The effects of microdose LSD on time perception: a randomised, double-blind, placebo-controlled trial
Steliana Yanakieva, Naya Polychroni, Neiloufar Family, Luke T. J. Williams, David P. Luke, Devin B. Terhune
Doi : 10.1007/s00213-018-5119-x
Rationale : Previous research demonstrating that lysergic acid diethylamide (LSD) produces alterations in time perception has implications for its impact on conscious states and a range of psychological functions that necessitate precise interval timing. However, interpretation of this research is hindered by methodological limitations and an inability to dissociate direct neurochemical effects on interval timing from indirect effects attributable to altered states of consciousness.
Methods : We conducted a randomised, double-blind, placebo-controlled study contrasting oral administration of placebo with three microdoses of LSD (5, 10, and 20 μg) in older adults. Subjective drug effects were regularly recorded and interval timing was assessed using a temporal reproduction task spanning subsecond and suprasecond intervals.
Results : LSD conditions were not associated with any robust changes in self-report indices of perception, mentation, or concentration. LSD reliably produced over-reproduction of temporal intervals of 2000 ms and longer with these effects most pronounced- in the 10 μg dose condition. Hierarchical regression analyses indicated that LSD-mediated over-reproduction was independent of marginal differences in self-reported drug effects across conditions.
Conclusions : These results suggest that microdose LSD produces temporal dilation of suprasecond intervals in the absence of subjective alterations of consciousness.
Keywords : Interval timing . LSD . Microdosing . Older adults . Striatum
Our perception of time is important for momentary updating and integration of perceptual information in working memory and is thereby increasingly being recognised as an integral feature of consciousness (Wittmann 2015; Yin et al. 2016). In turn, distortions in interval timing (time perception in the milliseconds to minutes range) are a hallmark feature of altered states of consciousness (Berkovich-Ohana and Wittmann 2017; Preller and Vollenweider 2016; Wittmann et al. 2014), as well as psychiatric disorders characterised by disruptions of consciousness, such as schizophrenia and the dissociative disorders (Allman and Meck 2012; Giersch et al. 2015; Simeon et al. 2007; Spiegel et al. 2013).
A striking instance of the close coupling of consciousness and interval timing is observed under lysergic acid diethylamide (LSD). As part of a broad set of alterations in different dimensions of consciousness (Preller and Vollenweider 2016), such as declines in self-related processing and other changes in perception, LSD is associated with both subjective distortions in time perception (DeShon et al. 1952; Kenna and Sedman 1964; Liechti et al. 2016; Savage 1955) and changes in performance on behavioural measures of interval timing (Aronson et al. 1959; Boardman et al. 1957) (for a review see Preller and Vollenweider 2016). For example, LSD (1–2 μg/kg) has been shown to produce a tendency to underestimate the duration of long suprasecond intervals (15–240 min; Aronson et al. 1959) or to increase variability in interval timing for 1 min intervals (Boardman et al. 1957) (although the latter finding has not been replicated [Aronson et al. 1959; Wittmann et al. 2007]). One of the most methodologically rigorous studies to date in this domain observed that the serotonin agonist psilocybin, which has similar characteristics to LSD (Nichols 2016), produced under-reproduction of long supra-second intervals (4000–5000 ms, but not 1500– 2500 ms) (Wittmann et al. 2007). This result implicates serotonin in supra-second human interval timing (see also Rammsayer 1989; Wackermann et al. 2008), potentially through 5-HT2A-mediated inhibition of dopamine (De Gregorio et al. 2016), which is believed to play an important mechanistic role in the perception of time (Allman and Meck 2012; Coull et al. 2011; Matell and Meck 2004; Rammsayer 1999; Soares et al. 2016; Terhune et al. 2016b; Vatakis and Allman 2015;Wiener et al. 2011) (for a review, see Coull et al. 2011). Given the role of interval timing across a range of psychological functions (Allman et al. 2014; Matthews and Meck 2016; Merchant et al. 2013), distorted timing under LSD may contribute to, or underlie, broader cognitive and perceptual effects of this drug. Therefore, elucidating its impact on interval timing is likely to inform neurochemical models of interval timing as well as our broader understanding of the effects of LSD on cognition and perception.
Although multiple studies have reported that LSD produces distortions in time perception as indexed by subjective reports, the small number of studies that used behavioural tasks (Aronson et al. 1959; Boardman et al. 1957) possessed one or more methodological limitations including the absence of placebo controls, randomisation, and double-blind protocols, and small sample sizes and number of experimental trials. A further as of yet unaddressed issue has the potential to directly inform the neurochemical basis of distorted timing.
Previous research has been unable to determine whether distorted timing under LSD is attributable to the neurochemical impact of LSD on the neurophysiological substrates of interval timing (Coull et al. 2011) or the induction of an altered state of consciousness per se (Liechti et al. 2016; Nichols 2004; Preller and Vollenweider 2016). The administration of LSD doses that are only barely perceptible (< 20 μg; microdosing) produces only minor changes in perception and cognition (Greiner et al. 1958) and thereby offers the possibility of partially dissociating the direct, albeit attenuated, neurochemical impact of LSD on interval timing subsystems from its indirect effects on timing through the modulation of conscious states. Indeed, previous research has shown that interval timing tasks may be more sensitive to the effects of psychedelics relative to other cognitive (e.g., working memory) tasks (Wittmann et al. 2007). Accordingly, behavioural measures of interval timing might be especially well suited to study the psychological effects of microdoses of LSD (see also Wackermann et al. 2008).
The present study used a randomised, double-blind, placebo-controlled design to explore the effects of microdose LSD on time perception. Older adults were randomly allocated to a placebo condition or one of the three LSD microdoses (5, 10, and 20 μg) and completed a temporal reproduction task spanning subsecond and suprasecond intervals (800– 4000ms) approximately 3 h post-dosing.To determine whether any impact of LSD on interval timing converged with peak times of self-perceived drug effects and the potential induction of an altered state of consciousness, participants regularly completed self report measures of different subjective drug effects. Insofar as there is substantial evidence that LSD alters psychological functions by targeting 5-HT2A receptors (Halberstadt 2015; López-Giménez and González-Maeso 2018; Nichols 2016; Preller et al. 2017), one possible outcome was that microdoses of LSD would produce temporal underreproduction, as observed with psychoactive doses of psilocybin in this same interval range (Wittmann et al. 2007) and with LSD for longer intervals (Aronson et al. 1959).
By contrast, preliminary non-human animal research suggests that LSD might have biphasic effects in which it functions as a serotonin agonist during an early phase and as a dopamine agonist at a later phase (Freedman 1984; Marona-Lewicka and Nichols 2007; Marona-Lewicka et al. 2005; Watts et al. 1995) (for reviews, see De Gregorio et al. 2016; Nichols 2016). These effects have not yet been replicated in human studies or microdoses, to our knowledge, but if this biphasic effect generalises to the present context, microdose LSD after 3 h postdosing might be expected to produce temporal over-reproduction, as observed with dopamine agonists (Coull et al. 2011).