know whether adjunctive niacin was necessary to generate a significant antidepressant effect.  It is possible that standalone L-tryptophan sans niacin may have been as effective as L-tryptophan with niacin.
      • 1953: Depressive and anxiety reactions treated with nicotinic acid and phenobarbital.
        Thompson and Proctor (1953) recruited 100 patients with a combination of depression and anxiety to participate in a study involving treatment with nicotinic acid and phenobarbital.  Patients were given niacin and phenobarbital in tablet and elixir formats containing a starting dosage of 100 mg niacin plus 8 mg phenobarbital.  By Day 15 of the trial the dosages of participants had been titrated upwards to peak at 900 mg of niacin and 72 mg phenobarbital.
        From Day 16 through 21, dosages were decreased to 450 mg niacin and 36 mg phenobarbital.  The entire combination was implied to have been discontinued by all participants after Day 21.  Changes in severity of depressive and anxiety symptoms were tracked throughout the study.  Results indicated that 47.2% of patients reported significant improvement in symptoms, 34% reported some improvement, 13.2% reported zero improvement, and 5.4% discontinued treatment altogether.Though the study included a reasonable sample size of 100 participants, it was not randomized nor controlled with a placebo.  Due to lack of randomization and controlling, it’s impossible to know whether the niacin and phenobarbital combo legitimately alleviated symptoms of depression and anxiety.  Furthermore, since niacin was administered with phenobarbital (a drug known as effective for managing a variety of neuropsychiatric conditions), it is possible that phenobarbital provided a bulk of (or perhaps all) the benefit and niacin simply tagged along as an ineffective adjunct.
        A better study would’ve been to specifically compare the efficacy of niacin, phenobarbital, and a placebo for the management of depression and anxiety.  If controlled with a placebo and administered as a standalone agent, we would be able to understand whether niacin might facilitate antidepressant or anxiolytic effects at high supplemental doses.  Disappointingly, nothing of significance can be concluded regarding the efficacy of niacin, phenobarbital, or a combination of niacin plus phenobarbital for the treatment of depression (or anxiety).Results suggested that 3 patients derived antidepressant benefit from niacin, but needed additional treatment after the first course to maintain mood improvement.  Another 2 patients attained lasting but only partial symptomatic relief.  The remainder of patients failed to derive any antidepressant benefit from supplementation with niacin.
        Overall, it didn’t appear as though there was a significant antidepressant effect associated with administration of niacin.  At the time of this study, researchers believed that niacin might bolster cerebral circulation and vasodilatory function to improve mood.  Though niacin appeared promising in a few users, this may have been nothing more than a placebo effect.
        Various problems with this study include its small sample size, including patients with all depressive subtypes, and extremely short duration of treatment.  Perhaps results may have differed in a larger sample over a longer term (e.g. 3 months).
        • 1950Nicotinic acid in the treatment of certain depressed states; a preliminary report.
          In 1950, results from a preliminary trial conducted by Washburne were published in which nicotinic acid was administered as an adjunct intervention for depression.  The trial recruited 15 patients that had been diagnosed with depressive disorders.  All patients were enrolled in psychotherapy and assigned to receive niacin as an adjunct antidepressant intervention.
          The niacin was administered intravenously and followed up with oral niacin for a starting dose of 300-400 mg per day.  Next, the dose of niacin was gradually titrated upwards until it reached 900 mg per day, however, one patient managed to titrate upwards to a mega-dose of 2500 mg per day.  Peak dosages at around 900 mg per day were maintained for a duration of 7 to 10 days and then gradually tapered down over a 2 to 6-week term.
          Results of this preliminary trial were favorable in that 14 out of 15 participants experienced significant subjective and objective mood improvement.  The problem with this trial is that it is non-controlled, non-randomized, and tested niacin paired with a clinically-effective antidepressant intervention (psychotherapy).  Though it is possible that niacin contributed to mood improvement of participants, it cannot be proven

          For all we know a placebo effect may have occurred as a result of the niacin administration and synergistically enhanced mood with the psychotherapy.  Furthermore, the study was extremely small-scale, making it difficult to know whether similar findings would occur in a larger population.  Unfortunately, zero quality evidence to support the antidepressant efficacy of niacin can be derived from this study.For all we know a placebo effect may have occurred as a result of the niacin administration and synergistically enhanced mood with the psychotherapy.  Furthermore, the study was extremely small-scale, making it difficult to know whether similar findings would occur in a larger population.  Unfortunately, zero quality evidence to support the antidepressant efficacy of niacin can be derived from this study.

Limitations of Research associated with Niacin for Depression

        • There are many limitations associated with the research of niacin supplementation for the treatment of major depression.  A notable limitation is that a bulk of trials testing the antidepressant efficacy of niacin among patients with depression is that the trials lack quality designs (e.g. randomized, controlled, double-blinded).  Other limitations include: small numbers of participants, failure to test niacin as a standalone antidepressant, and lack of incentive to conduct additional research.
          • Adjunct-only: Most studies documenting the therapeutic efficacy of niacin involve its co-administration with L-tryptophan. Even if it appears as though niacin is effective when concurrently administered with L-tryptophan, there’s no reason to believe that the niacin contributes substantially to an antidepressant response.  It is possible that in studies in which L-tryptophan is administered with niacin, that the L-tryptophan is responsible for the entire mood enhancement effect (or a significant majority of it).  To know its adjunctive efficacy, it is reasonable to ask researchers to compare standalone L-tryptophan to the tryptophan/niacin combination and determine whether significant differences in mood enhancement are observed.  If no significant differences are discovered, it may be that niacin, for the majority of users, is devoid of antidepressant effect.
          • Depressive subtypes: Another problem with many of the studies attempting to determine the antidepressant effect of niacin is that they incorporate populations with an array of depressive subtypes. Some studies test the effect of niacin on persons with anxious depression, whereas others recruit participants with distinctly different types of depression.  There’s reason to believe that not all subtypes of depression will respond well to niacin.  Considering the mixture of depressive subtypes plus the extremely small sample sizes in most studies, it’s difficult to know whether niacin might be effective.  It is reasonable to assume that niacin may yield greatest efficacy in depressed patients with blunted niacin-induced flushing (possibly suggesting impaired receptor sensitivity and downstream neural consequences).
          • Lack of incentive: There’s really no incentive for researchers to investigate the effectiveness of niacin for depression. Most pharmaceutical companies aren’t trying to patent niacin (other than Niaspan) and won’t sink R&D dollars into determining whether niacin supplementation might improve mood.  Furthermore, determining whether niacin supplements may yield an antidepressant effect is probably not the smartest way to allocate research dollars.  The lack of incentive to determine niacin’s antidepressant efficacy is likely the reason research ceased in the late 1970s.
          • Few studies: There are very few studies that have taken the time to investigate the effect of niacin (as a standalone or adjunct) for the treatment of depression. Most studies that have assessed the antidepressant efficacy of niacin were conducted between 1950 and 1980.  Not only are there few studies, but the majority are not the randomized controlled trials necessary to yield convincing evidence.
          • Niacin details: The dosage of niacin administered, modality of administration (e.g. oral, IV, etc.), as well as the format (e.g. nicotinic acid, nicotinamide, etc.) may each influence the effectiveness of niacin for the treatment of neuropsychiatric conditions. It may turn out that nicotinamide exerts a completely different effect on mood than nicotinic acid.  We might also find that to be effective, niacin should be administered intravenously instead of orally (or perhaps vice-versa).  Lack of knowledge regarding the optimal modality of niacin administration for mood enhancement could be of detriment to trial results.
          • Small studies: Though one study tested the effect of niacin as a treatment for depression on 100 participants, it was an uncontrolled pilot study, meaning nothing of significance can be concluded from the results. Studies that incorporated blinding, randomization, and/or controlling happen to be extremely small scale with around 15 to 30 participants.  Though randomization and controlling generate more reliable results than uncontrolled pilot studies, a small sample size makes the evidence attained from small studies extremely weak.  For this reason, to know whether niacin is likely to work for depression, larger studies (with randomized controlled designs) are needed.
          • Study designs: As was already mentioned, a significant problem associated with research of niacin for depression is the design of studies investigating its efficacy. Most studies lack randomization, controlling, and blinding.  The lack of placebo controlling makes it difficult to know whether niacin legitimately improves mood.  Furthermore, nearly every study was conducted over an extremely short duration (usually 4 weeks or less), making it difficult to know whether niacin was associated with sustained mood improvement (in cases where it was seemingly effective).

Does niacin help treat depression?

        • At this point it’s unknown as to whether niacin can be taken as a supplement to successfully treat symptoms of depression.  Most would agree that getting enough niacin in the diet is helpful to maintain neurological and physiological health, however, assuming you aren’t suffering from pellagra or a subclinical niacin deficiency, there isn’t compelling evidence to suggest that supratherapeutic intake facilitates a clinically-relevant antidepressant effect.  That said, there is some evidence to suggest that niacin (in the form of nicotinamide) could reduce depressive symptoms when administered along with L-tryptophan.Some believe that niacin inhibits excessive peripheral metabolism of L-tryptophan, thereby increasing the amount of serotonin that enters the CNS to enhance mood.  Whether nicotinamide actually inhibits peripheral tryptophan breakdown is questionable and necessitates research.  In any regard, research by MacSweeny (1975) showed that tryptophan-nicotinamide combinations were as effective as ECT over a 4-week duration for the treatment of depression.
          Another study by Chouinard, Young, Annable, et al. (1978) documented that tryptophan-nicotinamide (6 grams and 1.5 grams, respectively) combinations appeared to reduce symptoms of depression, however, this study was uncontrolled.  A follow-up investigation by Chouinard, Young, Annable, and Sourkes (1979) was controlled and compared tryptophan-nicotinamide to the prescription antidepressant imipramine, as well as imipramine plus tryptophan-nicotinamide.  In this study, it was shown that all 3 groups exhibited significant mood improvements, suggestive of the fact that tryptophan-nicotinamide combinations can attenuate depression.Though the research quality is relatively poor, many studies suggest that niacin may provide antidepressant benefit.  Furthermore, numerous anecdotal accounts (online) document substantial mood improvement after supplementation with niacin.  It is reasonable to theorize that a subset of depressive subtypes as caused by polymorphisms influencing methylation and COMT function may derive a therapeutic mood improvement from niacin supplementation.
          Most likely to derive an antidepressant and cognitive enhancing effect from niacin supplementation are individuals with preexisting niacin deficiencies.  At this point, niacin supplementation cannot be recommended as an antidepressant treatment option.  There are numerous medications, as well as dietary supplements with significantly stronger data supporting an antidepressant effect compared to niacin.Anyone considering niacin should not only beware of possible adverse effects resulting from high-doses, but understand that it could exacerbate underlying depressive symptoms.  There’s not really much harm in trying niacin for yourself to see if it provides any additional antidepressant benefit, but always double check with your doctor to confirm that its safe with your current medical status and medication/supplement regimen.  Unless more solid research emerges suggesting that niacin treats depression, we should remain skeptical of its efficacy for the majority

Have you taken niacin for depression?

        • If you’ve taken niacin for the treatment of depression, share your experience in the comments section below.  On a scale of 1 to 10, with “1” being least effective and “10” being highly effective, how would you rate the antidepressant efficacy of niacin?  To help others get a better understanding of your situation, provide some additional details including: your age, why you started taking niacin, other medications/supplements you use, and whether you have any medical conditions besides depression.
          Also mention things like: the dosage of niacin you take (each day), format of niacin (e.g. nicotinic acid, nicotinamide, standard niacin, inositol hexanicotinate, etc.), brand of niacin, and how long you’ve been taking it.  For those that have derived some subjective mood benefit from niacin, document how long it took for the antidepressant effect to emerge after initiation of treatment (e.g. days, weeks, etc.).  Did you notice any unwanted effects from your supplementation with niacin such as: facial flushing, dizziness, or GI dysfunction?If you have a theory regarding a potential mechanism of niacin’s antidepressant action (even if it may be individualized), explain it within your comment.  Understand that if you haven’t tried niacin for depression, you can always talk to your doctor about giving it a shot.  Theoretically you could conduct a blinded self-experiment, although it may be tough to determine the optimal dosage range, but a medical professional should be able to help you out.


















No comments: