Psychedelic-Assisted Psychotherapy : A Paradigm Shift in Psychiatric Research and Development, Eduardo E. Schenberg, 2018

Psychedelic-Assisted Psychotherapy : A Paradigm Shift in Psychiatric Research and Development

Eduardo Ekman Schenberg

Frontiers in Pharmacology, 2018, Volume 9, Article 733, 1-11

doi: 10.3389/fphar.2018.00733


Mental disorders are rising while development of novel psychiatric medications is declining. This stall in innovation has also been linked with intense debates on the current diagnostics and explanations for mental disorders, together constituting a paradigmatic crisis. A radical innovation is psychedelic-assisted psychotherapy (PAP): professionally supervised use of ketamine, MDMA, psilocybin, LSD and ibogaine as part of elaborated psychotherapy programs. Clinical results so far have shown safety and efficacy, even for “treatment resistant” conditions, and thus deserve increasing attention from medical, psychological and psychiatric professionals. But more than novel treatments, the PAP model also has important consequences for the diagnostics and explanation axis of the psychiatric crisis, challenging the discrete nosological entities and advancing novel explanations for mental disorders and their treatment, in a model considerate of social and cultural factors, including adversities, trauma, and the therapeutic potential of some non-ordinary states of consciousness.

Keywords : psychedelic-assisted psychotherapy, LSD, MDMA, ibogaine, psilocybin, ketamine, explanation in neuroscience, states of consciousness



Mental disorders increasingly contribute to the global burden of disease, with huge socio-economic
costs (Catalá-López et al., 2013; Whiteford et al., 2013). However, research and development in
psychopharmacology—psychiatry’s primary mode of intervention—came to a halt in 2010 (Miller,
2010; Hyman, 2013). Approval of new molecular entities for psychiatric conditions by the US Food
and Drug Administration (FDA) fell from 13 in 1996 to one in 2016, with 49 approved between
1996 and 2006 and 22 from 2007 to 20161 In pharmacology conferences in the period, just about
5% of presentations were dedicated to human studies involving drugs with novel mechanisms of
action (van Gerven and Cohen, 2011). These occurrences are part of a complex picture clearly
dissected as a triple crisis in psychiatry : of therapeutics, diagnostics and explanation (Rose, 2016).

Problems surrounding psychiatric diagnosis also surfaced  in 2010, when the UK Medical Research Council published a strategy for mental health and wellbeing (Sahakian et al., 2010) and the US National Institute for Mental Health (NIMH) launched its ResearchDomain Criterion (RDoC). It proposed five domains based on specific neural systems that can be impaired in mental illness, a radical departure from the hundreds of discrete conceptual disorders of the much older Diagnostic and Statistical Manual (DSM) (Casey et al., 2013; Insel, 2014; Kraemer, 2015). Thus, the RDoC advanced a multidimensional approach to diagnosing mental disorders in a continuous spectra (Adam, 2013). At around the same time, a network psychopathology perspective was conceptualized and empirically assessed with statistical models for psychometrics based on thousands of patient reports’ and hundreds of symptoms (Fried et al., 2017).

The treatment and diagnostic axes of the crisis are connected by the explanatory domain: despite huge investment in neuroscience as the ultimate source for understanding mental illness, both classification and diagnosis (Stephan et al., 2016a) as well as knowledge about pathogenesis and etiology still faces many challenges (Stephan et al., 2016b). The explanatory debate about mental disorders is summarized by the contrasting declarations that “mental disorders are brain disorders” (Deacon, 2013; Insel and Cuthbert, 2015) or that psychiatry runs the risk of “losing the psyche” (Parnas, 2014).


Synthetic substances like Lysergic Acid Diethylamide (LSD), 3,4-MethylenodioxyMetamphetamine (MDMA), 2-(2- Chlorophenyl)-2-(methylamino) cyclohexanone (ketamine) and naturally occurring alkaloids including 4-phosphoriloxy- N,N-dimethyltryptamine (psilocybin, present in hundreds of Psilocybe mushroom species) and 12-Methoxyibogamine (ibogaine, from Tabernanthe iboga) have been used in a series of studies (Passie et al., 2008; Brown, 2013; Tylš et al., 2014; Mithoefer et al., 2016; Nichols, 2016; for reviews seeWinkelman, 2014; Dos Santos et al., 2016; Johnson and Griffiths, 2017; Nichols et al., 2017) as well as Phase 2 clinical trials (Table 1). These substances are orally active but have different mechanisms of action. LSD and psilocybin effects’ critically depend on 5-HT2A agonism, MDMA inhibits monoamine transporters, especially for serotonin, while ketamine is an NMDA antagonist and ibogaine non-specifically binds to many receptors.

The most studied is ketamine, which in higher doses is an anesthetic in use for decades. In lower dosages it temporarily modify consciousness including changes in mood and cognition (Mion, 2017). It is the experimental intervention in almost 70 Phase 2 trials for psychiatric disorders and two Phase 3 trials for depression. Protocols involve single or repeated administrations in different doses, routes of delivery and research designs. Most are for depressive disorders, but is also studied for Obsessive- Compulsive Disorder (OCD), Post-Traumatic Stress Disorder (PTSD), suicide, alcohol, and cocaine use disorders (Table 1). Nine meta-analysis from depression trials (Fond et al., 2014; Coyle and Laws, 2015; Lee et al., 2015; McGirr et al., 2015; Parsaik et al., 2015; Romeo et al., 2015;Wan et al., 2015; Kishimoto et al.,
2016; Xu et al., 2016) shows low frequency of serious adverse events in the short term (but see Short et al., 2017 for longterm reporting bias), with short-term positive outcomes for a significant proportion of patients.

MDMA is investigated in 17 Phase 2 trials (Table 1) and was designated a breakthrough therapy for PTSD by the FDA, a status that can expedite approval (Kupferschmidt, 2017). Also studied for social anxiety in autistic adults, existential anxiety and alcohol use disorder (Table 1), MDMA is commonly confused with the street drug “ecstasy” (also known as “molly”). However, these illegal products frequently do not contain MDMA, only adulterants (Vogels et al., 2009; Wood et al., 2011; Togni et al., 2015; Saleemi et al., 2017; Vrolijk et al., 2017). This loose terminology creates unfortunate confusion about MDMA’s safety (Amoroso, 2016). In research with healthy volunteers, occurrences of hypertension, tachycardia and hyperthermia are below 1/3 of cases, not leading to serious adverse events (Vizeli and Liechti, 2017). In clinical populations, serious adverse events were very rare, with only one brief and self-limiting case of increased ventricular extrasystoles in more than 1,260 sessions (MAPS, 2017). Therapeutic results obtained with severe, treatment-resistant PTSD patients in Phase 2 studies were considered “spectacular” (Frood, 2012), with approximately 70% or more of participants no longer qualifying for the diagnosis after 12 months, while the remainder third had less intense symptoms. Furthermore, the improvements lasted up to 4 years, mostly without additional treatments and without inducing drug abuse or dependence (Mithoefer et al., 2013; Yazar-Klosinski and Mithoefer, 2017). An independent preliminarymeta-analysis found MDMA-assisted psychotherapy was superior to prolonged exposure when evaluated by clinician-observed outcomes, by patient self-report outcomes and also by drop-outs (Amoroso and Workman, 2016).

Psilocybin is the third most studied psychedelic substance for clinical applications. It has a very high safety ratio (Gable, 2004; Tylš et al., 2014) and very low risk profile even in unsupervised settings (Nutt et al., 2010; van Amsterdam et al., 2011;)2 It’s orally administered in eight trials formajor depression, cigarettes, alcohol, and cocaine use disorders and existential anxiety in life-threatening diseases, mostly cancer. Despite moderately increasing blood pressure (Griffiths et al., 2011) and inducing transient headaches (Johnson et al., 2012), it has been safely administered to more than a 100 volunteers in neuroscientific research (Studerus et al., 2011) and another 100 in clinical studies with notable results (Table 1).

LSD, the most potent psychedelic currently administered in clinical trials, has very slow dissociation kinetics at the human 5-HT2A receptor and thus long lasting effects (Wacker et al., 2017). It has a very high safety ratio (Gable, 2004; Passie et al., 2008) and is not associated with major health impairments after unsupervised use (Krebs and Johansen, 2013; Hendricks et al., 2014, 2015; Johansen and Krebs, 2015). It is the active substance in just two recent Phase 2 trials for existential anxiety in the terminally ill (Table 1). This paucity is perhaps due to stigma surrounding large-scale recreational use since the 1960’s, with considerable political implications (Dyck, 2005; Nutt et al., 2013; Smith et al., 2014). However, before political turmoil, more than a 1,000 studies including 40,000 patients were done (Grinspoon, 1981), mostly showing positive potentials (Abraham et al., 1996). LSD was thus the prototypical substance in the development of radically new forms of psychotherapy, including psychedelic-assisted psychotherapy (Pahnke et al., 1970; Grof, 1971, 2008) and another approach based on repeated low doses (10 to 50 μg) to potentiate psychoanalysis, known as psycholytic psychoherapy (Maji´c et al., 2015). Despite the paucity of recent trials, a recent meta-analysis with rigorous research from 60 years ago confirmed LSD also has important potential for alcohol use disorders (Krebs and Johansen, 2012).

Finally, ibogaine is the less advanced psychedelic in the development pipeline, with no interventional clinical trials executed or registered since the National Institute on Drug Abuse (NIDA) cancelled efforts to develop this compound to treat opioid addiction in the 1990’s (Alper, 2001). And indeed there are important safety concerns, given ibogaine can prolong QT interval (Koenig and Hilber, 2015), potentially evolving to fatal cardiac arrhythmias (Koenig et al., 2014). This critically differentiates ibogaine’s safety profile from other psychedelics. However, given the seriousness of drug addiction and the difficulty to treat these patients, observational and retrospective studies for opioid (Brown and Alper, 2017; Noller et al., 2017) and psychostimulant addiction (Schenberg et al., 2014, 2016, 2017) reporting considerable success suggests Phase 2 trials focusing on cardiac safety should be performed. Given ibogaine is unscheduled in many countries and currently used as an alternative treatment with an unfortunate series of fatalities (Alper et al., 2012), financial support is needed.