Introduction
Scopolamine, also known as hyoscine, is a tropane alkaloid and a nonselective, pan-muscarinic antagonist that acts as an inhibitor at muscarinic cholinergic receptor sites in the parasympathetic nervous system. Muscarinic cholinergic receptors, which recognize the neurotransmitter acetylcholine (ACh), are a family of seven-transmembrane domain receptors consisting of five receptor subtypes (M1–5). Positron emission tomography (PET) studies exhibit scopolamine’s ability to occupy muscarinic cholinergic receptors in both human and nonhuman primates, demonstrating scopolamine’s involvement with the central nervous system (CNS) [Reference Frey, Koeppe, Mulholland, Jewett, Hichwa and Ehrenkaufer1, Reference Yamamoto, Nishiyama, Kawamata, Ohba, Wakuda and Takei2]. Scopolamine induces peripheral and central antimuscarinic effects and is utilized for conditions that require decreased parasympathetic activity, including an antiemetic for motion sickness, postoperative nausea, and a sedative before anesthesia. Adverse effects related to anticholinergic activity are generally mild, but can include pupillary dilatation, tachycardia, decreased production of saliva and mucus, urinary retention, and potentially more rare and severe side effects such as hallucinations and delirium.
The cholinergic system in the human CNS comprised projections from the nuclei of the basal forebrain that innervate the hippocampus and most cortical regions, projections from the brainstem to the thalamus, and interneurons in the striatum and nucleus accumbens [Reference Everitt and Robbins3]. Many of these neuroanatomical areas are responsible for cognition, motor function, and affect [Reference Scarr, Gibbons, Neo, Udawela and Dean4]. Psychiatric disorders, including schizophrenia, and mood disorders, such as major depressive disorder (MDD) and bipolar disorder (BD), have been linked to dysregulation in the cholinergic system and dysfunction of cholinergic muscarinic receptors, specifically the M1 and M4 receptor for schizophrenia and the M2 receptor for BD [Reference Gibbons, Scarr, McLean, Sundram and Dean5–Reference Kaul, Sawchak, Correll, Kakar, Breier and Zhu10]. An increase of ACh in the CNS has been linked to an exacerbation of depressive symptoms and, conversely, a lack of ACh has been linked to (hypo)manic symptoms [Reference Janowsky, el-Yousef, Davis and Sekerke11–Reference Janowsky, el-Yousef, Davis and Sekerke13]. Consequently, a number of small randomized controlled trials and a recent systematic review and meta-analysis demonstrated that scopolamine induces a rapid antidepressant effect in individuals experiencing a depressive episode in the context of either MDD or BD [Reference Furey and Drevets14–Reference Khajavi, Farokhnia, Modabbernia, Ashrafi, Abbasi and Tabrizi19]. Potential adverse sequelae of scopolamine, including on various aspects of cognition, would be important to elucidate if scopolamine becomes a more widely used treatment intervention for the management of acute depressive episodes, particularly as such sequelae have not been examined in detail in treatment trials to date.
Scopolamine has additionally been noted in several studies to produce amnestic effects, likely related to its central anticholinergic activity, resulting in its use to induce memory impairment in healthy humans in studies involving a “memory-loss model” and in studies investigating treatments for dementia [Reference Sunderland, Tariot, Cohen, Weingartner, Mueller and Murphy20–Reference Reches, Levy-Cooperman, Laufer, Shani-Hershkovitch, Ziv and Kerem39]. PET imaging in monkeys demonstrated impairment in working memory after scopolamine administration [Reference Yamamoto, Nishiyama, Kawamata, Ohba, Wakuda and Takei2]. Studies that have explored the potential impact of scopolamine on memory and attention have focused predominantly on constructs, such as working, episodic, semantic, implicit, immediate, visual, long-term, or delayed recognition and verbal memory, as well as on retrieval, coding, and storage of information. While several studies have demonstrated amnestic effects, these findings have not been universally demonstrated, with several studies noting no significant impact on either memory [Reference Molchan, Martinez, Hill, Weingartner, Thompson and Vitiello29, Reference Riedel, Hogervorst, Leboux, Verhey, van Praag and Jolles31, Reference Duka, Ott, Rohloff and Voet33, Reference Martinez, Molchan, Lawlor, Thompson, Martinson and Latham35] or attention tasks [Reference Brass, Polinsky, Sramek, Moore, Jones and Veroff32, Reference Tariot, Patel, Cox and Henderson34]. Variability in scopolamine’s effects may reflect individual differences, with CHRM2 genotype influencing inhibitory control and cholinergic pathways, potentially altering sensitivity to scopolamine-induced cognitive impairment [Reference Zink, Bensmann, Arning, Stock and Beste40]. Consequently, scopolamine’s validity as a model for cognitive dysfunction associated with dementia, including Alzheimer’s disease, has been questioned [Reference Flicker, Ferris and Serby41].
There are several factors that might influence the putative impact of scopolamine in relation to memory and attention. First, scopolamine can be administered via a range of different routes, all of which have different pharmacokinetic and metabolic profiles (Supplementary Table S1). Parenteral routes of administration, including intravenous (IV), subcutaneous (SC), and intramuscular (IM) routes, may produce more significant cognitive impairments pertaining to memory and attention [Reference Ebert, Siepmann, Oertel, Wesnes and Kirch42–Reference Sannita, Maggi and Rosadini44], compared to oral (PO) and transdermal (TD) scopolamine administration [Reference Brazell, Preston, Ward, Lines and Traub23, Reference Parrott45–Reference Bukala, Browning, Cowen, Harmer and Murphy47]. Second, higher dosages of scopolamine have been noted in some studies to induce more significant cognitive impairments, although there is limited data exploring if dosage across different modes of administration has a differential impact on performance in tasks pertaining to memory and attention [Reference Curran, Schifano and Lader27, Reference Sannita, Maggi and Rosadini44, Reference Newhouse, Sunderland, Tariot, Weingartner, Thompson and Mellow48].
Examining data systematically pertaining to the potential impact of scopolamine across different routes and dosages of administration in relation to a range of cognitive tasks assessing memory and attention will help inform clinicians of the risks and benefits of this medication, particularly given its continued use as a model of cognitive impairment and its potential future use as an agent with rapid antidepressant effects. Consequently, the aim of this systematic review and meta-analysis is to investigate the effects of scopolamine, across different routes of administration and across different dosages, compared to placebo in relation to its impact on a range of memory and attention performance tasks.
Methods
We conducted a systematic review that adhered to the Preferred Items for Reporting of Systematic Reviews and Meta-Analyses (PRISMA) checklist (Supplementary Table S2) [Reference Page, McKenzie, Bossuyt, Boutron, Hoffmann and Mulrow49] and preregistered our protocol (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=531634).
Eligibility criteria
We included human studies of healthy adult participants (≥18 years of age) to identify the impact of scopolamine administration via any mode of administration on cognitive tasks associated with both memory and attention. All included studies had a placebo arm and were written in English. Review articles, protocols, qualitative/case studies, open-label studies, research meeting abstracts, and conference presentations were excluded. In addition, studies including small sample sizes (≤6 individuals per study arm), where the impact of scopolamine was not possible to determine due to the concurrent administration of other study treatment(s) simultaneously, where the cognitive task included was conducted in less than three studies, or where studies were undertaken in unique environments (i.e., space craft and underwater) were excluded.
Search strategy
A database search was undertaken with no date restrictions applied, using Medline, Embase, PsychINFO, Web of Science, and the Clinical Trials (https://www.clinicaltrials.gov/) database. Relevant reviews and references of the included studies were searched manually to identify additional appropriate studies for this review. The search included the following medical subject key words: “((scopolamine) OR (hyoscine)) AND (cognition) OR (memory) OR (attention) OR (psychomotor) OR (emotion processing) OR (visual learning) OR (recall) OR (amnesia) OR (amnesic)).
Two authors (CM and BH) independently and blindly screened all the titles and abstracts against the eligibility criteria. Full texts of the remaining studies were assessed against the eligibility criteria (CM and BH), with any disagreements resolved through a discussion between these two authors.
Data extraction
CM extracted data from all the studies on 20 April 2024, with BH acting as a second blind rater. Any disagreements were resolved with discussion, with any unresolved differences discussed with DC. Effect measures, including mean and standard deviations, were reported as recorded by the study authors. Data extraction included relevant outcomes (observed effects of scopolamine on cognitive tasks), study characteristics (design including cognitive tasks employed, population, dose, and route of scopolamine), and clinical characteristics (population, sample size, age, sex, and education level).
Quality assessment
The Jadad scale [Reference Jadad, Moore, Carroll, Jenkinson, Reynolds and Gavaghan50] was used to assess the reliability and validity of studies. This tool assesses randomization, blinding, and study withdrawals on a 5-point scale. CM and BH independently and blindly completed the Jadad scale for all included studies, with any differences resolved with a discussion between the authors.
We assessed publication bias using funnel plots when 10 or more studies were included in the analysis. Funnel plots visually assess the symmetry of study effect sizes around the overall effect estimate. Symmetry suggests no significant publication bias, whereas asymmetry may indicate potential bias, such as missing studies with nonsignificant results. For analyses with fewer than 10 studies, funnel plots were not used, as fewer studies reduce the statistical power needed to distinguish a true asymmetry from random variation [Reference Sterne, Sutton, Ioannidis, Terrin, Jones and Lau51].
Statistical analysis
A meta-analysis was conducted where three or more studies examined the impact of scopolamine compared to placebo for the same cognitive task. Effect sizes were calculated for continuous data by attaining the mean, standard deviations, and sample size of the scopolamine and placebo groups. When standard deviations were not available, these were estimated based on the other statistical parameters reported in the individual study. Standard errors (SEs) were converted to standard deviations as appropriate. When continuous data were not available, we evaluated dichotomous data and calculated the odds ratios, which were converted into Hedge’s G effect size statistic (G). For studies using multiple arms of the drug and one arm of the placebo (e.g., different scopolamine doses compared with placebo), the “n” for the placebo group was divided by the number of strata in the study. Where sufficient data were available (≥3 studies), additional analyses were performed on “injection” (e.g., IV, IM, and SC) compared to “non-injection” (e.g., PO, TD, and intranasal (IN)) routes of administration. Doses were categorized as “high” (≥0.5 mg) or “low” (<0.5 mg). Age analysis grouped participants into “young” (18–40 years, mean age < 30 years) and “old” (>40 years, mean age > 60 years) cohorts.
“Comprehensive Meta-Analysis,” Version 3, evaluated differential medication effects on cognitive tasks between the scopolamine and placebo groups to ascertain the random-model treatment effect size (G), 95% confidence intervals (CIs), and SEs for each study [Reference Borenstein, Hedges, Higgins and Rothstein52]. Heterogeneity of interventions was assessed using the Cochrane Q and I 2 statistics, with significance determined at p < 0.05.
Results
Literature search
The PRISMA diagram summarizing the literature search strategy is presented in Figure 1. A total of 468 articles were identified, with 282 full texts reviewed and 106 studies included in the final analysis (eight from the reference lists). Studies were excluded if they lacked cognitive task data, involved open-label designs, used additional treatments, or had intervention arm sizes ≤6 participants. The sociodemographic and clinical characteristics of all included studies are provided in Supplementary Tables S3 and S4.
Flowchart describing the study selection process.
List of unique cognitive tasks included in Supplementary Table S5.
Memory
Six different tasks provided data pertaining to performance and reaction time. Scopolamine significantly impaired memory performance and reaction time, only when scopolamine was administered via injection.
Free/immediate recall (Figure 2)
Twenty studies (35 strata; scopolamine n = 493, placebo n = 492) assessed free/immediate recall. Scopolamine impaired accuracy compared to placebo (G = −0.86, 95% CI: −1.08 to −0.64, p < 0.001), with a significant effect in injection studies (G = −1.00, 95% CI: −1.25 to −0.76, p < 0.001), but not in non-injection studies (G = −0.16, 95% CI: −0.70 to 0.38, p = 0.57).
Post- versus pre-administration accuracy was lower in the scopolamine group (G = −0.93, 95% CI: −1.42 to −0.44, p < 0.001), with insufficient studies present to examine injection and non-injection groups separately (Supplementary Figure S1). Scopolamine impaired performance at both high and low doses, with both the dose categories showing significant effects (Supplementary Figure S2). Evidence of publication or reporting bias, along with heterogeneity among the studies, was observed (Supplementary Figure S3). Performance was assessed 30 min–6 h post-administration, with no discernible impact of timing.
Free/immediate recall: accuracy (% correct).
■ Old cohort.
□ Young cohort.
IM, intramuscular; IV, intravenous; PO, oral; SC, subcutaneous.
*Studies that used microgram doses have been converted to milligrams based on a 75 kg body weight.
Delayed recall (Figure 3)
Fourteen studies (21 strata; scopolamine n = 332, placebo n = 332) utilized delayed recall, with scopolamine impairing performance compared to placebo (G = −0.89, 95% CI: −1.16 to −0.61, p < 0.001). Both scopolamine injection (G = −1.07, 95% CI: −1.41 to −0.72, p < 0.001) and non-injection (G = −0.56, 95% CI: −1.02 to −0.08, p = 0.018) groups performed significantly worse compared to the placebo. Post-administration versus pre-administration accuracy showed no difference (G = −0.29, 95% CI: −1.08 to 0.50, p = 0.47); however, three of the five strata included non-injectable scopolamine (Supplementary Figure S1). Scopolamine impaired performance at both high and low doses, with both the dose categories showing significant effects (Supplementary Figure S4). Evidence of publication or reporting bias was observed in the delayed recall task assessing performance (Supplementary Figure S5). This task was assessed 30 min–4.5 h post-administration, with no apparent impact of the timing.
Delayed recall: accuracy (% correct).
IM, intramuscular; IV, intravenous; PO, oral; SC, subcutaneous.
*Studies that used microgram doses have been converted to milligrams based on a 75 kg body weight.
Digit span (Supplementary Figure S6)
Thirteen studies (24 strata; scopolamine n = 331, placebo n = 278) assessed digit span forward, while four studies (10 strata; scopolamine n = 157, placebo n = 119) assessed digit span backward. Scopolamine had no overall effect on the digit span forward (G = −0.158, 95% CI: −0.42 to 0.11, p = 0.239), although the injection group showed impairment (G = −0.29, 95% CI: −0.56 to −0.02, p = 0.034). Scopolamine impaired the digit span backward performance compared to placebo (G = −0.39, 95% CI: −0.68 to −0.09, p = 0.011). Comparing dose levels, digit span forward showed no significant effect at either high or low doses, while scopolamine impaired the performance at high doses but not at low doses for digit span backward (Supplementary Figure S7). No evidence of publication or reporting bias was observed (Supplementary Figure S8). Performance was measured across a large time duration (30 min–70 h) post-scopolamine administration with no clear impact of timing.
Buschke selective reminding task (Supplementary Figure S9)
Ten studies examined accuracy utilizing the Buschke selective reminding task (16 strata; scopolamine n = 225, placebo n = 173), while five studies (10 strata; scopolamine n = 137, placebo n = 85) investigated consistency. The scopolamine group performed worse than placebo on both accuracy (G = −1.13, 95% CI: −1.43 to −0.83, p < 0.001) and consistency tasks (G = −1.33, 95% CI: −1.8 to −0.86, p < 0.001). Scopolamine also significantly impaired accuracy and consistency at both high and low doses (Supplementary Figure S10). Evidence of publication or reporting bias was observed in the delayed recall task assessing performance (Supplementary Figure S11). This task was assessed 55 min–2.5 h post-scopolamine administration, with no distinguishable impact of time evident.
Recognition memory (Supplementary Figure S12)
For the recognition memory task, eight studies (19 strata; scopolamine n = 282, placebo n = 282) examined accuracy, while five studies (12 strata; scopolamine n = 208, placebo n = 208) investigated the reaction time. Scopolamine significantly impaired both accuracy (G = −0.43, 95% CI: −0.73 to −0.14, p = 0.004) and reaction time (G = 0.19, 95% CI: 0.001 to 0.37, p = 0.048) compared to the placebo group. High-dose scopolamine significantly impaired accuracy, while low-dose scopolamine had no effect (Supplementary Figure S13). This task was measured 30 min–4 h post-scopolamine administration, with no obvious impact of timing.
Sternberg memory scanning task (Supplementary Figure S14)
Four studies (five strata; scopolamine n = 89, placebo n = 89) utilized the Sternberg memory scanning task. Individuals in the scopolamine group performed worse on accuracy (G = −0.82, 95% CI: −1.27 to −0.38, p < 0.001) and had slower reaction times (G = 0.70, 95% CI: 0.20 to 1.20, p = 0.006) compared to placebo. This task was measured across 55 min–3 h post-scopolamine administration, although no observable impact of time was evident.
Age and sex
Age analysis was conducted for free/immediate recall, digit span forward, and the Buschke selective reminding task (Supplementary Figures S15–S17). Scopolamine impaired both young and old cohorts in free/immediate recall and the Buschke selective reminding task, but only affected the young cohort in digit span forward. There were insufficient studies to conduct a meaningful sex analysis.
Attention
Five tasks provided measures of performance and reaction time. Scopolamine negatively impaired performance and significantly delayed reaction time during attention tasks, especially when post-administration scores were compared to baseline.
Choice reaction time (CRT) (Supplementary Figures S18–S21)
Twelve studies (27 strata; scopolamine n = 423, placebo n = 385) assessed reaction time, and four studies (eight strata; scopolamine n = 131, placebo n = 93) evaluated accuracy. The scopolamine group demonstrated a slower reaction time (G = 0.80, 95% CI: 0.48 to 1.13, p < 0.001), but not reduced accuracy (G = −0.5, 95% CI: −1.04 to 0.03, p = 0.063) compared to placebo. The effect size for a slower reaction time was larger for those who received scopolamine by injection (G = 1.25, 95% CI: 0.78 to 1.71, p < 0.001) compared to non-injectable scopolamine (G = 0.39, 95% CI: −0.06 to 0.84, p = 0.091). Comparing pre- to post-administration scores, seven studies (28 strata; scopolamine n = 259, placebo n = 221) investigated change in reaction time, and three studies (seven strata; scopolamine n = 114, placebo n = 76) examined change in accuracy. Scopolamine demonstrated slower reaction times (G = 2.08, 95% CI: 1.54 to 2.61, p < 0.001) and reduced accuracy (G = −0.86, 95% CI: −1.3 to −0.42, p < 0.001) compared to placebo, with the injection group demonstrating slower reaction times. Scopolamine impaired reaction time at both high and low doses compared to placebo and worsened reaction time from pre- to post-administration (Supplementary Figures S22 and S23). This task was measured 45 min–70 h post-administration, with no impact of timing. Publication or reporting bias was evident for the CRT task assessing reaction time (Supplementary Figure S24). The adjusted values with the imputed studies reduced the effect size from G = 0.83 to G = 0.64 (95% CI: 0.21−1.08, p = 0.004).
Simple reaction time (SRT) (Supplementary Figures S19 and S21)
Eight studies (13 strata; scopolamine n = 179, placebo n = 179) utilized the SRT task. The scopolamine group showed slower reaction times (G = 0.48, 95% CI: 0.15 to 0.81, p = 0.004) compared to placebo, with injectable administration demonstrating a larger effect size (G = 0.85, 95% CI: 0.22 to 1.56, p = 0.008) compared to the non-injection group (G = 0.34, 95% CI: −0.05 to 0.73, p = 0.083). Comparing pre- to post-administration scores, scopolamine was associated with slower reaction time (G = 0.88, 95% CI: 0.37 to 1.40, p = 0.001) compared to placebo. Comparing doses, scopolamine impaired reaction time at low doses but not at high doses (Supplementary Figure S25). Tasks ranged from 30 min to 4.5 h after scopolamine administration, with no apparent impact of time of administration.
Continuous performance task (CPT) (Supplementary Figure S19)
Four studies (10 strata; scopolamine n = 115, placebo n = 117) utilized the CPT (seven strata utilized an injectable mode of administration), with no significant effects of scopolamine compared to placebo. Measurements ranged from 1.5 to 70 h post-administration, with no impact of time of administration.
Rapid visual information processing (RVP) (Supplementary Figures S20 and S21)
Three studies (three strata (all injectable routes); scopolamine n = 48, placebo n = 48) utilized RVP. Examining change scores from baseline to post-scopolamine administration, scopolamine demonstrated slower reaction time (G = −1.16, 95% CI: −1.89 to −0.44, p = 0.002) and less accuracy (G = 1.74, 95% CI: 1.28 to 2.21, p < 0.001) compared to placebo. This task was measured 1–2 h post-scopolamine administration, with no impact of time of administration.
Vigilance task (Supplementary Figure S18)
Three studies (five strata; scopolamine n = 127, placebo n = 127, three strata used an injectable mode of administration) utilized the vigilance task. No differential effects of scopolamine compared to placebo were noted for this task. This task was measured across 1–15.5 h post-scopolamine administration, with no impact of the time of administration.
Age and sex
There were too few studies to conduct a meaningful age or sex analysis for attention tasks.
Discussion
Scopolamine demonstrated a clear impairment for both memory and attention, particularly for tasks associated with working, episodic and recognition memory, and sustained attention utilizing this comprehensive systematic review and meta-analysis in healthy adults (Supplementary Tables S6 and S7). Similarly, scopolamine’s adverse impact on memory and attention was greater with an injectable method of administration (e.g., IV, IM, and SC) compared to non-injectable routes (e.g., PO, TD, and IN).
Despite some previous divergent findings [Reference Flicker, Ferris and Serby41], we believe the results of this systematic review support scopolamine administration in an injectable format as a useful model for cognitive dysfunction and dementia, with delayed recall (a working memory task), for example, noted as impaired in early-stage Alzheimer’s disease and clearly worsened by scopolamine administration [Reference Cerami, Dubois, Boccardi, Monsch, Demonet and Cappa53, Reference Welsh, Butters, Hughes, Mohs and Heyman54]. Furthermore, scopolamine-induced cognitive impairments are potentially relevant to understanding the cognitive deficits seen in schizophrenia, MDD and BD. The cholinergic system’s role in these psychiatric disorders is underscored by our findings that scopolamine can impact cognitive functions such as memory and attention, which are core components affected in these psychiatric disorders. These results not only support the hypothesis of cholinergic dysregulation in schizophrenia and MDD but also suggest that anticholinergic agents like scopolamine could potentially provide a valuable tool for investigating the neurochemical underpinnings of these conditions.
In comparison to placebo, scopolamine significantly impaired performance and consistency on the Buschke selective reminding test (Supplementary Figure S9), which evaluates the organization of long-term memory retrieval. Scopolamine also worsened performance and reaction times on the recognition memory (Supplementary Figure S12) and Sternberg tasks (Supplementary Figure S14), with the latter assessing working memory retrieval speed. While the digit span forward task (Supplementary Figure S6), a measure of working memory and attention, was not significantly affected, the scopolamine group did perform worse on this task. Scopolamine modestly impaired performance on the digit span backward task (Supplementary Figure S6), likely due to its lower difficulty compared to other working memory tasks (i.e., immediate and delayed recall) [Reference Mintzer and Griffiths55].
Similarly, the route of scopolamine administration affects its impact on cognitive performance in attention tasks. The injectable group exhibited slower reaction times on the CRT task compared to the non-injectable group (Supplementary Figure S19). The CRT task assesses sustained attention, and slower reaction times are indicative of poorer performance in attention tasks. Scopolamine also led to slower reaction times for both the SRT and RVP tasks (Supplementary Figure S21). Across all routes of administration, scopolamine negatively impacted performance on the CRT and RVP tasks compared to placebo (Supplementary Figure S20). There was no effect of scopolamine on the CPT and the vigilance task (Supplementary Figures S18 and S19); however, only three studies included these tasks, suggesting that the analysis may be underpowered to detect significant effects.
A likely rationale for the more significant cognitive deficits associated with injectable methods of scopolamine relate to its higher bioavailability with 100% absorption into the blood stream (half-life ~68.7 min) for IV scopolamine compared to 13% bioavailability (half-life ~63.7 min) for PO administration and even slower delivery for TD administration of (>4 h) [Reference Renner, Oertel and Kirch56]. PET imaging utilizing [11C] scopolamine further supports this by demonstrating that IV administration enables rapid CNS penetration and significant receptor occupancy, reflecting high bioavailability [Reference Frey, Koeppe, Mulholland, Jewett, Hichwa and Ehrenkaufer1]. Therefore, methods with higher bioavailability, such as injectables, consequently have a greater impact on memory and attention than lower bioavailability.
The varied timing of task administration in this meta-analysis complicates conclusions about scopolamine’s impact on cognition. Cognitive deficits were observed as early as 1 h post-administration, but studies assessing memory 30–45 min post-administration found no significant effects [Reference Kopelman and Corn22, Reference Flicker, Ferris and Serby41, Reference Bedard, Pillon, Dubois, Duchesne, Masson and Agid57, Reference Petersen58], and adverse effects were minimal after 6 h. For instance, free/immediate recall was unaffected after 6 h [Reference Canal, Franceschi, Alberoni, Castiglioni, De Moliner and Longoni28, Reference Riedel, Hogervorst, Leboux, Verhey, van Praag and Jolles31], and digit span forward displayed no deficits compared to placebo at 22, 46, and 72 h [Reference Brazell, Preston, Ward, Lines and Traub23]. Similarly, the CRT task displayed no effect on reaction time 30 min post-administration [Reference Vitiello, Martin, Hill, Mack, Molchan and Martinez59], with negligible effects for attention tasks evident after 11 h [Reference Brazell, Preston, Ward, Lines and Traub23, Reference Gordon, Binah, Attias and Rolnick46]. These results should also be considered in the context of differing pharmacokinetic profiles associated with the route of administration. For example, injectable scopolamine achieves rapid systemic availability and peak effects, potentially explaining the early cognitive deficits observed, while PO or TD administration produces a slower onset of action with more sustained plasma concentrations. Consequently, although scopolamine, particularly when administered via injectable methods, impacts cognition, these effects are not long-lasting. This is of particular importance given the potential benefit IV scopolamine may impart for individuals experiencing a depressive episode [Reference Furey and Drevets14, Reference Drevets and Furey15, Reference McCaffrey, Cannon and Hallahan18].
Higher doses of scopolamine consistently impaired memory and attention, while lower doses also produced significant deficits in several tasks, particularly free/immediate recall, delayed recall, and CRT reaction time. However, some tasks, such as digit span forward, were unaffected, and in certain cases (e.g., digit span backward, recognition memory, and SRT reaction time), impairments were observed only at high or low doses, suggesting task-specific dose sensitivity. In addition, physiological factors such as body weight and gender may impact scopolamine’s pharmacokinetics. As scopolamine is highly lipid soluble, facilitating its redistribution into fatty tissues, gender (i.e., women generally have a higher fat content than men with a similar body mass index) and body weight may result in different distribution and clearance rates of scopolamine. Further research should consider body weight, sex differences, and other physiological variables. In addition, microgram doses have been converted to milligrams based on a 75 kg body weight for 11 studies, which potentially adds confounding variation to the analyses. While this approach helps standardize dosing, we acknowledge its limitations, as it may not fully account for individual differences in body composition and metabolism.
This study has other limitations. Older studies (pre-2000) had lower quality scores based on the Jadad rating scale, although all included trials were randomized and double-blinded [Reference Jadad, Moore, Carroll, Jenkinson, Reynolds and Gavaghan50]. Several studies fulfilling the inclusion criteria also had to be excluded due to insufficient extractable data. In addition, fewer studies evaluated certain memory and attention tasks, making comparisons between injectable and non-injectable administration methods unfeasible for some tasks. Moreover, an inadequate number of individual studies restricted the analysis of evidence for publication or reporting bias. However, where possible, consistency and precision across effects were examined.
In conclusion, this systematic review and meta-analysis, the largest to date investigating scopolamine’s effect on cognition in a healthy population, provides evidence of scopolamine’s negative effects on both memory and attention, with cognitive impairment more significant via injectable compared to non-injectable routes of administration. Despite scopolamine’s long-established use in medical practice, notable gaps persist in our understanding of its pharmacological impacts, especially its potential as a rapid antidepressant. Given the preliminary evidence supporting scopolamine’s use in treating depressive episodes, additional randomized controlled trials are suggested to determine optimal dosages and administration methods that maximize antidepressant benefits while minimizing adverse effects. Future clinical trials should evaluate the bioavailability of scopolamine across different routes of administration, to ensure its therapeutic benefits outweigh any potential adverse cognitive effects.
Supplementary material
The supplementary material for this article can be found at http://doi.org/10.1192/j.eurpsy.2025.2446.
Data availability statement
Data are available upon request.
Author contribution
Cerena Miravalles and Brian Hallahan designed the study. Cerena Miravalles conducted the bibliographical literature searches and the statistical analyses. Cerena Miravalles, Brian Hallahan and Dara M. Cannon drafted and revised the manuscript. All authors have agreed on the final manuscript and the decision to submit for publication.
Financial support
This work was supported by the Hardiman Scholarship, awarded by the University of Galway.
Competing interests
All authors report no financial interests or any potential conflicts of interest.
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