A recent publication in The Journal of Physiology by Di Lazzaro et al. (2005) highlighted a fascinating distinction between two benzodiazepines (BZ), lorazepam and diazepam, concerning short latency afferent inhibition (SAI). Their findings indicated that lorazepam (2.5 mg orally) reduced SAI, while diazepam (20 mg orally) increased it, revealing a dissociated effect. This observation strengthens the already substantial body of evidence pointing towards the atypical nature of lorazepam’s pharmacological actions, a characteristic that might not be fully recognized in the context of other benzodiazepines.
Previous research has consistently demonstrated that lorazepam exhibits atypical effects when compared to other benzodiazepines (Pompéia et al. 2003a). These differences span both behavioral and physiological domains. In behavioral studies, lorazepam displays a unique profile in animal discrimination tasks (Ator & Griffiths, 1997; Ator & Kautz, 2000) and also in studies of human cognition. Contrary to a potential underestimation, diazepam, like other benzodiazepines, significantly impairs episodic memory (Curran, 2000). However, unlike lorazepam, diazepam and most other benzodiazepines do not consistently disrupt repetition priming, another type of memory (Vidailhet et al. 1994 – as an exception). Furthermore, lorazepam atypically affects visual perception (Pompéia et al. 2003a; Giersch & Herzog, 2004; Lorenceau et al. 2005), although some studies suggest diazepam might induce even greater visual effects than lorazepam (Boucart et al. 2000). Acute doses of lorazepam have also been shown to produce: (a) less EEG fast activity compared to diazepam in dynamic brain mapping, despite lorazepam causing more pronounced side effects (Itil et al. 1989); (b) atypical disruptions in visual event-related potentials (ERPs) when contrasted with flunitrazepam, a benzodiazepine with similar receptor affinity, even when doses were carefully matched (Pompéia et al. 2003b); and (c) as initially mentioned, a reduction in SAI, in opposition to diazepam’s increasing effect (Di Lazzaro et al. 2005).
It is crucial to consider that many of the studies mentioned above did not employ rigorous methodologies for determining equipotent doses of lorazepam and the comparator benzodiazepines. Variations in drug dosage can lead to qualitatively different effects, potentially reflecting test difficulty or sensitivity rather than fundamental differences in drug action (Duka et al. 1996). A robust approach to address this issue is to establish a double-dissociation, where each drug exhibits greater effects on different measures (Pompéia et al. 2003b), or, as notably demonstrated by Di Lazzaro et al., to show opposite effects between drugs. The strength of Di Lazzaro et al.’s findings, particularly concerning purely physiological parameters like SAI, is that these measures are less susceptible to confounding factors such as effort, motivation, education, or intelligence, which can influence behavioral scores. Nonetheless, to solidify the evidence for lorazepam’s atypical effects on SAI, replication of Di Lazzaro et al.’s results through randomized, placebo-controlled studies, ideally within-subject designs comparing lorazepam to another benzodiazepine, would be valuable. Exploring different dose levels would also be insightful to investigate if lower doses or less potent benzodiazepines, such as diazepam relative to lorazepam, decrease SAI, while higher doses or more potent drugs increase it.
The underlying mechanisms for the divergent effects of lorazepam compared to other benzodiazepines, despite their chemical similarities, remain unclear. The atypical profile of lorazepam has been tentatively attributed to its unique pharmacodynamics, although our understanding of benzodiazepine compound binding characteristics to distinct receptor subtypes in various brain regions is still limited. A compelling hypothesis for lorazepam’s atypical effects is that it may exhibit specific binding profiles to yet uncharacterized benzodiazepine receptors, a phenomenon observed with other drugs that display qualitatively distinct effects within their class (Lelas et al. 2000). Intriguingly, Ator & Griffiths (1997), referencing Sanger & Benavides (1993), astutely pointed out that lorazepam showed markedly different potency across rat brain regions, unlike other benzodiazepines, a finding that was not emphasized by Sanger & Benavides themselves. Adding another layer of complexity, lorazepam is one of the few benzodiazepines of non-synthetic origin found naturally in the brain, serum, and milk of various species, including humans (Sand et al. 2000). This raises a provocative possibility: could there be specific receptors specifically for this naturally occurring benzodiazepine?
In conclusion, accumulating physiological evidence underscores the atypical pharmacological profile of lorazepam among benzodiazepines. Further research, building upon the work of Di Lazzaro et al., is essential to elucidate the factors that make lorazepam unique within this drug class. Unraveling these distinctions will undoubtedly contribute significantly to a more comprehensive understanding of GABAA receptor physiology and the nuanced actions of benzodiazepines.
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