Medication II — Immunomodulatory / Antiviral / Symptomatic / Supplements

10. Medication II — immunomodulatory / antiviral / symptomatic / supplements

For Long COVID, ME/CFS and POTS there is so far no approved, causally effective medication. Almost all the options described here are used either off-label (outside the approval) or as an over-the-counter OTC product, mostly on a low evidence level. The overarching principle of all guidelines remains PEM-avoiding pacing/energy management — the NICE guideline NG206 places recognising post-exertional malaise and energy management at the centre and explicitly advises against activating exercise therapy (GET) as a cure; no food supplement counts as curative [17]. Medications do not replace this approach.

General note: this section is an information overview, not a treatment recommendation. All the substances named are prescription-only or at least require advice and may only be taken after medical assessment, taking pre-existing conditions and one's individual medication into account. Dosages are orders of magnitude from the literature, not an intake instruction.

Immunomodulatory

Low-dose naltrexone (LDN). At a low dose (a fraction of the 50 mg standard dose approved for addiction treatment), naltrexone acts via a brief opioid-receptor blockade with reactive endorphin up-regulation and via a TLR4 antagonism at microglia — from which an anti-inflammatory, immunomodulatory effect is inferred; this mechanism is hypothetical and unproven in Long COVID [1][3]. The evidence comes from small, mostly uncontrolled studies; a 2025 systematic review could meta-analyse only two studies with around 95 patients, and the GRADE quality is very low [1][2]. Signals of improvement in fatigue, brain fog, headache and sleep are reported — on this data basis these are preliminary indications, not proof of efficacy [3]. LDN is off-label and is prescribed as a compounded formulation/capsule. Side effects are mostly mild (headache, vivid dreams/sleep disturbances, dizziness, gastrointestinal complaints). Safety: contraindicated during ongoing opioid therapy (triggering withdrawal, loss of analgesia) — pause under medical guidance before planned operations/opioid analgesia; caution in liver disease; use in pregnancy/breastfeeding not sufficiently studied [1][3]. Randomised studies are ongoing and are urgently called for.

Low-dose aripiprazole (LDA). Well below the dose approved for psychiatric indications (typically 10–30 mg/day there), aripiprazole is used in ME/CFS and Long COVID in the range of 0.1–2 mg/day — at this "whisper dose" the drug does not act like a classic dopamine blocker but more as a partial D2/D3 receptor stabiliser. A dampening of microglial activation and neuroinflammation is also discussed (supported among other things by TSPO-PET imaging studies) — this mechanism, too, is hypothetical, not proven. The evidence comes exclusively from retrospective observational studies: a Stanford analysis of 101 people with ME/CFS (2021) found improvement in 74% across fatigue, brain fog, sleep and PEM frequency (mean dose 1.1 mg/day); a more recent retrospective analysis of 50 people with Long COVID (2025/26) showed a significant improvement in functional status, with 22% achieving a clinically meaningful improvement (≥30% reduction in composite symptom score). Neither study had a control group or randomisation, and the authors themselves call for controlled follow-up trials. A patient survey (TREATME, summarised at MEpedia) also reports that the effect fades over time in some users (tachyphylaxis) and does not always return after a break. Status: off-label, no randomised controlled trial (RCT) has been conducted so far, and there is no approval for ME/CFS or Long COVID. At this low dose, side effects are mostly mild (headache, restlessness/agitation, sleep disturbances) with on average modest weight gain; the starting dose is extremely low (often 0.1–0.25 mg/day) and must be titrated individually under close medical supervision.

Antihistamines in suspected MCAS. In assumed mast cell activation syndrome, H1 blockers (second generation, mildly sedating, e.g. cetirizine — can cause slight drowsiness —, loratadine, fexofenadine; sedating e.g. ketotifen) are combined with an H2 blocker (famotidine) to dampen histamine-mediated symptoms [4][5]. The evidence rests on case series and observational data with reported improvement; large RCTs are lacking, and the MCAS diagnosis in Long COVID remains professionally disputed (consensus criteria are often not met) [4]. Status: off-label or OTC (H2 blockers/H1 blockers partly available without prescription). Safety: ranitidine was withdrawn from the market because of NDMA contamination — use famotidine instead; watch for interactions and QT-relevant combinations [5]. More on MCAS as its own topic in the MCAS chapter.

Antiviral / metabolic

Metformin (prevention in the acute phase). The antidiabetic metformin inhibits, among other things, viral translation (mTOR-dependent) and acts anti-inflammatorily (mechanistically plausible, not proven). In the COVID-OUT RCT (1,126 included in the Long COVID analysis), a 14-day early dose during the acute infection lowered the Long COVID incidence over 10 months to 6.3 % compared with 10.4 % under placebo (relative reduction ~41 %, absolute ~4.1 percentage points); when started within the first few days after symptom onset, the relative reduction in the subgroup was larger (up to ~63 %) [6][7]. Important: this effect is preventive in the acute phase. A benefit as a fatigue therapy in already established Long COVID is not proven — in the 2026 adaptive RCT (Annals of Internal Medicine; see fluvoxamine below), which tested metformin and fluvoxamine against fatigue in established Long COVID, metformin brought no improvement in fatigue over placebo [8]. Off-label in this context. Safety: gastrointestinal side effects; contraindicated in relevant renal insufficiency and in situations with hypoxia/dehydration (rare but dangerous lactic acidosis); attention to contrast-agent administration and alcohol.

SSRI/SNRI (fluvoxamine). Sigma-1 receptor agonism and anti-inflammatory effects are discussed (hypothesis). A 2026 adaptive RCT (n=399, exclusively at 22 centres in Brazil — generalisability thereby limited) showed, after 60 days of fluvoxamine, a moderate improvement in fatigue that faded after stopping (after 30 days ~50 % more often low fatigue [score ≤3], after 60 days ~0.5 points lower, after 90 days — 30 days after stopping — only ~19 % advantage) [8]. Observational data point to a lower Long COVID risk with SSRI use in depressive patients — an association, not proof of causation [9]. Off-label for Long COVID; robustly evidence-based is its use in comorbid depression/anxiety. Safety: discontinuation syndrome (do not stop abruptly), serotonin syndrome with serotonergic combinations, initial activation/nausea; fluvoxamine is a strong CYP1A2 inhibitor with clinically relevant drug interactions (among them caffeine, theophylline, clozapine, tizanidine, some anticoagulants) — have combinations checked by a doctor [9].

What is advised against: the unlicensed "microclot" triple therapy (two platelet aggregation inhibitors plus a DOAC) is supported by no RCT; experts explicitly advise against it because of substantial bleeding risk and a thin causal basis [10][11]. Do not use on your own.

Symptomatic (POTS) and supplements

Salt and fluid intake (POTS). Increased table salt (in guidelines often up to ~8–10 g NaCl/day) and fluid intake (~2–3 l/day) are non-pharmacological first-line measures to increase blood volume [18]. Contraindicated, or only under medical guidance, in hypertension, heart or kidney failure — the amount should be set individually by a doctor, not applied across the board.

The following OTC supplements all have low evidence and are mainly useful in a proven deficiency. None is proven effective for Long COVID/ME/CFS:

• CoQ10 (mitochondrial antioxidant): a small RCT (CoQ10+NADH) with signs of improvement in fatigue/heart-rate parameters after exertion; mostly well tolerated, possible interaction with warfarin (can weaken its effect) and antihypertensives [12][13].
• D-ribose (ATP substrate): only uncontrolled pilot studies, high susceptibility to placebo; can lower blood sugar (caution with diabetes/tendency to hypoglycaemia) [14].
• Magnesium: useful in deficiency; high doses → diarrhoea; caution/risk of accumulation in renal insufficiency.
• B vitamins/B12: subjective benefit reported, no robust RCTs; B12 very safe, but long-term high B6 doses → sensory neuropathy (observe dose limits) [15].
• Omega-3 (EPA/DHA): anti-inflammatory plausible, evidence mixed/negative; possibly additive bleeding risk with anticoagulants.
• Vitamin D: correcting a deficiency is useful; no Long COVID therapy evidence; overdose → hypercalcaemia.
• NAC: antioxidant/mucolytic, only preliminary PASC signals (e.g. dyspnoea); available in Germany over the counter as a mucolytic, in rare cases bronchospasm — caution in asthma [16].

Conclusion: all the substances named are off-label or OTC, are not proven curative for Long COVID/ME/CFS and should be used individually, with medical guidance and after weighing benefit and risk (including checking interactions) — and do not replace pacing [17].