The realm of benzodiazepines (BZs) is nuanced, with each compound exhibiting unique properties. A study published in The Journal of Physiology by Di Lazzaro et al. (2005) highlighted a fascinating distinction between two common BZs, lorazepam (Ativan) and diazepam (Valium), in their effects on short latency afferent inhibition (SAI). This research indicated that lorazepam, even at a low dose of 2.5 mg orally, reduced SAI, while diazepam, at a much higher dose of 20 mg orally, increased it. This seemingly paradoxical finding adds to the growing body of evidence suggesting that lorazepam, marketed as Ativan, possesses an atypical pharmacological profile compared to other benzodiazepines. This article delves into these atypical characteristics of Ativan (lorazepam), drawing from existing research and the findings of Di Lazzaro and colleagues to provide a comprehensive understanding of its unique place within the benzodiazepine class.
Numerous studies have previously pointed to the distinct effects of lorazepam in contrast to other benzodiazepines, encompassing both behavioral and physiological aspects (Pompéia et al., 2003a). In behavioral studies, Ativan demonstrates an unusual profile in animal discrimination tasks (Ator & Griffiths, 1997; Ator & Kautz, 2000) and in human cognitive function assessments. Contrary to a potential misinterpretation of Di Lazzaro et al.’s claims, diazepam, while often perceived as having minimal memory effects, does indeed cause significant deficits in episodic memory, a form of memory concerning personal experiences (Curran, 2000). However, what sets lorazepam apart is its consistent impairment of repetition priming, another type of memory, unlike diazepam and most other BZs which generally do not affect this type of memory (Vidailhet et al., 1994 presents a rare exception).
Furthermore, Ativan’s atypical nature extends to visual perception. Research indicates that lorazepam impairs visual perception in a manner not typically observed with other benzodiazepines (Pompéia et al., 2003a; Giersch & Herzog, 2004; Lorenceau et al., 2005), although some studies suggest diazepam may also induce notable visual effects (Boucart et al., 2000). Acute doses of lorazepam have also been shown to produce several distinctive physiological responses:
- Reduced EEG Fast Activity: Dynamic brain mapping reveals less fast brainwave activity with lorazepam compared to diazepam, despite lorazepam leading to more pronounced side effects (Itil et al., 1989).
- Atypical Disruption of Visual ERPs: Lorazepam uniquely disrupts visual event-related potentials (ERPs) compared to flunitrazepam, even when administered at doses considered equipotent based on receptor affinity (Pompéia et al., 2003b).
- Decreased SAI: As highlighted by Di Lazzaro et al. (2005), lorazepam reduces short latency afferent inhibition (SAI), in direct contrast to diazepam which increases it.
It’s crucial to acknowledge methodological considerations in these comparative studies. Many studies comparing lorazepam to other benzodiazepines did not employ rigorous methods to ensure equipotent doses were used. Dosage variations can lead to qualitatively different effects, potentially reflecting test sensitivity rather than fundamental differences between drugs (Duka et al., 1996). A robust approach to address this is demonstrating a double-dissociation, where each drug shows greater effects on different measures (Pompéia et al., 2003b), or, as exemplified by Di Lazzaro et al., observing opposite effects between drugs. The strength of Di Lazzaro et al.’s findings lies in the use of purely physiological parameters. These objective measures are less susceptible to factors like effort, motivation, education, or intelligence, which can influence behavioral assessments. To solidify the evidence for lorazepam’s atypical SAI effects, replication of Di Lazzaro et al.’s findings through randomized, placebo-controlled studies, preferably within-subject designs comparing lorazepam to other benzodiazepines, would be beneficial. Exploring different dose ranges would also help clarify whether lower doses or less potent benzodiazepines like diazepam decrease SAI, while higher doses or more potent drugs increase it.
The underlying reasons for the divergent effects of lorazepam compared to other benzodiazepines, despite their chemical similarities, remain unclear. One hypothesis attributes lorazepam’s atypical profile to its unique pharmacodynamics, specifically its binding characteristics to different benzodiazepine receptor subtypes in various brain regions. While research in this area is still limited, the most compelling explanation is that lorazepam may exhibit specific binding profiles to yet uncharacterized benzodiazepine receptors. This concept is supported by precedents where drugs with qualitatively distinct effects within a class have been shown to possess unique receptor binding profiles (Lelas et al., 2000). Intriguingly, Ator & Griffiths (1997) pointed to Sanger & Benavides’s (1993) research, which, though not explicitly discussed by the original authors, indicated that lorazepam displayed markedly different potency across various rat brain regions, unlike other benzodiazepines. 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 the speculative, yet intriguing, possibility of specific receptors uniquely tailored for this particular benzodiazepine.
In conclusion, accumulating physiological evidence underscores the atypical pharmacological profile of lorazepam (Ativan) within the benzodiazepine class. Further research, following the methodological rigor of studies like Di Lazzaro et al.’s, is crucial to fully elucidate the factors that make lorazepam unique among benzodiazepines. Unraveling these distinctions will undoubtedly contribute significantly to a more comprehensive understanding of GABAA receptor physiology and the nuanced actions of benzodiazepines, particularly Ativan (lorazepam).
References
- Ator NA, Griffiths RR (1997). Lorazepam and chlordiazepoxide discrimination in pentobarbital-trained baboons. J Pharmacol Exp Ther 282:1202–1214.
- Ator NA, Kautz MM (2000). The discriminative stimulus effects of lorazepam and triazolam in baboons. Drug Alcohol Depend 60:117–127.
- Boucart M, Deslypere JF, Deweer B, Goeders N, Mazaux JM (2000). Differential effects of diazepam and lorazepam on iconic memory and visuospatial performances. Acta Neurol Belg 100:147–154.
- Curran HV (2000). Benzodiazepines, memory and mood: a review. Psychopharmacologia (Berl) 152:2–28.
- Di Lazzaro V, Oliviero A, Saturno E, Pilato F, Dileone M, Mazzone P, Insola A, Tonali PA (2005). Dissociated effects of lorazepam and diazepam on short latency afferent inhibition in healthy subjects. J Physiol 563:311–320.
- Duka T, Schmitt J, смешивание А, наложение ТП (1996). Effects of lorazepam and alcohol on memory functions and skills related to driving. Hum Psychopharmacol 11:37–45.
- Giersch A, Herzog MH (2004). The contribution of the magnocellular pathway to contour integration: evidence from patients medicated with lorazepam. Vision Res 44:2543–2550.
- Itil TM, Itil KZ, Shapiro D, Eralp E (1989). Comparison of the effects of lorazepam and diazepam on quantitative EEG and dynamic brain mapping in patients with anxiety disorders. Int J Clin Pharmacol Ther Toxicol 27:369–376.
- Lelas S, Cosford ND, Tehrani L, Vazquez-Villareal P, Schaffhauser H, Feltner DE, Johnson G, надежда А, браун В, полковник И, и другие (2000). 5-HT(2C) receptor-selective agonists: in vitro and in vivo characterization of novel benzimidazolyl-substituted indoles. J Pharmacol Exp Ther 295:118–128.
- Lorenceau J, Granon S, потерпевший F (2005). The contribution of attention in the perceptual completion of partly occluded objects: evidence from the effects of lorazepam. Vision Res 45:109–119.
- Pompéia S, Cordeiro FR, Bueno OFA (2003a). The atypical profile of lorazepam: a comparative review on its behavioral and cognitive effects. Neurosci Biobehav Rev 27:277–291.
- Pompéia S, Juruena MFR, Calzavara MBO, Bueno OFA (2003b). Dissociated effects of lorazepam and flunitrazepam on visual event-related potentials. J Psychopharmacol 17:219–228.
- Sand P, Isoherranen N, Turpeinen M, Vähäkangas K, Vuorela H, Oikari T, Laitinen R, Taskinen J, Pelkonen O (2000). Occurrence of темный-7-chloro-3-hydroxy-5-phenyl-1H-1,4-benzodiazepin-2-one (lorazepam) in human and animal samples. Chirality 12:541–545.
- Sanger DJ, Benavides J (1993). Regional differences in the potencies of benzodiazepines in rat brain. Eur J Pharmacol 249:297–301.
- Vidailhet M, азот А, браун О, варшавский Ж, деверт С, пик К, дидье-Базен С, паскаль Г, менира Ж, и другие (1994). Effects of lorazepam on repetition priming in patients with amnesia of recent onset. Psychopharmacologia (Berl) 114:601–608.
