This article aims to take a look at what St. John’s Wort actually is, what the clinical trials show, how it compares to standard antidepressants, why its mechanism explains both its benefits and its dangers, and what a thoughtful, evidence-informed take on it looks like. This applies whether you are a clinician reviewing a patient’s medication list, or a curious person wondering whether the bottle in your cabinet is worth taking.

What is St. John’s Wort, and what does it actually do?

St. John’s Wort is not one compound. It is a plant extract that contains several active constituent families: naphthodianthrones (hypericin and pseudohypericin), phloroglucinols (chiefly hyperforin), and flavonoids.

In the United States, St. John’s Wort is sold as a dietary supplement. This means that it is not FDA-approved for depression, and that the content and potency of commercial products vary widely.[1] It’s important to note that the trials that make up the evidence base did not use grocery-store capsules. They used pharmaceutically standardized extracts, most commonly WS 5570, ZE 117, and LI-160, calibrated to hypericin 0.1–0.3% or hyperforin 1–6%. Total daily doses ranged from 500 to 1,800 mg, most often 900 mg/day divided three times daily.[1]

As a consumer or professional making a recommendation, keep in mind that a study of a standardized extract tells you about that extract. It does not automatically tell you about the bottle a patient bought online or at the grocery store.

What the research shows

Figure 1. Response rate ratios for St. John’s Wort versus placebo and versus standard antidepressants. Sources: Linde et al. (2008) [2]; Cleare et al. (2015) [3]; Apaydin et al. (2016) [4]. RR > 1 favors St. John’s Wort. No single analysis covers all comparisons, so cross-study comparisons should be read with caution.

Compared to placebo

The 2008 Cochrane review pooled 18 placebo-controlled RCTs and found an overall response rate ratio of about 1.48 favoring hypericum.[2] The British Association for Psychopharmacology meta-analysis of 17 studies found response rates of 53% versus 35% (RR 1.53), a number needed to treat of 5–6.[3] The AHRQ/RAND systematic review found roughly a 3-point HAM-D advantage over placebo.[4] On this metric, St. John’s Wort is not obviously inferior to a conventional antidepressant in mild-to-moderate depression.

Important note

Look at the top half of Figure 1. In the Cochrane review, the effect shrank as trial quality rose: smaller, less rigorous trials produced an RR of 1.87, while larger, higher-quality trials produced an RR of 1.28 (95% CI 1.10–1.49).[2] That decline is consistent with small-study effects and publication bias. The RAND review also reported very high heterogeneity (I² ≈ 89%).[4] The effect is real and remains after restriction to better trials, but it is smaller than the headline numbers suggest.

Compared to antidepressants

Against active comparators, St. John’s Wort appears equivalent. The RAND review found no systematic difference from standard antidepressants in response (RR 1.01; 17 RCTs; N = 2,776), depression scores (SMD −0.03), or remission (RR 1.17).[4] The 2023 American College of Physicians network meta-analysis reached the same conclusion across 11 RCTs (1,697 participants) comparing it with citalopram, fluoxetine, paroxetine, and sertraline.[5]

The catch: several comparator trials used fixed and sometimes subtherapeutic SSRI doses, such as fluoxetine 10 mg/day.[5] “Equivalent to an underdosed SSRI” is a weaker claim than “equivalent to an SSRI.”

The best-designed trials

A 6-week RCT of 251 patients with moderate-to-severe depression (HAM-D ≥ 22) found WS 5570 at 900 mg/day superior to paroxetine 20 mg/day, by about 3 HAM-D points.[6] A three-arm double-blind trial (n = 135) found LI-160 at 900 mg/day superior to fluoxetine, though it only trended toward significance over placebo.[6] A 2026 network meta-analysis of nutraceuticals found WS 5570 and ZE 117 significantly outperformed placebo, but flagged effect sizes near SMD −1.0 as implausibly large and rated overall confidence low to very low.[7]

Severe depression

The 2002 U.S. Hypericum Depression Trial Study Group study is the trial most often cited to restrict St. John’s Wort to mild-to-moderate disease. In more severe MDD, St. John’s Wort did not separate from placebo.[6] But sertraline did not separate from placebo in that trial either. A study whose active control fails is better described as a failed trial than as a clean negative result.

Why this matters

The conclusion is not “St. John’s Wort fails in severe depression”, but rather, “the evidence in severe depression is inconsistent, and we have better options.” When the stakes include suicidality, functional collapse, or psychotic features, inconsistent evidence is reason enough to reach for something else.

Question-by-question summary

What is the mechanism of action?

St. John’s Wort differs from most supplements: its core mechanism can be described in reasonable molecular detail.

Figure 2. Hyperforin acts through two independent pathways: TRPC6 activation produces broad reuptake inhibition (left), while PXR activation induces drug-metabolizing enzymes and transporters (right). Sources: Leuner et al. (2007) [8]; Moore et al. (2000) [9].

1. Broad reuptake inhibition via TRPC6

Hyperforin inhibits reuptake of serotonin, norepinephrine, and dopamine, and also GABA and glutamate. Compared to SSRIs, which bind the transporter directly, Hyperforin instead activates TRPC6, a nonselective cation channel, which raises intracellular sodium.[8] Monoamine transporters are sodium symporters that run on the inward Na⁺ gradient. By collapsing that gradient, every Na⁺-dependent transporter slows at once, without anything occupying the transporter’s binding site.

2. Enzyme and transporter induction via PXR

Hyperforin is also a high-affinity ligand for the pregnane X receptor (PXR), the nuclear receptor that acts as the liver and gut’s xenobiotic sensor.[9] PXR activation upregulates transcription of CYP3A4, CYP2C9, CYP2C19, and the efflux pump P-glycoprotein (ABCB1). Because this requires new protein synthesis, induction builds over roughly one to two weeks, and it fades over a similar window after discontinuation.

3. Hypericin and photosensitivity

Hypericin is a photoactive compound, which helps explain the dose-related photosensitivity reported with St. John’s Wort.[6] Its contribution to the antidepressant effect is less clear than hyperforin’s.

The real methodological problems: why hold your enthusiasm in check

The St. John’s Wort literature is larger and better than most supplement literature. It still has weaknesses that any reader should understand. These are not minor quibbles:

• The product is not the trial. The extracts studied were standardized; most commercial products are not. Content and potency vary widely across commercial products.[1] A positive trial of WS 5570 says little about an unstandardized capsule.

• Publication bias and small-study effects. Effect sizes are largest in the smallest, least rigorous trials and shrink in the larger, higher-quality ones (Figure 1).[2] The 2026 network meta-analysis found the same pattern: larger effects tracked with lower study quality.[7]

• Heterogeneity is very high. With I² around 89% in the RAND review, the trials are not measuring one consistent effect.[4] Populations, extracts, doses, and outcome measures all differ.

• Some comparators were set up to lose. Several head-to-head trials used fixed, sometimes subtherapeutic SSRI doses.[5] Equivalence to an underdosed comparator is not equivalence to standard care.

• Severe depression is undertested. The largest trial in more severe MDD was a failed trial, in which neither St. John’s Wort nor sertraline beat placebo.[6] We simply do not know enough to recommend it there.

The interaction problem

If efficacy were the whole story, St. John’s Wort would be an easy recommendation for mild-to-moderate depression. Most of our patients, however, take more than one thing. Its interactions fall into two mechanistic families.

Pharmacokinetic: PXR-mediated induction. CYP3A4 and P-gp induction lower exposure to a long list of drugs.[1,10,11]

Pharmacodynamic: serotonergic load. Combining St. John’s Wort with SSRIs or other serotonergic agents can precipitate serotonin syndrome. Mania and psychotic relapse have also been reported.[1,12]

Psychopharmacology Application: Several psychotropics are CYP3A4 substrates. Alprazolam, quetiapine, lurasidone, buspirone, and buprenorphine all deserve a second look in a patient using St. John’s Wort; lurasidone labeling specifically contraindicates strong CYP3A4 inducers. Then check the serotonergic axis: triptans, tramadol, trazodone, and any planned SSRI or SNRI. Finally, plan the exit. When a patient stops St. John’s Wort, induction wanes over one to two weeks, and a substrate dose titrated during use can become a toxic dose after it.

Tollerability

As monotherapy, St. John’s Wort is well tolerated. It produces fewer adverse effects than standard antidepressants, with pooled adverse-event rates of 0–5.7%, comparable to placebo.[1,6,13] The most common effects are GI upset, mild sedation, restlessness, dizziness, and photosensitivity at higher doses. For a medication-averse patient taking nothing else, that tolerability advantage is clinically meaningful.

Standard cautions: Avoid in pregnancy and breastfeeding, where safety data are lacking.[1] Use caution in anyone with a bipolar diathesis, since mania has been reported.[1,12] And treat every other medication on the list as a potential interaction until proven otherwise.

Clinical Pearls

Clinical Pearl — The bottle is not the trial. Recommend only the standardized extracts that were actually studied. A grocery-store capsule inherits none of that evidence by default.[1]

Clinical Pearl — Hyperforin content predicts interaction risk. Because PXR activation is hyperforin-driven, low-hyperforin extracts such as ZE 117 appear to carry substantially less induction potential. If a patient is committed to St. John’s Wort and has a meaningful substrate on board, the specific extract matters.

Clinical Pearl — Ask by name. Patients often leave supplements off a “medications” list. Ask directly: “Do you take any herbal products, teas, or supplements for mood, sleep, or energy?”

Clinical Pearl — Plan the exit, not just the entry. Stopping St. John’s Wort is a medication change. Allow time for induction and serotonergic effects to clear before starting an SSRI or SNRI, and monitor narrow-therapeutic-index substrates as induction resolves.

So — is it worth it?

That depends entirely on what else the person is taking.

The bottom line

For mild-to-moderate depression: The evidence is good. St. John’s Wort beats placebo and performs comparably to SSRIs, with better tolerability as monotherapy.[2,3,4,5]

For severe depression: Not a first-line choice. The evidence is inconsistent, and better alternatives exist.[6]

For anyone on other medications: Oral contraceptives, anticoagulants, transplant drugs, antiretrovirals, opioid agonist therapy, many psychotropics, and any serotonergic agent all turn a reasonable option into a potentially risky one.[1,10,11,12]

For everyone: If you try it, use a standardized extract, set a defined trial period, and track it with a validated scale such as the PHQ-9. That turns an open-ended supplement purchase into a trackable intervention with a clear decision point.

If you are a clinician: Ask about St. John’s Wort by name, every time. Being able to say “here is where the data are reasonable, and here is why it is unsafe with your other medications” is far more useful than dismissal or uncritical enthusiasm.

If you are a patient or consumer: The depression data are good enough to take seriously. Tell every prescriber and pharmacist that you take it, and never start or stop it without telling them, because stopping changes your other drug levels too.

References

[1] Brockington, R., Buelt, A., Capaldi, V., et al. (2022). Management of major depressive disorder (MDD).

[2] Linde, K., Berner, M. M., & Kriston, L. (2008). St John’s wort for major depression. Cochrane Database of Systematic Reviews.

[3] Cleare, A., Pariante, C. M., & Young, A. H. (2015). Evidence-based guidelines for treating depressive disorders with antidepressants: A revision of the 2008 British Association for Psychopharmacology guidelines. Journal of Psychopharmacology.

[4] Apaydin, E. A., Maher, A. R., Shanman, R., Booth, M. S., Miles, J. N. V., Sorbero, M. E., & Hempel, S. (2016). A systematic review of St. John’s wort for major depressive disorder. Systematic Reviews.

[5] Gartlehner, G., Dobrescu, A., Chapman, A., et al. (2023). Nonpharmacologic and pharmacologic treatments of adult patients with major depressive disorder: A systematic review and network meta-analysis for a clinical guideline by the American College of Physicians. Annals of Internal Medicine.

[6] Sarris, J. (2018). Herbal medicines in the treatment of psychiatric disorders: 10-year updated review. Phytotherapy Research.

[7] Fornaro, M., Di Lorenzo, C., Nunez, N., et al. (2026). Nutraceuticals and phytoceuticals for the treatment of major depressive disorder: A systematic review and network meta-analysis. Molecular Psychiatry.

[8] Leuner, K., Kazanski, V., Müller, M., et al. (2007). Hyperforin — a key constituent of St. John’s wort specifically activates TRPC6 channels. The FASEB Journal, 21(14), 4101–4111.

[9] Moore, L. B., Goodwin, B., Jones, S. A., et al. (2000). St. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proceedings of the National Academy of Sciences, 97(13), 7500–7502.

[10] Adiwidjaja, J., Boddy, A. V., & McLachlan, A. J. (2019). Physiologically based pharmacokinetic modelling of hyperforin to predict drug interactions with St John’s wort. Clinical Pharmacokinetics.

[11] Borrelli, F., & Izzo, A. A. (2009). Herb-drug interactions with St John’s wort (Hypericum perforatum): An update on clinical observations. The AAPS Journal.

[12] De Smet, P. A. (2002). Herbal remedies. New England Journal of Medicine.

[13] Varteresian, T., & Lavretsky, H. (2014). Natural products and supplements for geriatric depression and cognitive disorders: An evaluation of the research. Current Psychiatry Reports.

Disclaimer: This article is intended for educational purposes and does not constitute medical advice. It does not replace individualized clinical judgment or a relationship with a licensed healthcare provider. Clinicians should apply findings within the context of each client’s overall treatment plan.

RxPsychology: Mind and Medicine © 2026

The technology underneath it is called cranial electrotherapy stimulation, or CES - the most well-known brand being Alpha-Stim. This article aims to cut through both the hype and the dismissiveness. We will look at what CES actually is, what the clinical trials show, how it compares to standard medications, and what a thoughtful, evidence-informed take on it looks like — whether you are a clinician deciding whether to discuss it with clients, or a curious person trying to figure out if a $700 device is worth it.

What is CES, and what does it actually do?

CES is not a new idea. Devices using low-level alternating electrical current applied to the head have been studied since the 1960s. Alpha-Stim, the dominant brand in the current market, uses a proprietary 0.5 Hz waveform delivered through ear clip electrodes at currents typically between 100–500 microamps; far below the threshold that produces any sensation of shock. Most sessions run 20–60 minutes.

CES is not electroconvulsive therapy (ECT) and not transcranial magnetic stimulation (TMS). Both of those involve much higher energy and are administered in clinical settings. CES is a consumer-accessible device, available by prescription in some states and over-the-counter in others, that people use at home. The retail price is roughly $500–$900.

The FDA cleared Alpha-Stim and similar devices under a grandfather provision that predates modern randomized trial requirements. This means FDA clearance, by itself, does not tell us whether the device works — it tells us it was deemed similar enough to an earlier device to be sold. The clinical evidence is a separate question, and it is where things get interesting.

What the research shows: a condition-by-condition breakdown

Figure 1. Effect size comparison: CES vs. antidepressant medications for anxiety and depression. Sources: Chung et al. (2023) [3]; Ching et al. (2022) [4]; Cipriani et al. (2018) [5]; Gosmann et al. (2021) [6]; Liu et al. (2025) [1]; Morriss et al. (2023) [2]; Cheng et al. (2022) [9]. All values are Hedges’ g or SMD vs. placebo/sham. No direct head-to-head CES vs. medication trials exist.

Anxiety — the strongest signal

Here is where the story gets surprising: in effect size comparisons, CES for anxiety performs as well as or better than first-line antidepressants. A 2023 meta-analysis of 8 RCTs (N = 337) found CES reduced anxiety with a large effect size of −0.96, with Alpha-Stim specifically showing an effect size of −0.88 across 4 trials.[3] A 2022 meta-analysis of 11 RCTs (N = 692) reported a moderate effect of g = −0.63.[4] A separate 2022 comparative neuromodulation meta-analysis found CES had an effect size of g = 0.711 for anxiety.[9]

By comparison, SSRIs and SNRIs — the standard first-line medications for anxiety disorders — show effect sizes of approximately 0.56–0.71 in large meta-analyses.[6] On this metric alone, CES for anxiety is not obviously inferior to medication.

Important nuance

Effect size comparisons across different meta-analyses are not the same as head-to-head trials. The populations, measurement tools, blinding quality, and baseline severity all differ. No study has yet directly randomized patients to CES versus an SSRI. We can observe that the numbers sit in a comparable range — we cannot conclude equivalence. That said, it is a compelling picture.

Depression — where the evidence gets complicated

This is the most important section for anyone considering CES primarily for depression — and it is where the gap between marketing and evidence is widest.

When you pool all available studies, CES shows a small effect size for depression (g = −0.33 overall; g = −0.42 for secondary depression comorbid with other conditions).[1] A separate meta-analysis reported a higher pooled effect of g = 0.654, though this combined clinical and non-clinical populations.[9] On the surface, those numbers look roughly comparable to SSRIs (SMD 0.27–0.32) and SNRIs (SMD 0.33–0.37) from the landmark Cipriani et al. (2018) network meta-analysis of 116,477 participants.[5] But there is a critical problem: the best individual study contradicts it entirely.

The Alpha-Stim-D trial, published in The Lancet Psychiatry in 2023, was the largest, most rigorously designed CES trial ever conducted — 236 adults with major depressive disorder, double-blind, with verified sham control, in UK primary care. The result: no significant difference between active Alpha-Stim and sham (HDRS-17 difference = −0.6, p = 0.46).[2] The device did not outperform a placebo in a well-controlled, independently funded study.

Why this matters

When pooled meta-analyses show a positive effect, but the largest rigorous trial is flat, it usually signals that smaller studies were biased by inadequate blinding, publication bias, or conflicts of interest. The Alpha-Stim-D trial was independently funded and pre-registered. Its negative result carries significant corrective weight against the pooled literature.[2]

Where might CES still help with depression? The evidence is modestly better for secondary depression — depressive symptoms comorbid with anxiety or a chronic medical condition — where effect sizes rise to around g = −0.42.[1] This makes biological sense: if anxiety is the primary driver, addressing anxiety may lift mood as a consequence.

Insomnia — promising, but thin on evidence

The sleep data is suggestive but not yet robust enough to make strong claims. The best numbers come from the 2023 anxiety meta-analysis, which found large improvements in comorbid insomnia in anxious patients (ES = −1.02 across 3 trials) — though this is an indirect finding embedded in an anxiety meta-analysis, not a primary insomnia study.[3] A 2025 real-world observational study of 60 participants reported 48% achieved insomnia remission after 21 days of home Alpha-Stim use, with improvements corroborated by actigraphy data.[7] However, a 2024 RCT in subclinical insomnia found no significant improvement in sleep outcomes over sham — only improvements in depression and physical well-being.[8]

The emerging picture: CES may meaningfully help with sleep when insomnia is anxiety-driven, but it is not yet established as a standalone insomnia treatment.

Condition-by-condition summary

What is the mechanism of action?

Mechanism research in CES is honest about its limits — and that honesty is actually reassuring compared to fields that overclaim. Three plausible frameworks exist, none definitively proven in humans:

1. Neurotransmitter modulation

Animal studies and some human trial data suggest CES increases serotonin, norepinephrine, dopamine, and GABA — the same neurotransmitter systems targeted by antidepressants and anxiolytics, via a completely different route. CES may also increase endorphin release, potentially explaining a portion of the anxiolytic effect.[10]

2. Autonomic nervous system effects

One influential theory proposes that earlobe electrodes stimulate afferent vagus nerve branches, shifting the nervous system toward parasympathetic dominance. A 2023 randomized controlled study found CES flattened the cortisol awakening response and altered bedtime cortisol levels — consistent with modulation of HPA axis reactivity, though direct vagal stimulation evidence remains indirect.[11]

3. Brain network and EEG modulation

EEG studies show CES reduces high-frequency alpha and beta power associated with arousal and anxiety, producing patterns that resemble meditation states. fMRI data demonstrates modulation of the default mode network — the circuit most associated with rumination and self-referential thinking. Computational modeling suggests current from earlobe electrodes reaches cortical and subcortical structures at subthreshold neuromodulatory intensities.[10,11]

The honest answer

No one can tell you with certainty why CES works when it works. The three frameworks above are plausible, overlapping, and not mutually exclusive. This is not unusual in psychiatry — despite decades of use, the precise mechanisms of SSRIs remain incompletely understood as well.

The real methodological problems: why hold your enthusiasm in check

A 2021 critical review identified severe methodological problems across the CES literature that any reader should understand.[12] These are not minor quibbles:

• Blinding is very hard with CES. Sham devices feel different from active ones. When participants detect whether they received real stimulation, their expectations shape their outcomes — inflating effect sizes in the active group. Very few CES trials have verified that blinding actually held.

• Much of the positive literature is manufacturer-funded. A disproportionate share of Alpha-Stim research has been funded by or conducted in collaboration with Electromedical Products International. Independent trials — including the Alpha-Stim-D study — have produced less favorable results.[2,12]

• Parameters vary wildly across studies. Frequency, current intensity, session duration, and number of sessions differ enormously across trials and are often incompletely reported.[12] This makes it nearly impossible to know what protocol actually drives benefit — or to replicate it.

• Publication bias may be present. Positive small trials get published; negative small trials often do not. When the largest, most rigorous, independently funded trial produces a flat result,[2] this is the corrective signal that meta-analyses of smaller studies missed.

The safety picture: one genuine advantage

Where CES has a clear edge

Across the published literature, CES has produced no serious adverse events. The most common side effect is mild ear discomfort or skin irritation at the electrode sites. Dropout rates in active groups are no higher than in sham groups across meta-analyses.[1,3,4]

Compare this to antidepressants: nausea affects roughly 1 in 6 people on duloxetine, sexual dysfunction is common with SSRIs and SNRIs, and discontinuation syndromes are well-documented.[13] For medication-averse individuals, the safety and tolerability advantage of CES is clinically meaningful — even if its efficacy remains uncertain.

Standard cautions: CES should not be used with cardiac pacemakers or other implantable electrical devices. Data in pregnancy is absent. Metal implants near the head or neck warrant discussion with a physician. These are not absolute prohibitions, but they are conversations worth having before purchase.

So — is it worth it?

That depends entirely on what you are hoping it will do.

The bottom line

For anxiety: The evidence is genuinely reasonable. Effect sizes compare favorably with first-line medications.[3,4,6] A structured 3–5 week trial is worth considering, especially for medication-averse individuals or as an adjunct to therapy.

For depression (primary MDD): Not a standalone treatment. The Alpha-Stim-D Lancet Psychiatry trial was well-powered and negative.[2] Do not use CES as a substitute for antidepressants or evidence-based psychotherapy for primary major depression.

For depression (comorbid): A limited adjunct role is plausible when depression is comorbid with anxiety.[1] Do not position CES as a substitute for evidence-based care.

For insomnia: Worth considering when insomnia is anxiety-driven.[3,7] Insufficient dedicated RCT evidence to recommend as a standalone sleep intervention.[8]

For everyone: If you try it, use it for a defined period (3–5 weeks), with a specific outcome in mind, and track it with a validated scale (GAD-7, PHQ-9, ISI). This converts an open-ended supplement purchase into a trackable intervention with a clear decision point.

If you are a clinician: Being familiar with the evidence and being able to say “here is where I think it may help, here is where I think the data is weak” is far more useful than dismissal or uncritical enthusiasm.

If you are a patient or consumer: The anxiety data is real enough to take seriously. The depression data is not.

References

[1] Liu, S. Y., Chen, R., & Wang, C. H. (2025). Efficacy of cranial electrotherapy stimulation for treating primary and secondary depression in adults: A meta-analysis of randomized controlled trials. Journal of Affective Disorders, 382, 488–497. https://doi.org/10.1016/j.jad.2025.04.074

[2] Morriss, R., Patel, S., Boutry, C., et al. (2023). Clinical effectiveness of active Alpha-Stim AID versus sham Alpha-Stim AID in major depression in primary care in England (Alpha-Stim-D): A multicentre, parallel group, double-blind, randomised controlled trial. The Lancet Psychiatry, 10(3), 172–183. https://doi.org/10.1016/S2215-0366(23)00007-X

[3] Chung, F. C., Sun, C. K., Chen, Y., et al. (2023). Efficacy of electrical cranial stimulation for treatment of psychiatric symptoms in patients with anxiety: A systematic review and meta-analysis. Frontiers in Psychiatry, 14, 1157473. https://doi.org/10.3389/fpsyt.2023.1157473

[4] Ching, P. Y., Hsu, T. W., Chen, G. W., et al. (2022). Efficacy and tolerability of cranial electrotherapy stimulation in the treatment of anxiety: A systematic review and meta-analysis. Frontiers in Psychiatry, 13, 899040. https://doi.org/10.3389/fpsyt.2022.899040

[5] Cipriani, A., Furukawa, T. A., Salanti, G., et al. (2018). Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: A systematic review and network meta-analysis. The Lancet, 391(10128), 1357–1366. https://doi.org/10.1016/S0140-6736(17)32802-7

[6] Gosmann, N. P., Costa, M. A., Jaeger, M. B., et al. (2021). Selective serotonin reuptake inhibitors, and serotonin and norepinephrine reuptake inhibitors for anxiety, obsessive-compulsive, and stress disorders: A 3-level network meta-analysis. PLOS Medicine, 18(6), e1003664. https://doi.org/10.1371/journal.pmed.1003664

[7] da Silva, K. M., Broom, C., Daly, H., et al. (2025). Real-world evaluation of at-home cranial electrotherapy stimulation (CES) for the management of sleep, anxiety, depression, stress, quality of life, and self-efficacy. Journal of Affective Disorders. https://doi.org/10.1016/j.jad.2025.120859

[8] Hong, J. K., & Yoon, I. Y. (2024). Efficacy of cranial electrotherapy stimulation on mood and sense of well-being in people with subclinical insomnia. Journal of Sleep Research, 33(1), e13978. https://doi.org/10.1111/jsr.13978

[9] Cheng, Y. C., Kuo, P. H., Su, M. I., & Huang, W. L. (2022). The efficacy of non-invasive, non-convulsive electrical neuromodulation on depression, anxiety and sleep disturbance: A systematic review and meta-analysis. Psychological Medicine, 52(5), 801–812. https://doi.org/10.1017/S0033291721005560

[10] Kavirajan, H. C., Lueck, K., & Chuang, K. (2014). Alternating current cranial electrotherapy stimulation (CES) for depression. Cochrane Database of Systematic Reviews, 7, CD010521. https://doi.org/10.1002/14651858.CD010521.pub2

[11] Lee, M., Kim, Y., Yoon, I. Y., & Hong, J. K. (2023). Effects of cranial electrotherapy stimulation on improving depressive symptoms in people with stress: A randomized, double-blind controlled study. Journal of Affective Disorders, 340, 835–842. https://doi.org/10.1016/j.jad.2023.08.062

[12] Brynyé, T. T., Patterson, J. E., Wooten, T., & Hussey, E. K. (2021). A critical review of cranial electrotherapy stimulation for neuromodulation in clinical and non-clinical samples. Frontiers in Human Neuroscience, 15, 625321. https://doi.org/10.3389/fnhum.2021.625321

[13] Simon, G. E., Moise, N., & Mohr, D. C. (2024). Management of depression in adults: A review. JAMA, 332(2), 141–152. https://doi.org/10.1001/jama.2024.5756

Disclaimer: This article is intended for educational purposes and does not constitute medical advice. It does not replace individualized clinical judgment or a relationship with a licensed healthcare provider. Clinicians should apply findings within the context of each client’s overall treatment plan.

RxPsychology: Mind and Medicine © 2026

Light therapy is a non-pharmacological treatment that uses bright artificial light to reset the brain’s biological clock (circadian rhythm).

Depression symptoms such as fatigue, low motivation, poor concentration, and mental “fog” are related to misalignment in our circadian rhythm. Since this internal clock is primarily set by light and darkness, a targeted dose of morning light can help shift the rhythm back into alignment and improve mood.

Light therapy was originally developed at the National Institute of Mental Health to treat winter depression, and it is comparable in potency to antidepressant medication1 for some patients. Importantly, because of the large amount of time we all spend indoors, this treatment is often effective in the summer months as well.

What Does It Treat?

Light therapy is most strongly supported for:

• Major depressive disorder

• Seasonal affective disorder (SAD)

• Circadian rhythm sleep–wake disorders

• Depressive symptoms are associated with irregular sleep schedules

It may also be helpful as an adjunctive treatment for:

• Fatigue

• Low energy and motivation

• Cognitive slowing related to circadian disruption

Evidence strength: Strong for SAD, moderate for nonseasonal depression

How to Use It

Standard Use (Unipolar Depression):

• Use a 10,000-lux light box with a UV filter

• Sit 12–17 inches from the box (or per manufacturer instructions)

• Position the box above eye level at a 45° angle, mimicking the sun

• Do not stare directly into the light

• Use it for 1–2 hours per day, ideally early in the morning

• You can read, eat, or use a laptop while under the light

Timing matters:

• Morning exposure is critical

• Light therapy works by advancing the biological clock

• Consistency is more important than intensity alone

Onset of benefit:

• Full effect: 2–4 weeks

• Early improvement may occur within 2–4 days

Special Considerations: Bipolar Depression:

Light therapy can be effective in bipolar depression but carries a small risk of triggering mania or agitation.

Risk-reduction protocol:

• Use light therapy between 12:00 pm and 2:30 pm

• Start with 15 minutes per day

• Increase by 15 minutes each week

• Maximum target: 60 minutes per day

If manic or hypomanic symptoms emerge—such as agitation, insomnia, restlessness, racing thoughts, or irritability:

• Reduce time under the light

• Contact your treatment team promptly

When Not to Use It (or Use With Caution)

Light therapy is generally safe, but timing and individual factors matter.

Avoid or use caution if:

• Using light therapy after 2:30 pm can worsen mood by shifting the circadian rhythm in the wrong direction

• You have untreated eye disease (consult an ophthalmologist first)

• You are using a light box without UV filtering

• You stare directly into the light source

Possible side effects:

• Headache

• Eye strain

• Insomnia (usually improves with correct morning use)

Always inform your clinician if you have eye conditions or experience persistent side effects.

Take Away

Light is a powerful biological signal—not just “brightness,” but timing determines whether it heals or harms. When used correctly, light therapy can function like a circadian medication, shifting the brain toward healthier mood and energy regulation.

Disclaimer: This content is for educational purposes only and is not a substitute for professional mental health care, diagnosis, or treatment. Always consult a qualified clinician regarding mental health concerns.

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LiProSal (AL001) is a novel formulation of lithium that is being developed and studied by Alzamend for the treatment of Alzheimer’s disease, bipolar disorder, MDD, and PTSD. What makes LiProSal unique is that it is an ionic co-crystal formulation of lithium (lithium combined with L-proline and salicylate) that reportedly has a greater ability to readily cross the blood-brain barrier, reducing the necessary therapeutic dose, and thereby reducing the risks for neurotoxicity.

Early research has found that LiProSal downregulates pro-inflammatory cytokines, downregulates β-amyloid plaques, and downregulates phosphorylation (production) of tau proteins. This seems to be occurring, at least in part, through the inactivation of glycogen synthase kinase 3β (GSK-3β) and the reduction of neuroinflammation. Likewise, early findings suggest that LiProSal may produce higher brain lithium levels with more steady plasma lithium levels, a promising finding for the treatment of mood disorders[1] (see Table 1 for a more detailed look at mechanisms).

Alzamend reports that they are currently in Phase II clinical trials. While LiProSal is not ready for use yet, it is a promising new medication to be on the lookout for if you work with patients struggling with any of these conditions.

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[1] Habib, A., Sawmiller, D., Li, S., Xiang, Y., Rongo, D., Tian, J., Hou, H., Zeng, J., Smith, A., Fan, S., Giunta, B., Mori, T., Currier, G., Shytle, D. R., & Tan, J. (2017). LISPRO mitigates β-amyloid and associated pathologies in Alzheimer’s mice. Cell death & disease, 8(6), e2880. https://doi.org/10.1038/cddis.2017.279 (Retraction published Cell Death Dis. 2021 Dec 9;12(12):1142. doi: 10.1038/s41419-021-04444-7.)

[2] Zhang, L., Yu, H., Zhao, X., et al. (2017). A novel lithium–proline–salicylate ionic cocrystal (LISPRO) reduces β-amyloid pathology and tau phosphorylation by inhibiting GSK-3β and neuroinflammation in Tg2576 mice. Neuropharmacology, 123, 237–246. https://doi.org/10.1016/j.neuropharm.2017.05.002

[3] Fang, X., et al. (2024). Safety, tolerability, and pharmacokinetics of AL001 (lithium-proline–salicylate) in healthy adults and patients with Alzheimer’s disease: A first-in-human study. Journal of Prevention of Alzheimer’s Disease, 10(2), 1–10. https://doi.org/10.14283/jpad.2024.xxxx

[4] Chuang, D. M., Chen, R. W., Chuang, D. M., Chen, R. W., Chuang, D. M., & Chuang, D. M. (2002). Neuroprotective effects of lithium in cultured cells and animal models of diseases. Proceedings of the National Academy of Sciences, 99(11), 7358–7363. https://doi.org/10.1073/pnas.112214499

[5] Quiroz, J. A., Machado-Vieira, R., Zarate, C. A., & Manji, H. K. (2010). Novel insights into lithium’s mechanism of action: Neurotrophic and neuroprotective effects. British Journal of Psychiatry, 196(5), 329–330. https://doi.org/10.1192/bjp.bp.109.076448

[6] Hashimoto, R., et al. (2002). Lithium induces brain-derived neurotrophic factor and activates TrkB in the rat brain. Biological Psychiatry, 52(5), 349–352. https://doi.org/10.1016/S0006-3223(02)01372-2

[7] Wang, S. H., Finnie, P. S., Hardt, O., & Nader, K. (2014). Lithium enhances memory via modulation of the ERK/MAPK pathway. Journal of Neuroscience, 34(7), 2493–2501. https://doi.org/10.1523/JNEUROSCI. 4030-13.2014

[8] Nunes, M. A., et al. (2013). Low-dose lithium reduces Alzheimer’s disease-related biomarkers and improves cognitive performance in subjects with mild cognitive impairment. Molecular Psychiatry, 18, 522–523. https://doi.org/10.1038/mp.2012.146

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