Creatine and Bipolar Disorder – The Manic Switch Risk

Every tub of creatine carries a standard warning about consulting a physician. You will rarely find a warning about mania.

In clinical footnotes, the signal is clear. For a specific subset of the population, this energy supplement acts less like a battery and more like a detonator. Two separate trials have documented patients switching from depression into mania after taking creatine.

The industry sells the molecule for ‘mood support’. The science suggests that for the bipolar brain, it is often too much of a good thing.

The Roitman Incident

The investigation begins with a 2007 open-label study by Roitman et al. The researchers sought to test creatine as a booster for treatment-resistant depression.

The study primarily targeted unipolar depression (standard depression or major depression). However, the cohort included two participants with bipolar disorder. This detail serves as the pivot for the entire safety investigation.

Both bipolar patients developed hypomania or mania shortly after commencing daily supplementation at 3 to 5 grams. Hypomania is a milder form of mania, but it involves a distinct shift in judgment and stability. The key finding was the direction of travel, a rapid shift from depression to elevated mood following supplementation.

Both patients were forced to withdraw from the study. Roitman et al. explicitly concluded that creatine poses a ‘possible triggering of a manic switch in bipolar depression’. This warning exists in the primary text of the study, yet has largely evaporated from consumer consciousness.

The Toniolo Confirmation

Sceptics might dismiss the Roitman findings as an anomaly of a small, open-label study. This argument fails against the 2018 findings of Toniolo et al.

They conducted a randomised, double-blind, placebo-controlled trial specifically focused on bipolar depression. This design represents the gold standard of clinical evidence.

The study showed efficacy. The creatine group achieved a remission rate of 66.7 per cent compared to 18.2 per cent in the placebo group. This result is striking for a condition where treatment is often difficult.

Yet the study also recorded the risk often omitted from consumer messaging. Two patients in the creatine group switched to mania or hypomania. Zero patients in the placebo group experienced this switch.

In a sample of 35 participants, two switches constitute a significant safety signal. The benefit and the risk appear to stem from the same mechanism. If creatine lifts a depressed patient into remission by increasing energy availability in the frontal cortex, that same mechanism can overshoot the target.

The Exclusion Trap

If the signal is clear in studies involving bipolar patients, the absence of this warning in the general narrative requires explanation.

The answer lies in trial design. Clinical trials rely on exclusion criteria to ensure clean data. A review of clinical trial protocols reveals a consistent pattern. Protocols studying creatine in depression, such as NCT04504253 and NCT01543139, explicitly list ‘Bipolar I, Bipolar II’ and ‘History of Mania’ as exclusion criteria.

Researchers remove the population most at risk of a manic switch before the trial begins. The resulting data shows a clean safety profile for the population allowed to participate.

This design cannot measure risk for the excluded group. The retail narrative frequently ignores this distinction. ‘Safe in unipolar depression’ transforms into ‘supports mood’ for the general population. The caveats vanish. This creates the Safety Blind Spot.

The Bioenergetic Mechanism

The ‘Bioenergetic “brain energy” Hypothesis’ offers a framework for understanding why creatine helps some patients while destabilising others.

This hypothesis suggests that some mood disorders involve a failure of brain energy metabolism. Neurons in the frontal cortex struggle to maintain the energy required for planning and emotional regulation. Creatine increases the fuel reserves, which rapidly regenerates cell energy, the molecule cells use for immediate energy.

Increased backup power allows neurons to fire more effectively under load. In unipolar depression, this restoration of function looks like a benefit. It lifts the patient out of a low-energy state.

Bipolar disorder differs because mood can swing high. The energy surge that restores function in depression can become destabilising in a system prone to over-excitement. The mechanism pushes the brain past stability into mania.

The Stress Clause I

Moving to the general population, the investigation pivots to the conditions under which creatine actually works for the brain: acute stress.

McMorris et al. (2006, 2007) subjected participants to 24–36 hours of total sleep deprivation. Placebo groups showed catastrophic declines in mood and performance. Creatine groups showed a less severe decline.

Crucially, creatine did not improve performance at the rested baseline. It acted as a buffer during the crisis. It resembles an emergency battery pack rather than a daily nootropic.

The Stress Clause II

Further reinforcing the ‘Buffer’ theory, Turner et al. (2015) examined cognitive performance under hypoxia (oxygen deprivation). This mimics conditions of high altitude or compromised vascular supply.

Creatine supplementation restored brain responsiveness and attention to near-normal oxygen levels despite the lack of oxygen.

This confirms creatine’s role as a neuroprotective agent during physical crisis. It is useful for high-altitude aviators or stroke recovery, but irrelevant for the office worker in an oxygen-rich environment.

The Consumer Hazard

The danger lies in the marketing of these findings. Marketing translates ‘clinical efficacy in depression’ to ‘good for low mood’.

Given that Bipolar II Disorder is frequently misdiagnosed as Major Depression, a significant number of consumers buying creatine for ‘mood support’ may be unknowingly exposing themselves to a manic trigger.

The ‘Safety Blind Spot’ is not just academic. It is a live public health risk created by the distance between the clinical exclusion criteria and the retail shelf.

Sources

Sources include: the 2007 open-label study by Roitman et al. documenting the precipitation of mania in bipolar patients; the 2018 randomised controlled trial by Toniolo et al. confirming the distinct adverse event profile in bipolar depression; foundational research on acute metabolic stress, specifically the sleep deprivation protocols established by McMorris et al. (2006, 2007) and the hypoxia studies by Turner et al. (2015); clinical trial registry data from ClinicalTrials.gov (including protocols NCT04504253 and NCT01543139) evidencing standard exclusion criteria; and theoretical frameworks on brain bioenergetics including work by Kondo et al. (2011).