Psilocybin—the hallucinogenic pro-drug in magic mushrooms—has recently dominated the popular narrative on new approaches to treating depression. For example, recent papers from John’s Hopkins (1) and Imperial College (2, 3) demonstrate the potential for psilocybin to promote positive lifestyle changes, and as an intervention for treatment-resistant depression, respectively. They also provide an opportunity to highlight two recurrent issues with psychedelic research which we place in the context of more recent data in this article. Specifically, the absence of a placebo, active control, and lack of additional measures still limits the informative nature of these studies. In this article we hope to illustrate two key issues from the recent psychedelic literature, namely (a) the use of support models (psychotherapy assisted treatment) in the absence of a placebo or active control group and, (b) the importance of placebo and active control treatment to interpret neural changes, particularly in the light of potential placebo responders. These are not new issues and indeed are acknowledged by authors of recent studies in this field (1–3), but the specific contributions of these control conditions is not straightforward. The more recent studies mentioned complement the previous studies using psilocybin as a means to reduce anxiety and depression in terminal cancer patients, which were at the time hailed as the “most rigorous double-blind placebo-controlled trials of a psychedelic drug in the last 50 years” (4). Despite the growth of supportive studies and use of converging multimodal evidence our understanding of how psilocybin may be beneficial is in its infancy. Progress needs to be made in explicitly understanding the cognitive and neural mechanistic process by which psilocybin works, and also how specifically efficacious psychedelic treatment is outside of the sample used in these trials. This is pointed at by McCorvy et al. (5) in a commentary on the studies by Griffiths et al. (6) and Ross et al. (7), but we hope to expand on these future directions in light of new evidence. Griffiths et al. (1) studied the added-value of using supportive therapy to instill positive lifestyle change alongside psilocybin. Aside from meditation practice, high support and standard support interventions provided comparable results in terms of increased mystic and spiritual practice ratings when participants were given two different doses of psilocybin (20 mg/70 kg and 30 mg/70 kg). In essence, variance in support did not greatly impact the response observed in high-dose sessions. There is a paucity of evidence attempting to understand the dose-response effects of psilocybin. For this reason, these results significantly extend our understanding, but additional groups would add rigor. Inclusion of all four possible conditions—low/high psilocybin and standard/high support—in addition to psilocybin/no support and placebo standard/high support would strengthen Griffiths et al.’s (1) study. However, there are limitations. First, completing a multi-arm design is practically difficult and resource intensive. Second, guidelines from the same group (8) argue against the use of psilocybin without support. However, they do not argue against the use of placebo with support, or low dose psilocybin with high support. Lack of these groups constrict conclusions and renders the dose-response effect from both psilocybin and support groups unclear. Keywords: psychedelics, psilocybin, depression, clinical trials, methodology