The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act
Matthew W. Johnson, Roland R. Griffiths, Peter S. Hendricks, Jack E. Henningfiel
Neuropharmacology, 2018, 142, 143-166.
a b s t r a c t
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 : Psilocybin, Abuse potential, Controlled Substances Act, Depression, Anxiety, Addiction
1. Introduction . 144
1.1. Abuse potential and drug scheduling in the context of the CSA . 145
1.1.1. FDA is the sponsors’ focal point for the NDA including its abuse potential assessment .. 146
2. Evaluation of the abuse potential of psilocybin according to the 8 factors of the CSA . 146
2.1. Factor 1: Actual or relative potential for abuse . 146
2.1.1. Preclinical studies . 146
2.1.2. Human abuse potential assessment . 147
2.1.3. Clinical trials relevant to abuse potential assessment since 2000 . 148
2.2. Factor 2: Scientific evidence of its pharmacological effect . 148
2.2.1. Tolerance and physical dependence . 150
2.2.2. Toxicity . 150
2.2.3. Pharmacodynamics . 150
2.3. Factor 3: Current scientific knowledge regarding drug . 151
2.4. Factor 4: History and current pattern of abuse . 152
2.4.1. United States national surveys . 152
2.4.2. A note on “microdosing” . 154
2.5. Factor 5: The scope, duration, and significance of abuse . 155
2.6. Factor 6: Risk to public health . 157
2.6.1. Potential public health benefits . 158
2.7. Factor 7: Psychic or physiological dependence liability . 161
2.8. Factor 8: Immediate precursor of substance controlled . 161
3. Discussion . 161
3.1. Summary and recommendation for CSA scheduling. 161
3.2. Implications for research and policy. 162
4. Declaration of conflicting interests . 162
Funding . 162
Acknowledgements . 162
Supplementary data . 162
References . 162
Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is under development for the treatment of depression and anxiety for patients with life-threatening cancer diagnoses (Griffiths et al., 2016; Grob et al., 2011; Ross et al., 2016). Although at a more preliminary research state, promising open label results have also been reported for treatment-resistant major depression (Carhart-Harris et al., 2016a; Rucker et al., 2017) and addiction to tobacco (Johnson et al., 2014) and alcohol (Bogenschutz et al., 2015). Such treatments would be in the form of a clinically tested drug product that would provide psilocybin doses demonstrated to be safe and effective in a formulation that assures precision in dosing, which is rarely the case for illicitly consumed mushrooms (Bigwood and Beug, 1982), and in a clinical framework that would minimize the possibility of misuse or diversion. These drug formulation and intervention parameters would be addressed in an agreed upon risk management plan and would also likely be addressed in a legally binding Risk Evaluation and Mitigation Strategies (REMS) plan (U.S. Food and Drug Administration, 2015). The REMS would be based on the studies and approaches used to ensure safe and effective use and could include: a) limitations on the dose and the number of doses that could be administered to a given patient, b) administration of the drug in clinic settings with psychological support of specially trained staff, c) a variety of restrictions on distribution, access and storage, and d) a post-marketing surveillance plan to provide the FDA with timely and comprehensive communication of unintended consequences (Blanchette et al., 2015; Brandenburg et al., 2017; Dart, 2009; Dasgupta and Schnoll, 2009; U.S. Food and Drug Administration, 2015; Wu and Juhaeri, 2016).
The benefits of psilocybin in the treatment of depression, anxiety and other disorders were first suggested in the 1960s when psilocybin was marketed in many countries, including the United States (US) under the trade name Indocybin® by the Swiss pharmaceutical company, Sandoz. Indocybin® provided a shorter acting alternative to lysergic acid diethylamide (LSD) which has a similar primary pharmacological mechanism of action, now known to be agonist or partial agonist effects at the 5-HT2A receptor (Nichols, 2016). While Indocybin® was used safely as an adjunct to psychotherapy, eventually the societal backlash in the US and other countries in the 1960s (Matsushima et al., 2009) led to a ban on marketing and possession of “hallucinogenic” drugs in the US in 1965, and led Sandoz to discontinue manufacturing and marketing of Indocybin® in 1966 (Belouin and Henningfield, 2018; Bonson, 2018; Novak, 1997). The 1970 placement of psilocybin, LSD, and other “hallucinogens” in Schedule I of the CSA did not reflect an absence of therapeutic benefit, although the scientific evidence at the time was mixed. This mixed evidence included strong (at least for the time) pharmacological studies, as discussed later in this review, along with clinical studies suggesting potential safety and efficacy that were nonetheless considered by leading researchers during the 1960s to be limited and not sufficient to support efficacy and safety claims for LSD or other hallucinogens. This situation is discussed by Bonson (2018) in her review of human LSD research and regulation, and would appear to generally apply to psilocybin, which was being administered by some of the same research programs that administered LSD. These limitations in the evidence base and the rising tide of sensational media accounts of adverse consequences of classic psychedelic use, discussed later, fueled the perception by many public and political leaders that psilocybin posed serious risks to patients and the public that did not outweigh its benefits (Belouin and Henningfield, 2018; Hofmann, 1980; Nutt et al., 2013). Therefore, having not been formally approved by the FDA for therapeutic use, psilocybin was placed in Schedule I of the
CSA in 1970 and remains in Schedule I.1
As discussed in section 1.1, removal from Schedule I can only occur if a medicinal product containing a Schedule I substance is approved for therapeutic use as a drug by the FDA. Then, whether it will be scheduled, and, if so, into what schedule it will be placed, will be subject to the FDA’s abuse potential assessment that will include an analysis of the 8 factors of the CSA (Drug Enforcement Administration, 2017a; U.S. Food and Drug Administration, 2017a). As discussed by Calderon, Hunt and Klein in this journal issue, schedule placement is a process that considers “potential for abuse, medical use, and physical or psychological dependence liability,” among other lines of evidence (Calderon et al., 2017). For example, approval of the Schedule I compounds dextrorphan and difenoxin (with atropine) resulted in dextrophan becoming unscheduled, and difenoxin (with atropine) being placed into either Schedule IV or V, depending on dose. Similarly, the previously Schedule I compound piperazine was descheduled. Approval of an oral form of dronabinol (marinol) was initially placed in Schedule II and, in 1999, rescheduled to Schedule III, leaving cannabis and forms of dronabinol that were not approved drug products in Schedule I. As noted by Calderon et al., approved drugs with hallucinogenic effect vary widely in the scheduling from the Schedule I status of most hallucinogenic drugs without approved medical use, to Schedule II phencyclidine, Schedule III ketamine, and Schedule IV lorcaserin, and the not scheduled 2,5-dimethoxy- 4-iodoamphatamine, also known as DOI (Calderon et al., 2017).
Thus, if an NDA for a psilocybin product is submitted to the FDA and approved, then the CSA would require its rescheduling, and schedule placement would be determined by evaluation of its overall abuse potential (Drug Enforcement Administration, 2017a; Henningfield et al., 2017; U.S. Food and Drug Administration, 2017a). In fact, as discussed in Belouin and Henningfield (2018) (in this journal issue), there is increasing evidence supporting the eventual development and submission of an NDA for a psilocybincontaining product. Emerging science suggesting benefits of a psilocybin product warrant an official breakthrough designation by the FDA to address the large number of cancer sufferers whose depression and anxiety are not responsive to conventional therapies (Belouin and Henningfield, 2018; Griffiths and Johnson, 2015; Ross et al., 2016). In addition, advances in risk management and monitoring, which were absent in the earlier heyday of psychedelic research, necessitate that we revisit the potential for approving a classic psychedelic (i.e., psilocybin) as a medicine because risk management, particularly in the legally binding approach of REMS, is intended to provide conditions for distribution, use, oversite and other factors to ensure safe use (McCormick et al., 2009; U.S. Food
and Drug Administration, 2015).
Clinically, chemically, and pharmacologically, psilocybin has similarities with several substances that were generally termed “hallucinogens” in the 1950s and have been termed “psychedelics” since the 1960s. Although both of these terms are sometimes used to refer to compounds with other primary mechanisms of action (e.g., ketamine; salvinorin A, methylenedioxymethamphetamine or MDMA), 5-HT2A receptor agonist compounds, including psilocybin, LSD, mescaline, and dimethyltryptamine (DMT), are specifically referred to as “classic psychedelics” or “classic hallucinogens.” Although there are similarities in the effects, patterns of use and past clinical applications of LSD, psilocybin, and other classic psychedelics, the present evaluation is focused on a drug product in which the active ingredient is psilocybin. Moreover, approval would include not only the compound, but also its labeling and restrictions on manufacturing, marketing and use. These additional domains are critical to the benefit to risk evaluations which are foundational for drug evaluation and approval (U.S. Food and Drug
Research and licit clinical use of LSD and psilocybin greatly slowed in the 1960s as amendments in 1962 and 1965 to the 1938 US Food Drug and Cosmetic Act imposed severe restrictions on distribution, possession, use, and research (Barrigar, 1964; Bonson, 2018; Grabowski, 1976; Grinspoon and Bakalar, 1979). As discussed elsewhere in this journal issue and in other publications (Nutt, 2015; Nutt et al., 2013; Scientific American Editors, 2014; Sinha, 2001; Spillane, 2004; Woodworth, 2011), legal restrictions have greatly constrained research; however, research did not altogether cease, and began to accelerate by the late 1980s in preclinical laboratories, and in clinical settings by the late 1990s. This resurgence has been fueled in part by renewed appreciation of the potential importance of these substances in advancing the science of the brain and behavior and for their potential significance in the treatment of disease. Moreover, since the 1970s extensive national drug use and effects surveillance systems have been developed in the US, which show that the prevalence of abuse and serious adverse events associated with psilocybin and other classic psychedelics are relatively low compared to other major classes of abused drugs (Johnson, Hendricks, Barrett, Griffiths, submitted). In addition to the more recent clinical research, the reassuring results from these epidemiological data also increase interest in the evaluation of psilocybin as a potential therapeutic medicine (Roseman et al., 2017; Rucker et al., 2017). Because the FDA approved therapeutic medicines cannot be listed in Schedule I of the CSA, consideration of changes in scheduling recommendations becomes an important part of the clinical development of psilocybin. As discussed in this review the evidence continues to support the conclusion that if a psilocybin drug product was approved by the FDA, CSA scheduling would remain appropriate. Considerable additional study will be required for the development of an FDAacceptable
NDA, including the abuse potential assessment section of the NDA according to the FDA’s abuse potential assessment guidance (U.S. Food and Drug Administration, 2017a). Thus, it is premature to come to a definitive conclusion about which schedule would be most appropriate. This review is intended to stimulate further research and thinking in this area through its evaluation of key abuse potential-related science presently available and considered through the approach of the CSA 8-factor analysis
which is the key approach of the CSA for developing scheduling recommendations. The review includes a preliminary scheduling conclusion based on the research considered and the opinions of these authors, along with key gaps in the research that will also likely be of importance to the FDA.