Modern Clinical Research on LSD
Matthias E Liechti
Neuropsychopharmacology, 2017, 42, 2114–2127.
doi : 10.1038/npp.2017.86
All modern clinical studies using the classic hallucinogen lysergic acid diethylamide (LSD) in healthy subjects or patients in the last 25 years are reviewed herein. There were five recent studies in healthy participants and one in patients. In a controlled setting, LSD acutely induced bliss, audiovisual synesthesia, altered meaning of perceptions, derealization, depersonalization, and mystical experiences. These subjective effects of LSD were mediated by the 5-HT2A receptor. LSD increased feelings of closeness to others, openness, trust, and suggestibility. LSD impaired the recognition of sad and fearful faces, reduced left amygdala reactivity to fearful faces, and enhanced emotional empathy. LSD increased the emotional response to music and the meaning of music. LSD acutely produced deficits in sensorimotor gating, similar to observations in schizophrenia. LSD had weak autonomic stimulant effects and elevated plasma cortisol, prolactin, and oxytocin levels. Resting-state functional magnetic resonance studies showed that LSD acutely reduced the integrity of functional brain networks and increased connectivity between networks that normally are more dissociated. LSD increased functional thalamocortical connectivity and functional connectivity of the primary visual cortex with other brain areas. The latter effect was correlated with subjective hallucinations. LSD acutely induced global increases in brain entropy that were associated with greater trait openness 14 days later. In patients with anxiety associated with life-threatening disease, anxiety was reduced for 2 months after two doses of LSD. In medical settings, no complications of LSD administration were observed. These data should contribute to further investigations of the therapeutic potential of LSD in psychiatry.
The present article reviews studies on the clinical pharmacology and use of lysergic acid diethylamide (LSD) in psychiatry research, with a focus on recent clinical studies. Older studies that were published in the 1950s–1970s before the prohibition of LSD are summarized elsewhere (Passie et al, 2008). All modern controlled clinical studies of LSD published in the past 25 years were included in the present
review based on medline and clinicaltrials.gov database searches. Other authors have reviewed serotonergic hallucinogens, including LSD (Dos Santos et al, 2016; Nichols, 2016; Passie et al, 2008), but did not cover the recent experimental clinical LSD research.
LSD was first synthesized in 1938, and its psychoactive properties were discovered in 1943. The similarity between the subjective psychotomimetic effects of LSD and schizophrenia were noted in 1947, leading to the experimental use of LSD to model psychosis. From 1949 to 1966, LSD (Delysid, LSD 25) was provided to psychiatrists and researchers ‘to gain insights into the world of mental patients’ and to assist psychotherapy. In the 1950s–1960s, LSD and LSD-associated psychotherapy were investigated
with regard to anxiety associated with terminal cancer, alcoholism, opioid use disorder, and depression (Passie et al, 2008). LSD is a well-studied pharmacological substance, with more than 1000 published reports (Nichols, 2016). LSD has been an important tool in neuroscience and drug development (Nichols, 2016) and has influenced the arts and society. Clinical research on LSD came to a halt in the early 1970s because of political pressure following its widespread uncontrolled use. Nevertheless, the recreational use of LSD has remained high. In 2010, an estimated 32 million US residents reported lifetime use of LSD (Krebs and Johansen, 2013). In the 1990s, clinical hallucinogen research very slowly began again with experimental studies of psilocybin and dimethyltryptamine (DMT) (Gouzoulis Mayfrank et al, 2005; Strassman and Qualls, 1994a; Strassman et al, 1994b). The first modern research findings from studies of LSD (Gasser et al, 2014, 2015), psilocybin (Carhart-Harris et al, 2016a; Griffiths et al, 2016; Grob et al, 2011; Johnson et al, 2014; Ross et al, 2016), and ayahuasca (which contains DMT) (Osorio et al, 2015) in psychiatric patients have only very recently been published. Legally authorized LSD-assisted psychotherapy is currently offered to very few patients in Switzerland in the context of compassionate use and based on case-by-case authorizations by the Federal Health Office. In addition, experimental research on LSD in healthy subjects has gained new momentum and resulted in novel findings, which are reviewed herein.