Histamine

Brompheniramine

Brompheniramine is a first-generation alkylamine H1 antihistamine structurally almost identical to chlorpheniramine, differing only by a bromine atom in place of chlorine. It relieves allergic symptoms by antagonizing histamine H1 receptors, and its ready central nervous system penetration produces the characteristic sedation of this drug class. In vitro binding studies show that it also blocks all five human muscarinic acetylcholine receptor subtypes with affinity comparable to chlorpheniramine, which underlies its anticholinergic side effects and places it among the deliriants. Because sedation and impaired psychomotor performance can occur even at therapeutic doses, brompheniramine has been repeatedly detected in forensic toxicology of transportation fatalities; large overdoses can precipitate a dangerous anticholinergic delirium.

Chlorpheniramine

Chlorpheniramine (chlorphenamine) is a first-generation alkylamine H1 antihistamine ubiquitous in cold and allergy preparations, providing symptom relief through histamine H1 receptor blockade while causing sedation and, via muscarinic acetylcholine antagonism at all five subtypes, anticholinergic effects that classify it among the deliriants. A distinctive and less appreciated property is that it is a comparatively potent serotonin reuptake inhibitor; rodent studies show it raises prefrontal extracellular serotonin and produces anxiolytic-like effects independent of H1 blockade, and its in vitro profile resembles that of antidepressants. This serotonergic action carries clinical risk, since chlorpheniramine has contributed to serotonin toxicity in overdose, particularly when combined with dextromethorphan. High doses otherwise produce the anticholinergic delirium typical of the class.

Conessine

Conessine is a steroidal alkaloid found in the bark of tropical plants of the dogbane family (Apocynaceae), most notably Holarrhena and Funtumia species [1][4][5]. Long used in traditional medicine as a remedy for dysentery and other infections, it has drawn modern scientific interest as a naturally occurring blocker of the histamine H3 receptor in the brain [1][2]. It is not an approved medicine but is studied as a research compound and as a chemical starting point for designing new H3-targeting drugs [2][3].

Dimenhydrinate

Dimenhydrinate is a salt combining diphenhydramine with 8-chlorotheophylline, marketed as an antiemetic and antivertigo antihistamine for motion sickness. Its pharmacologically active moiety is diphenhydramine, a first-generation H1 antihistamine with strong antimuscarinic (anticholinergic) activity, while the 8-chlorotheophylline component contributes mild central stimulation intended to offset sedation. At therapeutic doses effects are chiefly sedation and typical anticholinergic signs, but at high doses dimenhydrinate behaves as a deliriant equivalent to the diphenhydramine it releases, producing confusion, hallucinations, and anticholinergic toxidrome. Systematic reviews document a distinct pattern of tolerance, dependence, and neuropsychiatric sequelae with heavy or chronic use, and management of severe intoxication parallels that of diphenhydramine overdose.

Diphenhydramine

Diphenhydramine is a first-generation H1 antihistamine sold over the counter for allergies and as a sleep aid, sedating at ordinary doses through histamine H1 blockade. It is also a potent muscarinic acetylcholine receptor antagonist, and at the high doses taken recreationally this antimuscarinic action produces a deliriant state of confusion, agitation, and frightening hallucinations characteristic of the anticholinergic toxidrome rather than euphoria. Toxicity is dose-dependent, with the risk of delirium, seizures, and coma rising sharply above roughly one gram, and diphenhydramine additionally blocks cardiac sodium channels, causing QRS prolongation and conduction abnormalities that may respond to sodium bicarbonate. Severe anticholinergic delirium can be reversed with centrally acting cholinesterase inhibitors such as physostigmine or, where unavailable, rivastigmine.

Doxylamine

Doxylamine is a first-generation H1 antihistamine marketed over the counter as a hypnotic and combined into nighttime cold and flu preparations. It produces sedation through histamine H1 receptor blockade and, like related ethanolamine antihistamines, is strongly anticholinergic, so that supratherapeutic doses can cause an unpleasant deliriant state with somnolence, agitation, hallucinations, mydriasis, and tachycardia. A characteristic and clinically important feature of doxylamine overdose is a comparatively high incidence of rhabdomyolysis, which can lead to acute kidney injury requiring haemodialysis; the amount ingested is the principal predictor, with risk rising steeply above roughly 20 mg per kilogram. Management centres on aggressive hydration, electrolyte monitoring, and support for renal and, less commonly, hepatic and pancreatic complications.

Antidepressant

Esmirtazapine

Esmirtazapine is an experimental drug that is the S-enantiomer of the antidepressant mirtazapine, a member of the tetracyclic class. It was developed as a potential treatment for insomnia and for the hot flashes of menopause, drawing on its sedating antihistamine-like action and a half-life shorter than that of mirtazapine itself. Although clinical trials showed it could lengthen sleep, its developer discontinued the program, and it was never brought to market.

Irdabisant

Irdabisant (CEP-26401) is a potent, highly selective histamine H3 receptor antagonist and inverse agonist developed by Cephalon. Because the H3 receptor is largely an inhibitory autoreceptor and heteroreceptor that restrains release of histamine and other arousal-related neurotransmitters, blocking it disinhibits wake-promoting signaling; in preclinical models irdabisant showed robust wake-promoting activity and improved short-term memory at low doses, alongside favorable central nervous system drug-like properties and high selectivity over other histamine receptor subtypes. It was studied as a candidate cognition-enhancing and wakefulness-promoting agent for conditions such as cognitive impairment and schizophrenia. Early human studies characterized its pharmacokinetics and pharmacodynamics, including dose-dependent effects on sleep, but the compound advanced only into early clinical trials and was never brought to market.

Latrepirdine

Latrepirdine, better known by its Soviet-era trade name Dimebon, is a multi-target small molecule originally marketed in Russia as a non-selective antihistamine and later repurposed as a candidate cognition enhancer. Among its many actions it is a moderate-affinity 5-HT6 receptor antagonist, and this activity is thought to contribute to its acute pro-cognitive effects in animal models. After an early positive Russian trial in Alzheimer's disease generated intense interest, large international phase 3 studies in both Alzheimer's disease and Huntington's disease were negative. It is now studied mainly as a promiscuous pharmacological tool and a lesson in multi-target drug development.

Luteolin

Luteolin is a naturally occurring flavone, a subclass of flavonoid, that carries a yellow color and is present in many plants used as foods and herbs, including celery, parsley, thyme, chamomile, and oregano. It has been studied in the laboratory for antioxidant, anti-inflammatory, and anticancer activity, although solid human clinical evidence is limited. It was first isolated in 1829 from the dye plant Reseda luteola.

Meclizine

Meclizine (also spelled meclozine; brand names Bonine and Antivert) is a long-acting first-generation piperazine antihistamine used chiefly for motion sickness and vertigo. It blocks histamine H1 receptors and central muscarinic acetylcholine receptors, dampening vestibular and emetic signaling; this same anticholinergic activity allows it to produce a deliriant, confusional state at high doses, alongside sedation from H1 blockade. It is metabolized largely by CYP2D6, giving wide interindividual variation in exposure and onset. Beyond its antihistamine role, meclizine has drawn research interest for an unusual metabolic action, partially inhibiting mitochondrial oxidative phosphorylation and redirecting energy production toward glycolysis, an effect studied for neuroprotection and cytoprotection.

Anxiolytic

Opipramol

Opipramol is an anxiolytic and antidepressant medication that is structurally related to the tricyclic antidepressants but has a distinct mechanism, lacking their characteristic reuptake inhibition of serotonin and noradrenaline. Instead it acts chiefly as a high-affinity ligand at sigma-1 and sigma-2 receptors, with additional histamine H1 antagonism and weaker D2 and 5-HT2 blockade; preclinical work indicates that its sigma activity, including selective downregulation of sigma-2 sites, underlies its anxiolytic profile. In a placebo-controlled trial it produced anxiolytic efficacy comparable to alprazolam in generalized anxiety disorder, and it retains use chiefly for generalized anxiety and somatoform disorders. Marketed in Germany and other European countries since the 1960s under brand names such as Insidon, it continues to be studied for sigma-mediated actions, including experimental effects on drug-seeking behavior via the Rac1 pathway.

Pitolisant

Pitolisant is a histamine H3 receptor antagonist and inverse agonist used to treat excessive daytime sleepiness and cataplexy in adults with narcolepsy. By blocking the H3 autoreceptor it boosts the brain's own histamine signalling, which promotes wakefulness and places it among the wake-promoting agents sometimes called eugeroics. Marketed mainly as Wakix, it was approved in the European Union in 2016 and by the United States FDA in 2019, and it is unusual among narcolepsy drugs in not being classified as a controlled substance in the United States.

Supplement

Quercetin Phytosome

Quercetin Phytosome is a formulated version of the dietary flavonoid quercetin in which the molecule is combined with phospholipids to make it far easier for the body to absorb. Ordinary quercetin is only minimally taken up when swallowed, and the phytosome delivery system was developed to overcome this limitation, raising blood levels of quercetin many times over. Sold as a dietary supplement, it has been studied mainly as a more bioavailable way to deliver quercetin's antioxidant and anti-inflammatory effects, including in trials during the COVID-19 pandemic.