The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future

Robin L Carhart-Harris and Guy M Goodwin

Neuropsychopharmacology, 2017, 42, 2105–2113

doi:10.1038/npp.2017.84; published online 17 May 2017

Plant-based psychedelics, such as psilocybin, have an ancient history of medicinal use. After the first English language report on LSD in 1950, psychedelics enjoyed a short-lived relationship with psychology and psychiatry. Used most notably as aids to psychotherapy for the treatment of mood disorders and alcohol dependence, drugs such as LSD showed initial therapeutic promise before prohibitive legislature in the mid-1960s effectively ended all major psychedelic research programs. Since the early 1990s, there has been a steady revival of human psychedelic research: last year saw reports on the first modern brain imaging study with LSD and three separate clinical trials of psilocybin for depressive symptoms. In this circumspective piece, RLC-H and GMG share their opinions on the promises and pitfalls of renewed psychedelic research, with a focus on the development of psilocybin as a treatment for depression.

THE THERAPEUTIC POTENTIAL OF PSYCHEDELIC DRUGS : TEMPERED OPTIMISM (RLC-H)

“Your assumptions are your windows on the world. Scrub them off every once in a while, or the light won’t come in.” (Isaac Asimov, 1919–1992)

A BRIEF HISTORY OF PSYCHEDELIC RESEARCH

Psychedelic drugs (Psychedelic is a neologism that combines the words psychē (ψ υ χ ή, ‘soul’) and dēloun (δ η λ ο ῦ ν, ‘to make visible, to reveal’), to denote ‘mind-revealing’ in reference to the category of drugs in question. I use the term in preference to ‘hallucinogens’ due to the latter’s arguably misleading emphasis on these compounds’ hallucinogenic properties.When using the term ‘psychedelics’ I refer to those compounds with appreciable serotonin 2A receptor agonist properties that can alter consciousness in a marked and novel way. LSD can be considered the prototypical or ‘referencestandard’ psychedelic.) awakened a significant cultural zeitgeist in mid-twentieth century (Stevens, 1987, see Table 1). Catalyzed by early reports on the unique potency and remarkable subjective effects of lysergic acid diethylamide (LSD) in the early 1950s, psychedelics, and particularly LSD, became widely used by psychologists and psychiatrists in research and clinical practice, with tens of thousands of patients estimated to have been treated with ‘psychedelic psychotherapy’ over a period of about 15 years (Grinspoon and Bakalar, 1979). From the mid-60s, psychedelic research was increasingly prevented from having the capacity to inform
and potentially advance thinking and practice in psychology and psychiatry, but as popular and countercultural movements increasingly embraced the drugs, their societal impact skyrocketed (Grinspoon and Bakalar, 1979; Lee and Shlain, 1992; Stevens, 1987).

THE PRESENT REVIVAL

Human psychedelic research fell into a 25-year hiatus before scientists in Germany (Hermle et al, 1992), the United States (Strassman and Qualls, 1994), and Switzerland (Vollenweider et al, 1997) began its revival. There now exists a foundation of human neuroimaging (Carhart-Harris et al, 2012a, 2016d; Daumann et al, 2010; Muthukumaraswamy et al, 2013; Palhano-Fontes et al, 2015; Preller et al, 2017; Riba et al, 2004, 2006; Vollenweider et al, 1997), psychology (Carhart-Harris et al, 2015, 2016c; Carter et al, 2007; Gouzoulis-Mayfrank et al, 2005; Griffiths et al, 2006; MacLean et al, 2011; Schmid et al, 2015), and psychopharmacology studies with psychedelics (Kometer et al, 2012; Preller et al, 2017; Valle et al, 2016; Vollenweider et al, 1998).

These foundational studies complement a small number of early phase clinical trials (Table 2). There are now positive preliminary reports on the safety and tolerability of psilocybin for obsessive compulsive disorder (Moreno et al, 2006), psilocybin, and LSD for end-of-life psychological distress (Gasser et al, 2014; Griffiths et al, 2016; Grob et al, 2011; 2015), and tobacco addiction (Johnson et al, 2014) and ayahuasca (Osorio Fde et al, 2015) and psilocybin for major depressive disorder (Carhart-Harris et al, 2016a,b). An important caveat here, is that many of these trials report on small sample sizes and would best be described as ‘safety and tolerability’ studies by conventional standards (Schunemann et al, 2006), and while all of them do report outcomes consistent with potential efficacy, most have not been appropriately designed to demonstrate it conclusively. GMG critically discusses two of the largest and better designed trials in the next section (Griffiths et al, 2016; Ross et al, 2016).

PSYCHEDELICS FOR MENTAL ILLNESS

Plant-based psychedelics have been used for hundreds if not thousands of years for holistic healing (Hofmann, 1980) and there remains an active culture of self-medication with psychedelics for mental health (Carhart-Harris and Nutt, 2010; Waldman, 2017). Contrary to the alarmist campaigning that so negatively affected perceptions of psychedelics after the 1960s, subjective (Carhart-Harris and Nutt, 2010, 2013; van Amsterdam et al, 2015), naturalistic/ observational (Bouso et al, 2012), and population-based data (Hendricks et al, 2015) indicate a positive association between psychedelic drug use and mental health, albeit with some important caveats, which will be discussed below.

Progressing to more controlled medical use, psychedelics piqued the interest of psychologists and psychiatrists in the 1950s, who noted early on that they may ‘serve as new tools for shortening psychotherapy’ (Busch and Johnson, 1950). A recent meta-analysis of 19 studies of psychedelics for mood disorders published between 1949 and 1973 found that 79% of patients showed ‘clinically judged improvement’ post treatment (Rucker et al, 2016). Moreover, a meta-analysis of studies of LSD for alcoholism performed in the 50–60s was similarly supportive of its potential (Krebs and Johansen, 2012). The absence of standardized diagnostic techniques, measures of symptom severity, and lack of randomization and control conditions in these studies needs to be properly heeded, but equally, it would be self-defeating to dismiss their findings outright.

The modern era of controlled research with psychedelics has seen the adoption of more careful experimental designs, together with a more critical approach to outcomes. In 2006, a double-blind randomized controlled (DB-RC) study compared the acute and longer-term psychological effects of single high doses of psilocybin (30 mg) and methylphenidate (40 mg) in healthy volunteers. Significantly, greater improvements in psychological well-being were observed after psilocybin than methylphenidate at the 2-month end point and more than half considered their psilocybin
experience to be among the most personally meaningful experiences of their lives (Griffiths et al, 2006). Since then, the focus has shifted to include patients with symptoms of depression and anxiety. Three DB-RC trials have assessed the impact of a single dose of psilocybin on depressive symptoms in patients with life-threatening cancer (Griffiths et al, 2016; Grob et al, 2011; Ross et al, 2016) and an open-label trial of
psilocybin for treatment-resistant depression (TRD) has been completed (Carhart-Harris et al, 2016a,b). All four studies, and particularly the three most recent, found rapid, marked, and enduring anti-anxiety and depression effects post psilocybin. Significant improvements in obsessive compulsive disorder symptoms (Moreno et al, 2006) and alcohol dependence with psilocybin (Bogenschutz et al, 2015), anxiety with LSD (Gasser et al, 2014), and depression with ayahuasca (Osorio Fde et al, 2015; Sanches et al, 2016) help supplement the case for psilocybin and inspire questions regarding the potential generalized therapeutic action of psychedelics.

Focusing on antidepressant action, psilocybin, and psychedelics more generally, share some similarities withconventional antidepressants (ie, serotonergic modulation); however, they also possess some important differences. Regarding similarities, an altered relationship with the environment may be critical to recovery with selective serotonin reuptake inhibitors (Belsky, 2016; Harmer and Cowen, 2013) and heightened sensitivity to the environment is a cardinal feature of the psychedelic state (Carhart-Harris et al, 2015; Hartogsohn, 2016; Kaelen et al, 2015), perhaps due to psychedelics’ direct agonist action at the 5-HT2AR (Dressler et al, 2016; Fiocco et al, 2007; Jokela et al, 2007). Regarding differences, the chronic antidepressant action of SSRIs includes reduced limbic responsiveness and emotional moderation or blunting, likely via post-synaptic 5-HT1A receptor signaling (Cowen and Browning, 2015; Deakin and Graeff, 1991; McCabe et al, 2010); this contrasts with the greater role for 5-HT2AR signaling with psychedelics, and emphasis on emotional release (Carhart-Harris et al, 2012b; Roseman et al, 2016; Watts et al, 2017). Contrasting approaches to emotion may be a fundamental difference between the SSRI and psychedelic treatment models (Figure 1).

In my opinion, if the science is allowed to progress without the kind of political interference that has hindered it in the past, psilocybin with psychological support (PwPS) will become an early option in the treatment of depression. I predict that PwPS will be found to have important areas of superiority over current early interventions such as SSRIs and CBT. Specifically, PwPS’s rapid and enduring action with minimal exposure, positive side-effect profile, and specific therapeutic action—working to address rather than suppress or side-step aversive memories and emotions, may set it apart from the alternative, largely ‘palliative’ treatment options for major depression.

“That is the essence of science: ask an impertinent question, and you are on the way to a pertinent answer.” (Jacob Bronowski, 1908–1974)

Another consideration is that chronic antidepressant medication strategies appear to have a muting effect on psilocybin’s acute and putative antidepressant effects (Bonson et al, 1996; Bonson and Murphy, 1996), implying that treating medication-heavy, treatment-resistant depressed patients with psilocybin will be especially challenging (Carhart-Harris et al, 2016a,b). Medication discontinuation would likely be required prior to receipt of the psychedelic and this often requires careful management (Baldwin et al, 2007).

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