A Survey Exploring People's Experiences With Lithium Bought as a Supplement: Une enquête sur l’expérience des personnes avec le lithium en supplément

Abstract

Objective

Lithium, despite its evidence base and range of indications, is often underutilized due to safety concerns associated with high-dose prescriptions and consequent necessity for regular blood monitoring. Emerging evidence suggests its potential benefits at lower doses, especially for its pro-cognitive effects and positive safety profile. While accessible as a supplement, empirical human evidence on neuropsychiatric effects is lacking. This study aimed to provide preliminary evidence regarding the utilization and perceived effects of low-dose lithium supplements (LiS) in the community.

Methods

Cross-sectional, opportunistic survey of 211 participants aged ≥18 years who disclosed taking over-the-counter lithium supplements. The survey assessed sample demographics, supplement details, overall perspectives, and personal experiences related to the use of LiS.

Results

The most common form of LiS taken was aspartate at 10 mg once per day, although lithium orotate and ionic lithium were also frequently used. The most common beliefs regarding the benefits of using lithium as a supplement concern efficacy for anxiety, but the most common improvements experienced was in the domain of cognition, closely followed by anxiety and mood. Mood was most commonly reported as the greatest improvement. Side effects and withdrawal phenomena were more prevalent than anticipated.

Conclusion

This study revealed a diverse range of lithium supplements taken, in terms of dosage, formulation, frequency, and duration of intake. Anecdotal evidence highlighted prevalent perceived benefits and adverse effects. The study is, however, limited notably by its cross-sectional opportunistic design; more robust evidence, especially from controlled trials, is needed to fully establish the specific benefits and drawbacks associated with different forms and doses of accessible lithium supplements.

Plain Language Summary Title

A survey exploring people's experiences with lithium bought as a supplement.

Plain Language Summary

Lithium is the oldest effective medication used in psychiatry and holds an important place today. However, there are challenges with lithium in high doses and it may still be effective in low doses. Lower doses of lithium can be bought as a supplement over the counter, but this version of lithium has not been studied in research. We did a survey aiming to tell us some information about the experiences of people who have taken this supplementary lithium (“LiS”). From 211 adults who completed our study, results suggested that LiS is taken in many different forms, at different doses, frequencies and for different durations. People commonly believed and/or found that LiS was beneficial for anxiety, mood and cognition. Side effects and symptoms after stopping LiS were, however, more common than expected. Because this was just an initial survey, more in depth and rigorous research studies are needed to fully understand the exact benefits and drawbacks associated with different forms and doses of accessible lithium supplements.

Introduction

Lithium is a first-line mood stabilizer ¹ supported by a wealth of evidence in bipolar ² and unipolar affective disorders. ³ The oral lithium carbonate formulation has been included on the World Health Organisation's list of essential medicines since its inception in 1977. ⁴ Accumulating evidence also indicates that lithium confers benefits in further neuropsychiatric (e.g., anti-suicidal efficacy, which may be independent from mood stabilization effects ⁵ ) and non-psychiatric (e.g., antiviral^6,7) domains. Most notable are its potential pro-cognitive effects in dementias^8,9 as well as affective disorders. ¹⁰ These findings are often linked to evidence of lithium's biological neuroprotective effects; for example on telomeres,^11,12 inflammation, ¹³ and neuroplasticity. ¹⁴

Lithium's utilization rates belie its profile as a versatile, effective medicine, with low prescription rates in many parts of the world (notably, North America and UK) ¹⁵ at least partly attributable to clinician and patient reticence surrounding toxicity/tolerability^15,16 and need for blood monitoring.^17,18 Its lack of pharmaceutical company promotion (unlike newer mood stabilizers) may also contribute to lithium's underutilization. ¹⁶ Although concerns can be somewhat allayed through education,^15,19 there are certainly dose-related adverse effects of lithium that require recognition and management. ²⁰

There is growing evidence for lithium's benefits at “sub-therapeutic” doses, even to the extent of trace levels present in environmental sources which appear inversely correlated with suicide ²¹ and dementia rates, ²² at least at a population level. A recent systematic review collating studies of sub-therapeutic lithium reported promising evidence for safety, as well as benefits to cognition and mood. ²³ There are even reports that in these doses, lithium may elicit positive effects on metabolic, cardiovascular, and musculoskeletal functions. ²⁴

The accumulating evidence for the benefits of low-dose lithium is yet to result in meaningful focus on the supplemental lithium formulations available over-the-counter internationally. This may be partly attributable to the notable methodological concerns of the only two clinical studies published of lithium orotate. ²⁰ Although research interest has recently refocussed on the potential utility of supplementary lithium (LiS),^25,26 with a recent preclinical study suggesting that lithium orotate may confer higher serum levels with reduced tolerability issues (vs. lithium carbonate), ²⁷ human research remains neglected.

Objectives

This study aimed to obtain preliminary evidence of the characteristics of LiS in the community. Specific objectives sought to obtain information on

1. Characteristics of LiS (formulation, administration route, dose, frequency, and duration).

2. General views about lithium (reasons for taking, beliefs of lithium's effects).

3. Positive LiS experiences (reported benefits, magnitude).

4. Negative LiS experiences (reported withdrawal effects, side effects, reasons for stopping).

5. Associations between supplement characteristics and experiences.

As a preliminary exploratory survey, specific hypotheses are not warranted, although author expectations prior to data examination ²⁸ posited that LiS would most commonly be used in lithium orotate formulation, tablet form, at 5 mg once per day^25,26; that general views would relate to lithium's benefits to mood^25,26; that participants would most commonly report benefits to mood and cognition^2,23; that reasons for not currently taking LiS would less commonly relate to negative (or lack of positive) effects of lithium than others (e.g., logistical) ²³ ; that side effects or experiences after stopping LiS would be uncommon and transient^23,29; and that higher doses and longer durations of LiS would be associated with greater benefit outcomes.^21,23

Methods

Design/Setting

Observational between-subjects cross-sectional online survey including people who have taken over-the-counter LiS was conducted. The survey was accessible globally, with recruitment strategies not targeting a specific area (although the survey was in English). A pre-registration plan preceded data examination ²⁸ and underwent only extremely minor, necessary alterations since (Supplement 1).

Participants

Participants were recruited through online/offline advertisement. To be included, potential participants were provided an information sheet. Participants were required to confirm that they had read the information and met each eligibility criteria, that is, (A) aged ≥18 years, (B) previously or currently taken commercial LiS, and (C) fluent in English. There were no other exclusion criteria.

Procedure

Upon completion, participants could optionally enter into a random prize draw where 10 randomly selected participants received a £10 shopping voucher. As a preliminary exploration, a sample size calculation was not undertaken.

Measures

Measures (Supplement 2) were categorized into sample characteristics, LiS characteristics, general views (of lithium), positive and negative LiS experiences:

Sample characteristics: age, current/previous use, physical/mental health conditions, concomitant medication/supplement use.

LiS characteristics: Formulation/anion, administration route, dose, frequency, duration.

General views of lithium: Reasons for starting LiS, what participants had heard—and believed—lithium is useful for, source of initial information about LiS, whether they had mentioned LiS to a healthcare professional (HCP), reaction of HCP, their dose preferences, feelings about being prescribed high-dose lithium.

Positive LiS experiences: Planned duration of use, benefits noticed by the amount/duration/etc. of LiS taken, domain of greatest improvement, magnitude of greatest improvement, time to improvements.

Negative LiS experiences: Reason(s) for lack of current use, withdrawal symptoms experienced upon discontinuation, LiS side effects, and resolution.

Data Analyses

Comparisons were pre-specified. ²⁸ All analyses were considered exploratory and hypothesis generating.

Descriptive statistics: All variables were described: raw percentages for categorical variables, mean and standard deviation for continuous variables. Where multiple binary options could be selected in response to a single question, each option was coded as a dichotomous separate variable and described i.e., formulation, route of administration, dose, reason for starting, what participants heard and believed lithium was useful for. For some, an additional variable was calculated, that is, highest dose taken per day (using dose and frequency variables).

Univariate statistics: For all planned comparisons (Supplement 3), univariate tests were conducted as follows: Chi-squared (χ²) tests between nominal/binary variables; T-tests or Mann–Whitney U tests between continuous/ordinal and binary variables; ANOVA between multicategorical variables and continuous variables; Spearman's correlation between continuous variables.

For univariate tests, p ≤ 0.05 was to be interpreted as potentially statistically significant. However, as these are exploratory analyses, all results were interpreted tentatively and without applying adjustment for multiple comparisons. Differences in descriptive statistics may be tentatively interpreted based on overlap of 95% confidence intervals (CIs).

Results

Sample Characteristics

From 266 total survey completions, 13 were not initiated and 42 were likely duplicate completions. After their removal, 211 participants were analyzed. 62% were aged 18–35, while only 1.6% were over 55. Participants were more likely to be currently taking LiS regularly (41%) or occasionally (47%), versus not taking (11%). 65% disclosed having a physical or mental health condition. Table 1 presents sample and supplement characteristics.

Table 1.

(A) Sample Characteristics.

Variable	Answer options	n	%	95% CI
Age	18–35	192	62%	55–69%
	36–54		36%	30–43%
	55+a		1.6%	0.5–4.5%
Current vs. previous use	Current—regular	211	41%	35–48%
	Current—occasional		47%	41–54%
	Previous		11%	8–16%
Health condition	Yes	195	65%	58–72%
	No		35%	28–42%
Concomitant supplement use	Yes	68	33%	21–43%
	No		67%	57–79%
Concomitant medication use	Yes	68	29%	19–40%
	No		71%	59–80%

^a Merged due to small cell sizes (<5%)—age: 55+ was merged with 36–54 (36+) for univariate analyses; Formulation—“not sure” and “other” were merged (only one responded “other”); dose: “not sure” and “other” merged (three responded other, one being 1 mg, one range 5–25 mg and one not reported); frequency: occasional use (5%) merged with more than once per week (17%); duration: 1–2 years (4.7%) merged with >2 years (3.8%).

Abbreviations: CI = confidence interval; mg = milligrams.

LiS Characteristics

Numerically, lithium aspartate was most common (42%), with ionic lithium (38%) and lithium orotate (37%) in fewer, while lithium chloride (21%) and unsure/other (7%) were less common. Thirty-one percent of the sample reported LiS in multiple forms.

The most common administration route was tablet, but those containing lithium plus other supplements (55%) were non-significantly more common than lithium alone (40%), and liquid being less common (20%). Thirteen percent had tried multiple types.

The most common dose was 10 mg (44%), non-significantly different from either 5 mg (32%) or 20 mg (28%), with unsure/other being less common (11%). Thirteen percent had tried different dosages.

The most common frequency was once per day (30%), although less than every other day (22%), twice per day (20%), more than every other day (17%) and three times per day (10%) were non-significantly different.

The most common duration of LiS was 2 to 4 weeks; this was non-significantly different from either 1 to 3 months and 3 to 6 months (19%), 6 to 9 months (12%), 2 to 4 weeks (11%), >1 year (8%), <1 week (6%), or 9 to 12 months (5%). Due to large cell sizes, we computed an exploratory additional variable merging these into <1 month (38%), 1 to 6 months (38%), and >6 months (25%).

The highest dose per day ranged from 0.3 to 60 mg, with a mean of 13.4 (SD = 3.5). When computed as a continuous variable, the duration of use ranged from 3.5 to 913 days (based on midpoint of each group), with a mean duration of 135 days (SD = 201).

General Views About Lithium

See Table 2. The most common reasons reported for initiating LiS related to anxiety (37%), followed by cognition (36%), mood (29%), motivation and agitation/anger (both 26%), alertness (23%) then anti-aging effects (19%). Addiction (7%) and anti-viral/other (11%) were less common. Sixty-one percent selected multiple categories.

Table 2.

General Views about Lithium.

Variable	Answer options	n	%	95% CI
Reasons for starting	Mood (low/fluctuating)	209	29%	23–35%
	Anxiety		37%	31–44%
	Cognition		36%	30–43%
	Motivation		26%	21–32%
	Alertness		23%	18–29%
	Agitation/anger		26%	21–32%
	Anti-aging		19%	14–25%
	Addiction		7%	4.3–11%
	Anti-viral/other a		11%	7.4–16%
Heard lithium is useful for	Mood (low/fluctuating)	209	37%	31–44%
	Anxiety		43%	36–50%
	Cognition		35%	29–42%
	Motivation		22%	17–28%
	Alertness		16%	12–22%
	Agitation/anger		30%	24–37%
	Anti-aging		19%	14–25%
	Addiction		14%	9.9–19%
	Anti-viral/other a		11%	7.4–16%
Beliefs about what lithium is useful for	Mood (low/fluctuating)	209	37%	31–44%
	Anxiety		42%	36–49%
	Cognition		33%	27–40&
	Motivation		19%	14–25%
	Alertness		18%	13–24%
	Agitation/anger		32%	26–39%
	Anti-aging		21%	16–27%
	Addiction		11%	7.4–16%
	Anti-viral/other a		6%	3.5–10%
Source of initial information about lithium	Healthcare professional	192	33%	27–40%
	Reading/news (general)		21%	16–27%
	Word of mouth (not taking)		20%	15–26%
	Someone taking it		13%	9–18%
	Sales website		10%	6.5–15%
	Advert/other		4%	2–7.8%
Mention LiS to health professional	Yes	193	67%	60–73%
	No		33%	27–40%
Reaction of health professional	Extremely negative	129	5%	2.4–10%
	Somewhat negative		31%	24–39%
	Neutral		41%	33–50%
	Somewhat positive		17%	11–24%
	Extremely positive		5%	2.4–10%
Beliefs of dose effects	Higher better	195	42%	35–49%
	Lower better		41%	34–48%
	The same dose		17%	12–23%
Feelings about being prescribed high-dose lithium	Wholly positive	193	18%	13–24%
	Somewhat positive		42%	35–49%
	Somewhat negative/concerned		36%	30–43%
	Wholly negative		4%	2–7.8%

^a Merged due to small cell sizes (<5%): Reasons for starting lithium—other physical (3%), mental (1%) or general (1%) health reasons merged along with anti-viral (8%) into a general “other” category (some participants selected multiple categories, within the above). Most did not state the specific reasons; one stated blood disorder and one stated sleep. Benefits heard about—other physical (2%), mental (2%) or general (0%) health reasons merged along with anti-viral (8%) into a general “other” category (some participants selected multiple categories, within the above). Most did not state the specific reasons; one stated sleep and inflammation, and one stated suicide. Beliefs about what lithium is useful for - other physical (0.5%) merged with anti-viral (6%); no participants selected other mental or general health effects.

Abbreviations: CI = confidence interval; LiS = lithium supplement use.

Similarly, the most common indications of LiS that participants reported hearing about related to anxiety (43%) followed by mood (37%), cognition (35%), agitation/anger (30%), motivation (22%), anti-aging (19%), alertness (16%), addiction (14%) with anti-viral and other (11%) reasons less common. Sixty-nine percent selected multiple categories.

Results were similar for what participants themselves believed lithium is useful for: most commonly anxiety (42%) followed by mood (37%), cognition (33%), agitation/anger (32%), anti-aging (21%), motivation (19%), alertness (18%), addiction (11%) then anti-viral and other indications (6%). Sixty-five percent selected multiple categories.

For both of the above, an average of two domains were selected, both for what they had heard (SD = 1.3; range 1–9) and believed (SD = 1.2, range 1–7) lithium to be useful for.

Most commonly, participants reported hearing about lithium supplements from a HCP (33%), followed by general reading (21%), people who were not taking lithium (20%) or who were (13%), with others being sales website (10%), adverts (3%), or other (0.5%).

When asked whether they would feel a higher or lower dose would be more beneficial than the one taken, 42% would have preferred higher, 41% preferred lower, and 17% reported the dose they took to feel best.

Positive Experiences of LiS

See Table 3A. Most commonly, benefits (from the LiS dose/frequency/duration taken) were reported for cognition (23%), followed by anxiety (20%), mood (19%), agitation/anger (17%), anti-aging effects (14%), alertness (11%), motivation (10%), then addiction (7%), or anti-viral/other (7%).

Table 3.

(A) Positive Experiences of Lithium Supplementation.

Variable	Answer options	n	%	95% CI
Which were helped by the amount / duration of LiS you took	Mood (low/fluctuating)	208	19%	14–25%
	Anxiety		20%	15–26%
	Cognition		23%	18–29%
	Motivation		10%	6.6–15%
	Alertness		11%	7.4–16%
	Agitation/anger		17%	13–23%
	Anti-aging		14%	9.9–19%
	Addiction		7%	4.3–11%
	Anti-viral/othera		7%	4.3–11%
Greatest effect domain b	Mood (low/fluctuating)	62	31%	21–43%
	Anxiety		15%	8.2–26%
	Cognition		10%	4.7–20%
	Motivation/Alertnessa		3%	0.79–10%
	Agitation/anger		11%	5.4–21%
	Anti-aging		5%	1.7–14%
	Addiction/other specifica		7%	2.9–16%
	Non-specific/unsure		16%	8.9–27%
	Little improvement		3%	0.8–11%
Size of greatest effect	Small	185	15%	11–21%
	Moderate		58%	51–65%
	Large		22%	17–29%
	Very large		5%	2.7–9.2%
Planned duration of future use	Might stop soon	195	21%	16–27%
	>Few weeks		40%	33–47%
	>Few months		29%	23–36%
	>1 year		10%	6.5–15%
Time to improvements	Days	156	17%	12–24%
	Weeks		35%	28–43%
	Months		35%	28–43%
	Years		12%	7.8–18%

^a Merged due to small cell sizes (<5%): Reasons for non-current use: other (2%) merged with non-HCP advice (7%). Effects after discontinuation: other (1%) merged with weight gain (7%). Negative effects: other (1%) merged with fatigue (6%). Abbreviations: CI = confidence interval; LiS = lithium supplement use; HCP = healthcare professional.

The greatest benefit was most commonly mood (31%) followed by non-specific benefits (e.g., “hard to say which is best”), anxiety (15%), agitation/irritability (11%), cognition (10%), with others below 10% frequency. However, fewer participants (n = 62) answered this text-based question.

The magnitude of the greatest benefit was most commonly reported as moderate (58%), followed by large (22%), small (15%), or very large (5%). The time to improvement was reported to be an average of 110 days (3–4 months), although the SD was large (131), ranging between 3 days and 2 years (n = 155).

Most participants planned to continue LiS, with 21% reporting that they might stop soon, 40% plan to continue for at least a few weeks, 29% for at least a few months, and 10% for at least a year.

Negative Experiences of LiS

See Table 3B. Reasons for not currently taking lithium most commonly related to side effects (39%), forgetting to take it (36%), cost saving (28%), lack of benefit (22%), starting to take prescription lithium or being advised by a HCP (both 17%), with others’ advice or other reasons (7% and 3%, respectively) being less common.

In the days after stopping LiS, the most common effects reported were improvements in anxiety (39%) followed by worsening in anxiety (31%), improvements in mood (30%) while worsening of mood was reported in 11%. Decreased alertness was reported by 22% while 20% reported increased alertness. Twenty-two percent reported a worsening in agitation, while 13% reported an improvement in agitation. Seven percent reported each of weight loss and weight gain.

Side effects were most commonly reported as related to mood (39%), followed by anxiety (26%), headache (24%), weight changes (23%), shakiness (19%), dizziness (18%), funny taste in mouth (13%), nausea (11%), then fatigue or other (7%). Five percent stated no side effects.

Associations Between Supplementation and Experiences

Several positive and negative effect outcomes were not suitable for analysis, however the following significant effects were identified (Table 4; full statistics in Supplement 4). The findings are loosely categorized for clarity, noting overlap between the selected domains.

Table 4.

(A) Continuous-Continuous Univariate Comparisons (Spearman's Rank Correlations).

	Highest dose est.			Duration estimate			N heard uses			N believed uses
Highest dose est.
Duration estimate	r = 0.004	p = 0.958	n = 211
N heard uses	r = 0.092	p = 0.183	n = 209	r = 0.224	p = 0.001	n = 209
N believed uses	r = 0.200	p = 0.004	n = 209	r = 0.271	p < 0.001	n = 209	r = 0.728	p < 0.001	n = 209
Time to benefits	r = 0.134	p = 0.096	n = 155	r = 0.263	p < 0.001	n = 155	r = −0.022	p = 0.787	n = 155	r = 0.050	p = 0.540	n = 155

Bold text denotes significance at p < 0.05. Abbreviations: N = number, OTC = over the counter, HCP = healthcare professional, med = prescribed medication, est. = estimate, + = positive association (i.e., with “yes” in most binary variables; older participants; positive feelings about being prescribed high-dose lithium), − = negative association as previously, ∼ = no numerical between-group difference, ANOVA = analysis of variance, Li = lithium, n/a = inapplicable analysis due to participants taking LiS now vs. participants not taking LiS now—or no reaction of HCP where not mentioned to HCP.

^a Adjusted residuals examined post-hoc; putatively significant differences (z-score > 1.96) reported.

LiS duration: Duration of use was positively associated with the time to benefits experienced as well as a positive (versus negative) reaction of HCP when told about LiS, and the number of domains people had heard, and believed, lithium to be useful for (the latter also being highly positively associated with one another). The number of domains people believed lithium to be useful for was also higher in those who had mentioned taking LiS to their HCP, whose HCP had a positive (versus neutral) reaction, and who felt positively about the idea of being prescribed lithium.

LiS dose: Daily dose was also positively associated with the number of believed benefits of lithium, a positive/neutral (vs. negative) HCP reaction, and positive feelings about prescribed lithium. Dose was higher too in participants who were currently taking LiS frequently (vs. not taking). Individuals not taking LiS were less likely to have mentioned it to their HCP. Positive HCP reactions were linked to a longer time for participants to experience benefits from LiS. Conversely, negative HCP reactions were more common when participants had a positive view of prescribed lithium, while neutral reactions were frequent among those not positive about prescribed lithium. Participants who were positive about prescribed Li were more likely to indicate that they would prefer to take a higher dose, while participants who were not positive about prescribed lithium were more likely to rate their preference in being their current dose. Participants who preferred their own lithium dose had heard about more uses of lithium than those preferring a lower dose; they were also more likely to have a neutral HCP reaction, and were inclined to continue LiS for >1 month (while those favoring a lower dose were more likely to plan continuation for weeks). A preference for a higher dose was found more frequently in those not currently taking LiS while occasional users tended to report preference for a lower dose. Duration of LiS, dose preference and planned duration were indeed all associated, with longer durations of LiS in those preferring their own dose and in participants planning to take LiS for at least a year (compared to all shorter durations).

Magnitude of benefit: Minor benefit was more frequently rated in people not currently using LiS. A large/very large benefit was associated with longer durations of use (vs. minor benefit) as well as preferring the current dose (vs. minor benefit, associated with preferring a higher dose), mention of LiS to HCP (vs. moderate benefit), neutral HCP reaction, negative feelings about being prescribed high-dose lithium and older age (vs. moderate benefit).

Other: Older participants were more likely to have mentioned LiS to their HCP, have a health condition, and those with health conditions were also more likely to mention LiS to their HCP.

In terms of reasons for not currently taking LiS, those who had reasons both associated with lithium (i.e., adverse effect or lack of benefit) and other reasons (termed “non-lithium”) had heard/believed lithium to benefit a higher number of domains; for those whose reason for not currently taking LiS was solely lithium-related had reported a longer time to improvement while taking it.

Concomitant medication and supplement use were inter-related, but neither was associated with any other variable in univariate analyses.

Discussion

We believe our findings constitute the first information from people taking about commercially available LiS in the community worldwide. Several findings were converse to our prior expectations:

The characteristics of lithium supplementation (formulation, dose, frequency, and duration) varied widely, with 5 mg once daily of lithium orotate not being numerically most common.

Anxiety was the domain most commonly believed to be useful, although cognition and mood were also frequently reported. Cognition was also the domain most frequently noted as improved after LiS, although the most common “largest” benefit was for mood (most commonly of moderate magnitude). For each of the above, anxiety, cognition and mood were all frequently reported. Positive experiences were additionally indicated, for example, a high proportion willing to take a higher dose.

Other information suggested negative experiences were relatively frequent, with over 2/3 of participants not currently taking LiS citing side effects as a reason. Side effects and withdrawal effects were frequent.

Participants taking lithium for longer had more and larger perceived benefits, and planned to continue taking LiS for longer.

Positive attitudes towards lithium here diverge somewhat from literature on reasons for the under-use of lithium as a medication. ¹⁵ This sample is by nature self-selecting, being only people who had opted to take LiS. Some individuals may have heard about lithium as a natural supplement, rather than as a medication; many people profess a preference for “natural” (vs. “synthetic”) substances, which may partially explain this. ³⁰ However, 33% had heard about lithium via a HCP, so it could be assumed that a key initial impression of lithium was its medical use. Additionally, relatively few participants were taking concomitant supplements/medications (33/29%, respectively).

An unrepresentative sample, in terms of likely pre-existing positive attitude, may have increased the reported benefits of LiS. ³¹ However, we did find that the domains which participants most commonly rated as beneficial largely reflect the evidence base, particularly for cognition and mood. ²³ It is interesting that anxiety emerged as numerically the most common domain which participants believed lithium to benefit. A potential efficacy of lithium for anxiety has been documented, including at lower serum concentrations, but the evidence is relatively limited. ³²

The most surprising finding to emerge was the frequency and range of withdrawal and side effects reported. This contrasts findings from 16 low dose lithium studies unanimously reporting an absence of adverse effects. ²⁸ Withdrawal effects are understudied, even in high-dose lithium with inconsistent findings reported (some studies finding no physiological withdrawal).^33,34 Frequent adverse effect reporting is not clearly attributable to the intervention of study ³⁵ and our result may be partially a nocebo effect due to, for example, expectation of side effects (given lithium's reputation), pre-existing symptoms, and/or specific provided suggestions in this survey. Each of these phenomena have been described as increasing adverse effect reporting. ³⁶ Had our survey requested a free text response to an open question, for example, “tell us about any side effects experienced,” our findings would likely differ.

Few respondents rated their “greatest benefit” as minor, with over 1/2 rating this as moderate and over 1/4 as large/very large. Participants were less positive about prescribed lithium if they experienced a larger benefit. The magnitude of benefits experienced was related to several other factors including dose satisfaction, current (vs. previous) use, and duration of use. Duration related to several positive outcomes, which aligns with other literature on very low lithium doses: the putative link between trace environmental lithium and suicide is one example, with prolonged exposure being a hypothesized mechanism of these advantages. ²¹ In these trace lithium studies, there may also be a dose effect, with benefits only exerted above a minimal quantity. We found higher dose to be associated with some, but not all, positive outcomes/attitudes. Although preliminary, our data indicate a subset of participants who were taking LiS for an extended period, felt they were taking the best dose, and planned to continue taking it for a further extended period; investigation of these individuals may be a starting point for future, low-resource, high-intensity studies, in addition to prospective clinical trials.

The need for further evidence is especially pertinent in areas where our findings have no clear interpretation. For example, participants rating greater positive beliefs about lithium's benefits were more often not taking LiS due to negative effects (vs. non-negative) of LiS. These may be “true” findings, pending replication and explanation, or they may be “false” findings; we note that participants often responded to several options in the survey. An “over-rating” in this instance may inflate the size of both benefits and harms, as well as other experiences/perspectives. Type I errors here are likely and/or results may be explained by unmeasured effect modification.

We acknowledge several limitations. We undertook numerous comparisons, without adjusting p-values or controlling for potential confounders. We justified this by virtue of the study's position as a preliminary exploration in the absence of previous evidence, with the aim of detecting signals to better inform future study directions. The survey was limited in not objectively assessing participants and we cannot exclude the possibility of duplicate/false completions of the forms. Similarly, geographical location was not restricted or measured. Although information on demographics was minimal, we expect that our sample is non-generalizable. Furthermore, we collected some information as “optional,” resulting in limited data for example on participants’ physical and mental health conditions, which could have been informative to examine. We argue that nevertheless our data provide a useful starting point.

LiS appears to have a favorable safety profile based on its widespread availability and use in the community worldwide for decades without published safety concerns. One case report details an individual who “overdosed,” ingesting <60 mg elemental lithium with a low serum lithium level and only mild symptoms. ³⁷ Despite some conflicting animal reports,^27,38–40 most lithium orotate articles are commentaries without primary data^{25,26,41–43} and the only two extant human clinical studies possessed severe methodological drawbacks precluding any conclusions about lithium orotate's clinical or biological effects.

Our findings reveal some unexpected trends, highlighting the importance of examining potential clinical applications of LiS. Exploration is needed into variable LiS responses, including potential adverse effects. Exploring factors influencing clinician/patients’ perspectives on LiS may yield valuable insights regarding clinical decision-making. This survey underscores the need for well-designed controlled trials to explore LiS’ putative clinical implications including around dosage, duration, and potential benefits, while also addressing tolerability. We would posit that clinical trials are warranted in various populations, including people with subjective cognitive impaired (potentially those with age-related cognitive concerns), those at risk of bipolar disorders, with a family history of suicide, and those experiencing depression with mixed features. These populations are in light of current synthesized evidence on lithium's effects at low doses and the present findings, in combination with consideration of populations who could benefit from an accessible supplement (i.e., in terms of severity and access to other interventions).^20,23,38 We highlight the several different formulations that are commercially available, many of which appear prevalently used, and thus comparisons between these also require investigation.