3.2 Lithium

3.2.1 Status

Second-line preventive; the only agent other than verapamil with any randomised evidence at all (PMC8748342, evidence level ++). peer-reviewed Historically the first drug shown to work in chronic CH — Ekbom’s work in the 1970s. Notably, lithium has always been described as working better in chronic than episodic CH, which makes it the one drug in this chapter with a chronic-favouring profile.

3.2.2 Efficacy — the open-label record vs the one RCT

The Spanish-hosted English-language systematic review of lithium in CH (Eur J Psychiatry 2009;23(1), SciELO) catalogues the whole literature. peer-reviewed Key studies:

Study	n	Dose / serum level	Result
Ekbom	5 (3 chronic, 2 episodic)	serum 0.7–1.2 mEq/L	Effective in all 5
Bussone et al.	20 chronic	900 mg – 2.2 g/day	All improved rapidly; headache returned within 36 h of stopping in some
Kudrow	32 chronic	serum <1.2 mEq/L	27 dramatic improvement; ineffective in 5
Mathew	31 (14 ep, 17 chr)	not stated	80% responded, 20% no improvement; effect <1 week; 55% mild side effects; 1 stopped
Peatfield	31	0.6–0.69 mmol/L	14 marked improvement in week 1; 10 lesser improvement
Ekbom 1981	19 (8 chr, 11 ep)	0.7–1.2 mmol/L	Immediate partial remission in all chronic cases; 4 episodic achieved complete suppression; rest slight/no benefit
Savoldi et al.	90 (68 ep, 22 chr)	600–1200 mg; plasma 0.3–0.8 (chr) / 0.3–0.7 (ep) mEq/L	>80% of chronic improved by >90% in week 2; ~3/4 of episodic improved by >60%
Manzoni et al.	90 (68 ep, 22 chr)	900 mg/day	Chronic: 11 (50%) definite improvement, 50% partial only; 9 relapsed on stopping. Episodic: 26 high response, 26 partial, 16 refractory
Damasio & Lyon	21 (9 ep, 12 chr)	not stated	52.4% absolute improvement; 23.8% partial; 23.8% none/temporary
Klimek et al.	15 (8 chr, 7 ep)	0.6–1.2 mmol/L	Symptoms disappeared in 5; significant improvement in 5; ineffective in 5

A meta-analysis of three open trials (n=103) found 77% reached complete response or >50% reduction (PMC8748342). peer-reviewed Early open studies averaged roughly two-thirds responding (same source).

The single placebo-controlled trial was negative

Steiner TJ, Hering R, Couturier EGM, Davies PTG, Whitmarsh TE. Double-blind placebo-controlled trial of lithium in episodic cluster headache. Cephalalgia 1997;17(6):673–675, PMID 9350389. peer-reviewed

• n=27 episodic CH: 13 slow-release lithium carbonate 800 mg/day vs 14 placebo
• Cessation of bout: 15% lithium vs 14% placebo
• Substantial improvement: 8/13 (62%) lithium vs 6/14 (43%) placebo — NS
• The trial was stopped because superiority of lithium could not be demonstrated

Note the important qualifier: PMC8748342 states that in this placebo-controlled study “lithium concentrations were described as too low.” peer-reviewed So the negative result may be a dosing failure rather than a drug failure — but that is a post-hoc rescue argument and should be treated as such.

The conflict, stated plainly: dozens of open studies over 30 years report 50–80% response rates, especially in chronic CH; the only RCT was in episodic CH, was possibly underdosed, and was negative. The SciELO reviewers conclude lithium is effective in both chronic and episodic CH but that evidence in episodic CH “may be controversial” (SciELO). Given that the one RCT was in episodic CH and the strongest open data are in chronic CH, the chronic-CH case for lithium has never actually been tested in a randomised trial. That is a striking gap for a chronic daily patient.

3.2.3 Dosing, serum levels and monitoring

• EAN 2023: 600–1500 mg/day; serum level ≥0.4 mmol/L required; ideal 0.6–0.8 mmol/L; never >1.2; effect within 1 week (EAN). peer-reviewed
• PMC8748342: plasma 0.4–0.8 mEq/L; monitor plasma concentration, kidney and thyroid function; avoid concomitant diuretics and NSAIDs. peer-reviewed
• Contested: the SciELO review notes explicit controversy — some authors require higher doses to reach 0.7–1.2 mmol/L; others find low doses producing 0.4–1.0 mmol/L adequate (SciELO). peer-reviewed

The fast onset (<1 week, vs 2–3 weeks for verapamil) is lithium’s distinctive practical advantage and is reported consistently across Mathew, Peatfield, Savoldi and the EAN guideline.

3.2.4 Side effects and contraindications

Short-term, generally tolerable: fine hand tremor, polyuria, polydipsia (SciELO). Longer term: hypothyroid goitre and renal impairment. Reversible goitre developed in 3 patients after 1–3 years in Manzoni’s series. Mild side effects in 55% of Mathew’s patients, with 1 discontinuation. peer-reviewed

Table-level: tremor, acne, goitre, hypothyroidism, muscle weakness. Contraindications: heart failure, Addison disease, sodium balance disorders, low-salt diet, renal failure, pregnancy, lactation (PMC8748342). peer-reviewed The same review states lithium has “more and potentially more dangerous adverse events than verapamil.”

The SciELO review makes a point worth keeping: lithium-induced hypothyroidism can be treated and should not by itself be a reason to stop lithium in a stable patient. peer-reviewed

3.2.5 Odd findings and minority observations

• HLA association with lithium response. Giacovazzo et al., among 35 episodic CH patients, identified 21 responders and 14 non-responders; responders had higher frequency of HLA-B18 and HLA-A9; non-responders had higher HLA-A1 (SciELO). peer-reviewed — A single small study, never replicated to my knowledge. If real, it would be the only pharmacogenomic predictor in CH. Unknown / unreplicated.
• Lithium shifts melatonin. In a preliminary report of lithium given at 19:00 daily for a week: melatonin amplitude decreased at day 0, then by day 7 melatonin secretion was delayed with a phase shift and a clear increase in acrophase; cortisol decreased (same source). peer-reviewed This is a direct mechanistic bridge between lithium and the circadian story in §4 and is rarely mentioned in clinical guidance.
• Proposed antiviral mechanism, with a speculative CH–herpes simplex association (same source). peer-reviewed but highly speculative. Contested.
• Other proposed mechanisms: effect on REM sleep, platelet serotonin and histamine, opiate-receptor affinity, correction of bilateral neuronal asymmetries, restoration of reduced erythrocyte choline, hypothalamic serotonin. The review concludes the exact mechanism of lithium’s rapid effect remains unclear.
• Tolerance: some authors found decreased effectiveness after prolonged lithium use, possibly tolerance or non-compliance (same source). peer-reviewed
• Case report: lithium produced complete recovery in a chronic CH patient on haemodialysis (Zuddas et al., same source). peer-reviewed

3.2.6 Community view

The Rusanen citizen-science synthesis places lithium in an ambiguous position. In the Sewell et al. survey, omitting “partially effective” responses made verapamil and lithium appear to underperform relative to other surveys; the reviewers state that reassigning those partial responses to “effective” would have matched other surveys almost exactly (Rusanen et al. 2022, PMC9436841). citizen science Lithium features far less in r/clusterheads discussion than verapamil or Emgality, appearing mostly in “drugs I’ve already failed” lists (e.g. Peres & Rozen case 1’s history of failed lithium 900 mg). This under-discussion may reflect genuine declining use, monitoring burden, or the drug’s psychiatric associations — unknown.