Trip killer

A trip killer, or hallucinogen antidote, is a drug that aborts or reduces the effects of a hallucinogenic drug experience (or 'trip').[1][2][3][4][5] As there are different types of hallucinogens that work in different ways, there are different types of trip killers.[6][7][8] They can completely block or reduce the effects of hallucinogens[6] or they can simply provide anxiety relief and sedation.[3] Examples of trip killers, in the case of serotonergic psychedelics, include serotonin receptor antagonists, like antipsychotics and certain antidepressants, and benzodiazepines.[4][6] Trip killers are sometimes used by recreational psychedelic users as a form of harm reduction to manage so-called bad trips, for instance difficult experiences with prominent anxiety.[2][4] They can also be used clinically to manage effects of hallucinogens, like anxiety and psychomotor agitation, for instance in the emergency department.[3][9]

Serotonergic psychedelic antidotes

See also: Trazodone § Antagonism of serotonergic psychedelics

Serotonergic psychedelics, such as psilocybin (found in psilocybin mushrooms), lysergic acid diethylamide (LSD), mescaline (found in peyote cactii), and dimethyltryptamine (DMT) (found in ayahuasca), are thought to produce their hallucinogenic effects via activation of the serotonin 5-HT2A receptor.[10][11][6] As a result, serotonin 5-HT2A receptor antagonists would theoretically be expected to block the hallucinogenic effects of serotonergic psychedelics.[6] 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.[6][12][13][14] This includes the effects of psilocybin,[15][16][17] LSD,[18][19] mescaline,[20] and ayahuasca.[21] Conversely, the antipsychotic chlorpromazine has shown inconsistent effects in reversing psychedelic effects,[6] while the antipsychotic haloperidol, which is a dopamine D2 receptor antagonist but not a serotonin 5-HT2A receptor antagonist, is ineffective.[6][22][15]

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 (or serotonin toxicity) caused by serotonergic drugs, including the toxicity of serotonergic psychedelics like the NBOMe drugs.[23][24][25] Certain other serotonin receptor antagonists, like chlorpromazine, have also been used for such purposes.[25][26]

Recreational psychedelic users sometimes employ trip killers to abort psychedelic trips.[2][4][5] The most commonly encountered putative trip killers in a 2024 online study of Reddit social media postings were the benzodiazepines alprazolam and diazepam, the antipsychotic quetiapine, the antidepressant trazodone, and alcohol.[4][5][27] Others used less frequently included the benzodiazepines lorazepam, clonazepam, and etizolam, the antipsychotic olanzapine, and the antidepressant mirtazapine, among others.[4][5] Antipsychotics like quetiapine and olanzapine and antidepressants like trazodone and mirtazapine are all potent serotonin 5-HT2A receptor antagonists.[6][28][29] Conversely, benzodiazepines and alcohol act as positive allosteric modulators of the GABAA receptor and have anxiolytic and sedative effects.[30] Such effects can be useful in managing the effects of serotonergic psychedelics, including clinically in the case of benzodiazepines.[3][31] While employed by recreational users for harm-reduction purposes, the use of trip killers to abort the effects of psychedelics and other hallucinogens is not fully characterized and could pose medical risks.[1][4][5][27]

Other serotonin 5-HT2A receptor antagonists that may block or reduce the effects of serotonergic psychedelics include other antipsychotics, like pipamperone, other antidepressants, like mianserin, nefazodone, and etoperidone, and the antimigraine agent pizotifen, among others.[6] The selective serotonin 5-HT2A receptor antagonist pimavanserin is also being studied as a blocker of the effects of psychedelics.[32] Conversely, 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.[6] Other drugs that have been reported to potentiate rather than inhibit the effects of serotonergic psychedelics include lithium, reserpine, pindolol, and methysergide.[6] Pindolol, a beta blocker and serotonin 5-HT1A receptor antagonist, has been reported to potentiate the hallucinogenic effects of DMT by 2- to 3-fold in humans.[33][34]

High-dose niacin (vitamin B3) was reported to reduce and block the effects of LSD in one early clinical study.[6][35][36] However, a subsequent clinical study attempting to replicate the findings found that it was not effective for this purpose.[35] Azacyclonol, a claimed ataractive (i.e., non-antipsychotic hallucination-suppressing medication) that is no longer marketed, likewise seems to be ineffective.[6]

Besides serotonin 5-HT2A receptor antagonists, other serotonergic drugs may also diminish the effects of serotonergic psychedelics.[6] Examples include serotonin 5-HT1A receptor agonists like buspirone, serotonin reuptake inhibitors like the selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, paroxetine, sertraline) and serotonin–norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs) (e.g., phenelzine, nialamide, isocarboxazid).[6] Buspirone, a partial agonist of the serotonin 5-HT1A receptor, has specifically been found to markedly attenuate the visual and certain other effects of psilocybin, although it did not completely block the hallucinogenic effects of psilocybin.[6][37][33] The reduced effects of psychedelics in the case of concomitant drugs that elevate serotonin levels may be due to desensitization of serotonin 5-HT2A receptors.[6] Although MAOIs can diminish the effects of serotonergic psychedelics, it must be noted that some serotonergic psychedelics, such as DMT, are highly susceptible substrates for monoamine oxidase (MAO), and hence can simultaneously be greatly potentiated by MAOIs (as in ayahuasca).[6][38]

Non-hallucinogenic partial agonists of the serotonin 5-HT2A receptor with sufficiently low intrinsic activity, such as 2-bromo-LSD and lisuride, are effective in blocking the hallucinogenic effects of serotonergic psychedelics as well.[39][40]

Other non-serotonergic drugs that may block or reduce the effects of serotonergic psychedelics based on animal studies include AMPA receptor antagonists, metabotropic glutamate mGlu2 and mGlu3 receptor agonists, μ-opioid receptor agonists, and adenosine A1 receptor agonists.[22][41][42]

Antidotes of other hallucinogens

Cannabinoid CB1 receptor antagonists like rimonabant, drinabant, and surinabant have been found to block or reduce the psychoactive effects of cannabinoids in clinical studies and could be useful as antidotes against cannabinoid toxicity.[7][43] Likewise, the hallucinogenic and other effects of κ-opioid receptor agonists like salvinorin A (found in Salvia divinorum), butorphanol, and pentazocine have been shown to be blocked by the non-selective opioid receptor antagonist naltrexone in clinical studies.[8][44][45][46] Although clinical management of antimuscarinic deliriant intoxication and poisoning, for instance due to scopolamine, is usually supportive, acetylcholinesterase inhibitors, such as physostigmine, have sometimes been used in this context as well.[47][48] Benzodiazepines and antipsychotics have also been used in such situations.[47][48]

Although trip killers exist for certain types of hallucinogens, antidotes do not exist for all types of hallucinogens, for instance NMDA receptor antagonist dissociatives like ketamine and phencyclidine (PCP).[49][3][50] NMDA receptor agonists, which theoretically could reverse the effects of NMDA receptor antagonists, can produce excitotoxic neurotoxicity and convulsions, which limits their potential medical use.[51][52][53] In any case, benzodiazepines can be useful in managing dissociative intoxication.[9][49] As with NMDA receptor antagonists, there is no antidote for Amanita muscaria intoxication.[54][55]

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