A trip killer, also known as a hallucinogen antidote or hallucinogen antagonist, is a drug that aborts or reduces the effects of a hallucinogenic drug experience (or 'trip'). As there are different types of hallucinogens that work in different ways, there are different types of trip killers. Antipsychotics can block and reduce the effects of hallucinogens directly. Benzodiazepines provide adjunct anxiety relief and sedation. Examples of trip killers, in the case of serotonergic psychedelics, include serotonin receptor antagonists, such as antipsychotics like risperidone and quetiapine and certain antidepressants like trazodone and mirtazapine, and benzodiazepines, for instance diazepam and alprazolam. Trip killers can be used clinically to manage effects of hallucinogens, like hallucinogenic effects, anxiety, and psychomotor agitation, for instance in the emergency department and in the setting of psychedelic therapy. They are also sometimes used by recreational psychedelic users as a form of harm reduction to manage "bad trips" or challenging experiences, for instance emotionally difficult experiences with prominent anxiety. While used for harm-reduction purposes, this use of trip killers has raised concerns about safety and possible adverse effects.
Serotonergic psychedelic antidotes
Serotonin 5-HT2A receptor antagonists
Serotonergic psychedelics, such as psilocybin (found in psilocybin mushrooms), lysergic acid diethylamide (LSD), mescaline (found in peyote cacti), and dimethyltryptamine (DMT) (found in ayahuasca), mediate their hallucinogenic effects by acting as agonists of the serotonin 5-HT2A receptor. As a result, serotonin 5-HT2A receptor antagonists would theoretically be expected to block the hallucinogenic effects of serotonergic psychedelics. Accordingly, the serotonin 5-HT2A receptor antagonists ketanserin, an antihypertensive agent, and risperidone, an antipsychotic, have been shown to block the effects of serotonergic psychedelics in clinical studies. This includes the effects of psilocybin, LSD, mescaline, and ayahuasca. Ketanserin is under formal clinical investigation as a "neutralizer" or "off-switch" for psychedelics. The more selective serotonin 5-HT2A receptor antagonist pimavanserin is also being studied as a blocker of the effects of psychedelics. Eplivanserin/volinanserin, a combination of eplivanserin and volinanserin, is being studied for such uses as well.
Other potent serotonin 5-HT2A receptor antagonists that may block or reduce the effects of serotonergic psychedelics besides the above-listed drugs include other antipsychotics like quetiapine, olanzapine, aripiprazole, and pipamperone, antidepressants like trazodone, mirtazapine, mianserin, nefazodone, and etoperidone, and the antimigraine agent pizotifen, among others. The typical antipsychotic chlorpromazine, which has significant but less-potent serotonin 5-HT2A receptor antagonism than many other antipsychotics, has shown incomplete and inconsistent effects in reversing psychedelic effects in clinical studies, while the typical antipsychotic haloperidol, which is a dopamine D2 receptor antagonist but not a significant serotonin 5-HT2A receptor antagonist, is ineffective and has actually been found to increase anxiety and dysphoria in the setting of psychedelic experiences. In spite of variably acting as serotonin 5-HT2A receptor antagonists, tricyclic antidepressants (TCAs), including desipramine, imipramine, and clomipramine, have paradoxically been reported to potentiate the effects of serotonergic psychedelics rather than diminish them, albeit based on very limited data. Cyproheptadine, a non-selective serotonin receptor antagonist including of the serotonin 5-HT2A receptor, is used as an antidote in the treatment of serotonin syndrome (serotonin toxicity) caused by serotonergic drugs, including the toxicity of serotonergic psychedelics like the NBOMe drugs. A positron emission tomography (PET) study found 85 to 95% blockade of serotonin 5-HT2 receptors with cyproheptadine at a total dose of 12 to 18 mg/day. Certain other serotonin receptor antagonists, like chlorpromazine, have also been used to treat serotonin syndrome. Cyproheptadine might be useful as a serotonergic psychedelic antidote. However, a few small studies on cyproheptadine as an antagonist of the hallucinogenic effects of DMT have been inconsistent and inconclusive, as well as complicated by the drug's pronounced antihistamine sedative effects. Serotonin 5-HT2A receptor antagonists that have been found to block the psychedelic-like effects of serotonergic psychedelics in animals but have not necessarily been tested for such purposes in humans include cinanserin, clozapine, loxapine, metergoline, metitepine (methiothepin), mianserin, pirenperone, pizotifen, ritanserin, and seganserin, among others. Non-hallucinogenic partial agonists of the serotonin 5-HT2A receptor with sufficiently low intrinsic activity, such as 2-bromo-LSD (bromolysergide; BOL-148) and lisuride, are effective in blocking the hallucinogenic-related effects of psychedelics in animals and/or humans as well. However, it has been argued that lisuride may actually be a psychedelic or hallucinogen itself at sufficiently high doses in humans. Serotonergic psychedelics are being developed as novel treatments for psychiatric disorders and other conditions such as depression. A practical limitation in terms of clinical use of many major psychedelics, for instance psilocybin, LSD, and mescaline, is their long durations of action (4–12 hours), which may require a whole day of clinical monitoring. In relation to this, shorter-acting psychedelics, like DMT, 5-MeO-DMT (mebufotenin), and bretisilocin (5-fluoro-MET; GM-2505), are also being investigated for potential therapeutic use. However, an alternative approach that is being investigated is use of serotonin 5-HT2A receptor antagonists like ketanserin as trip killers to shorten the experiences of psychedelics. In a clinical trial, ketanserin given 1 hour after LSD shortened its duration from 8.5 hours to 3.5 hours (i.e., by roughly 60%). It did not modify the pharmacokinetics of LSD, and its side effects, such as nasal congestion, were minimal.
GABAA receptor positive allosteric modulators
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