The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act

Abstract

This review assesses the abuse potential of medically-administered psilocybin, following the structure of the 8 factors of the US Controlled Substances Act (CSA). Research suggests the potential safety and efficacy of psilocybin in treating cancer-related psychiatric distress and substance use disorders, setting the occasion for this review. A more extensive assessment of abuse potential according to an 8-factor analysis would eventually be required to guide appropriate schedule placement. Psilocybin, like other 5-HT2A agonist classic psychedelics, has limited reinforcing effects, supporting marginal, transient non-human self-administration. Nonetheless, mushrooms with variable psilocybin content are used illicitly, with a few lifetime use occasions being normative among users. Potential harms include dangerous behavior in unprepared, unsupervised users, and exacerbation of mental illness in those with or predisposed to psychotic disorders. However, scope of use and associated harms are low compared to prototypical abused drugs, and the medical model addresses these concerns with dose control, patient screening, preparation and follow-up, and session supervision in a medical facility. CONCLUSIONS: (1) psilocybin has an abuse potential appropriate for CSA scheduling if approved as medicine; (2) psilocybin can provide therapeutic benefits that may support the development of an approvable New Drug Application (NDA) but further studies are required which this review describes; (3) adverse effects of medical psilocybin are manageable when administered according to risk management approaches; and (4) although further study is required, this review suggests that placement in Schedule IV may be appropriate if a psilocybin-containing medicine is approved. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

Keywords: Abuse potential; Addiction; Anxiety; Controlled Substances Act; Depression; Psilocybin.

Conflict of interest statement

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Roland Griffiths is on the Board of Directors of the Heffter Research Institute which supports psilocybin research and the potential development and submission of an NDA to the United States Food and Drug Administration (US FDA).

Through, Pinney Associates, Jack Henningfield has consulted and/or are presently consulting to the Heffter Research Institute and to the Usona Institute which are supporting the development of psilocybin as a new medication to be submitted for approval by the U.S. FDA, as well as to other sponsors of central nervous system acting products concerning their abuse potential, appropriate regulation, and medicinal application.

Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1:

The two upper panels show mean response rates (±SEM) during self-administration of classic psychedelic compounds by rhesus monkeys making lever presses under an FR-30 schedule of reinforcement. Left panel shows psilocybin and DMT; right panel shows mescaline and 4-iodo-2,5-dimethoxyphenylisopropylamine (DOI). The two bottom panels show the corresponding mean number of injections earned (±SEM) during these self-administration sessions. For all panels, the light horizontal lines show the range for saline response rates (upper panels) and saline injections earned (bottom panels; with the bottom of the range at 0). For all panels, n=4. Figure from Fantegrossi et al, 2004, Figure 1)

Figure 2:

Cardiovascular and observer-rated effects of oral psilocybin in cancer patients (n=50). Each panel shows the mean (±SEM) within-subject time-course effect of a moderately-high (~0.314 or ~0.429 mg/kg) versus low, placebo-like (~0.014 or ~0.043 mg/kg) dose of psilocybin. For observer ratings, the Y-axis spans the range of possible scores. Filled squares indicate that planned comparisons showed the high dose condition significantly differed from the low dose condition at that time-point (p<0.05). Figure from Griffiths et al, 2016, Figure 2)

Figure 3:

Normalized ratings of harm potential of psilocybin (“mushrooms”) relative to other drugs as rated by experts in the United Kingdom using on a multidimensional scale. Drugs are ranked by overall harm from left (most harmful) to right (least harmful), with harm to users (blue) and harm to others (red) shown separately. Abbreviations: CW=cumulative weight, GHB=gamma-hydroxybutyric acid. (Figure from Nutt et al., 2010, Figure 2)

Figure 4:

Normalized ratings of harm potential of psilocybin (“magic mushrooms”) relative to other drugs as rated by experts in the European Union using a multidimensional scale. Drugs are ranked by overall harm from left (most harmful) to right (least harmful), with harm to users (shaded texture) and harm to others (solid texture) shown separately. (Figure 2 from van Amsterdam et al., 2015)

Figure 5:

Persisting effects of psilocybin on depression- and anxiety-related outcome measures Outcomes were measured at baseline (pre-psilocybin), post session 1 (5 weeks after the first psilocybin session), post session 2 (5 weeks after the second psilocybin session), and the 6-month follow-up (n = 25, 25, 24, and 22 at baseline, post session 1, post session 2, and 6 months, respectively). Each panel shows the mean (±SEM) scores for two groups: The “Low Dose 1st” group received a low, placebo-like (~0.014 or ~0.043 mg/kg) dose of psilocybin in Session 1, and a moderately-high (~0.314 or ~0.429 mg/kg) dose of psilocybin in Session 2; the “High Dose 1st” group received the doses in the opposite order. Stars show a significant difference between the two groups at post session 1 by planned comparison (p<0.05). Crosses show a significant difference between the post session 1 and post session 2 times in the Low-Dose-1st group by planned comparison (p<0.05). (Figure from Griffiths et al., 2016, Figure 3)