This paper reviews the evidence for using psychedelics (MDMA, DMT, psilocybin) and the dissociative anesthetic ketamine to potentiate fear extinction in the treatment of fear-related disorders (phobias, PTSD). Overall the paper is well written and structured, with the authors making their case effectively in the main, but I do have some comments below for the authors to consider.

In the last paragraph of section 1, the main mechanism of action of ketamine (i.e. NMDA receptor antagonist) should be included, although I appreciate that other mechanisms are at play in its regulation of fear extinction (see also below).

In section 2, the description of the return of fear after extinction under certain conditions should come after the different phases of extinction (i.e. acquisition, consolidation, retrieval) are described. Fear reinstatement should also be added along with fear renewal and spontaneous fear recovery. The sentence ‘… insufficient reinforcement of extinction memory in extinction learning sessions…’ is unclear and should be revised. The last paragraph of section 2 is unrelated to animal models of fear extinction so it should be moved to a different section or the section should be re-named (e.g. ‘Fear extinction and its neural correlates’ or similar, to cover both animal and human studies).

The first sentence of section 3 implies that fear extinction learning is unique as it ‘encompasses several interwoven processes’ but the relevant signalling pathways regulating neuroplasticity are also involved in many other types of learning, so this sentence should be revised for clarity. In various places in this section it is unclear at times if the signalling pathways described apply to the brain in general or specifically in relation to fear extinction in the relevant brain areas.

In section 3 the authors imply that increased serotonin (5HT) transmission promotes fear extinction, which seems like an oversimplification. They state earlier on that 5HT reuptake inhibitors are used for treating fear-related disorders but they haven’t included anything on their regulation of fear extinction in animals, which seems quite relevant to cover at least briefly. Do they regulate fear extinction? If so, then how (e.g. 5HT2A receptors)? If not, then why not? Later on DMT is discussed in relation to ayahausca, which also contains monoamine oxidase inhibitors, so it’s not clear if any effects of ayahuasca would be mediated by DMT and/or monoamine oxidase inhibition. Later on psilocybin is also discussed in relation to 5HT1A autoreceptor signalling as being a possible mechanism of its action but this is speculative and couldn’t this also apply to MDMA / DMT? 5HT2A receptor activation seems to be a common putative mechanism of action of MDMA, DMT, and psilocybin but have any studies looked at the effects of other 5HT2A agonists (e.g. LSD, DOI) on fear extinction? These apparent discrepancies need to be addressed throughout the review.

In section 3 the authors imply that preclinical studies on the regulation of fear extinction by dopamine and noradrenaline has led to mixed results in the literature. However, there is a much larger body of evidence demonstrating dopamine and noradrenaline enhancement of fear extinction (for reviews see Giustino & Maren, 2018; Kalisch et al., 2019; Papalini et al., 2020; Warren et al., 2021), compared to the relative paucity of evidence for its regulation by psychedelics or ketamine. I appreciate the focus is not on dopamine and noradrenaline regulation of fear extinction but the authors should concede that their role here is well established. This is also potentially important when considering the mechanism/s of action of MDMA regulation of fear extinction (see below).

The authors rightly state that NMDA receptor signalling is important in extinction processing but I don’t think they stated explicitly that NMDA receptor antagonism has been shown in many studies to impair fear extinction learning. This is needs to be included when it comes to discussing the mechanisms of action of ketamine in regulating fear extinction, which likely involves the other downstream signalling mechanisms discussed in the review.

The first paragraph of section 4 can arguably be omitted as it just repeats what came earlier.

In relation to section 4.1, MDMA elicits the release and reuptake inhibition of 5HT but also dopamine and noradrenaline. MDMA regulation of fear extinction is discussed mainly in relation to 5HT2A receptor signalling and also oxytocin and glucocorticoid signalling. However, it is possible that MDMA regulation of fear extinction also involves dopamine and noradrenaline, given their role in regulating fear extinction (see above), so this possibility needs to be acknowledged.

The first sentence of the second paragraph of section 4.1 is unclear as it could be taken to infer that MDMA acts as a direct 5HT2A receptor agonist, which I don’t think was intended. In this paragraph the possibility that MDMA regulates fear extinction via 5HT2A receptor activation is raised but it is phrased more as a hypothetical then as being backed up by evidence. The studies referenced later showing that MDMA enhancement of fear extinction is blocked by 5HT2A receptor antagonism should be mentioned briefly here. However, one of those papers also showed that 5HT reuptake inhibition blocks the enhancement of fear extinction by MDMA; the relevance of this finding to the mechanism of action of MDMA should be discussed more as this seems important here.

Figure 1 implies that MDMA is a direct 5HT2A receptor agonist, which needs to be checked and revised if needed. MDMA-induced 5HT release also needs to be added to the figure.

Are the brain areas involved in mediating oxytocin and glucocorticoid regulation of fear extinction known, apart from a role for the amygdala with oxytocin? The point about the importance of the time of oxytocin application on fear extinction is unclear and needs to be revised.

In Table 1, the ketamine studies should be moved to last to reflect the order that each drug is covered in the text. One of the ketamine studies cited in the text (see below) is missing from the table and needs to be included.

At the end of section 4.1.1 it implies that the preclinical studies on MDMA regulation of fear extinction are in accordance with the clinical data but one of the MDMA studies cited showed no effect or even impaired fear extinction so this needs to be re-phrased. The authors should also consider that the beneficial effects of MDMA (and the other drugs discussed) in the clinic might not involve potentiated fear extinction per se, at least not directly. There doesn’t seem to be much direct evidence provided that MDMA (or any of the drugs discussed) can potentiate lab-based fear extinction in humans so this point could be raised in the Discussion or Conclusion.

At the end of section 4.2 it mentions that DMT can cause psychological adverse effects so these should be included briefly here.

Section 4.2.1 mentions that ayahuasca-induced amygdala hyper-activity might be involved in its therapeutic effects but earlier it also said that amygdala hyper-activity is involved in the etiology of fear-related disorders. This apparent discrepancy needs to be clarified. In discussing the effects of DMT on cued vs contextual fear extinction another possibility for its different effects in each paradigm is that might DMT act preferentially in certain brain areas over others. Negative metabolic repercussions of DMT are mentioned so these should be included briefly here.

Paragraphs 2 and 3 of section 4.4 are not directly relevant and can arguably be omitted.

At the start of section 4.4.1 it implies that the authors already mentioned earlier that increased glutamate / NMDA receptor signalling and impaired neuroplasticity are involved in fear-related disorders but I don’t think these were mentioned earlier so this needs to be addressed. The study showing impaired fear extinction with ketamine (Clifton et al., 2018) needs to be added to Table 1.

The second paragraph of section 5 should be incorporated into the Introduction and omitted here. When MDMA-assisted psychotherapy is mentioned, is this specifically referring to extinction-based exposure therapy? Later on ketamine is mentioned specifically in relation to the enhancement of extinction-based psychotherapy but it’s unclear if this is also the case for MDMA. If not then MDMA (or DMT / psilocybin) might not be beneficial for treating fear-related disorders by enhancing fear extinction per se but instead is beneficial for some other reason, which seems worthy of discussion. Human studies on psychedelic effects on lab-based fear extinction in healthy or clinical populations might be useful for addressing this issue, which might also be worthy of discussion.

The words proven, proved, etc. should be replaced with shown, demonstrated, etc. throughout.

The authors have done very well with addressing all of my comments on the original submission and the review is now much improved in my view.