Trip killers: which medications can potentially weaken or stop a bad trip

There is a new scientific article that investigates which medications might be useful to pharmacologically attenuate or stop a severe psychedelic disturbance, also known as a bad trip.

In it, we discuss:

Psychedelics are increasingly being investigated as a treatment for mental disorders and are also used recreationally. In some cases, use can lead to intense psychological dysregulation, involving panic, confused behavior, dangerous impulsivity, or even presentation at the emergency room or admission to a psychiatric hospital. The authors state that such situations are clinically relevant in practice, while there is remarkably little systematic evaluation of substances that can terminate the psychedelic state.

The real focus of this article is not on new patient data or a trial, but on a critical review of candidate drugs. The authors discuss, among others, serotonin antagonists, agents for psychosis, and selected agents for anxiety and depression. In doing so, they examine not only theoretical applicability but also mechanisms of action, pharmacokinetics, safety, and applicability in acute care settings. 

Products discussed in this review
Yes, now it is clear. Based on the full text, these are the substances or groups of substances that the authors really discuss as potential trip killers or as relevant means of comparison.

1. Selective 5-HT2A antagonists
The review primarily discusses ketanserin, pimavanserin, pirenperone, pizotifen, and ritanserin. Within this group, ketanserin and pirenperone are presented as the most plausible candidates based on receptor logic, although availability and side effects are significant limitations.

2. Antipsychotics
Several substances are discussed here. The most important are risperidone, paliperidone, olanzapine, quetiapine, asenapine, ziprasidone, loxapine, lurasidone, aripiprazole, brexpiprazole, chlorpromazine, and clozapine. Additionally, they mention haloperidol, specifically as an example of a substance that may be less suitable because it does not effectively attenuate the psychedelic state and can even worsen anxiety. Zotepine and sertindole are also briefly mentioned as theoretical options.

The authors ultimately conclude that risperidone is the most practical first choice when ketanserin is unavailable. Paliperidone is mentioned as an alternative.

3. Remedies for anxiety and depression
In this group, they primarily discuss trazodone, mirtazapine, buspirone, and mianserin. Additionally, they mention broader classes such as SSRIs and tricyclic antidepressants. Among the tricyclic agents, amitriptyline, clomipramine, and imipramine are specifically mentioned. Within this group, the authors view trazodone and mirtazapine as the most useful candidates, although they emphasize that these agents often also have a sedative effect.

4. Antihistamines
Here they discuss cyproheptadine, diphenhydramine, and promethazine. Of these three, cyproheptadine receives the most attention because, in addition to its antihistaminergic activity, it also possesses relevant 5-HT2A antagonistic properties.

5. Benzodiazepines
The review explicitly mentions benzodiazepines as substances that usually do not actually stop a trip, but can dampen anxiety and restlessness. The substances discussed are diazepam, alprazolam, midazolam, lorazepam, and clonazepam.

6. Other means
Additionally, the authors discuss niacin as a historical and speculative agent. They also mention alcohol and cannabis, but precisely as examples of strategies that, in their view, may be clumsy or harmful rather than helpful.

What the authors ultimately recommend:
Their practical order is roughly this. First, ketanserin as the agent of choice. If that is not available, then risperidone or paliperidone. In case of neuroleptic sensitivity, they mention cyproheptadine, trazodone, or mirtazapine as alternatives. They view benzodiazepines primarily as supplementary for anxiolysis and sedation, not as true receptor-targeted trip killers.

It is important to note, however, that this is a review and not a clinical efficacy study. Consequently, the article does not provide new trial outcomes, effect sizes, or direct evidence that one specific agent has already been proven to be the best trip killer. The authors therefore conclude with a preliminary pharmacological framework and emphasize that this actually exposes a major knowledge gap in the field.

In one sentence: this article shows that more systematic research is urgently needed into medications that can safely and specifically attenuate or stop severe psychedelic dysregulation.