Alprazolam (Xanax) & Cognitive Impairment: Brain Fog & Zombification

For the past 1.5 years, I’ve been struggling with intermittent bouts of sleep-maintenance insomnia (i.e. middle insomnia) and terminal insomnia (i.e. early morning awakening insomnia).

This causes me to wake up ~2-4 hours before my desired wake time and have difficulty falling back asleep despite feeling mentally and physically tired.

It all began ~1-2 months after a wicked COVID-19 infection, but I’m not 100% convinced that it was from the infection. (Read more about my experience here: Insomnia After COVID-19).

I’ve experimented extensively with supplements, diet/lifestyle, sunlight exposure, environmental adjustments (mattresses, room temperature, etc.), routine modifications, etc. – yet none of these  have had a significant impact on my insomnia.

As it turns out, one of the only medications that effectively abolishes my insomnia is alprazolam (Xanax). If I administer 0.125-0.25 mg (low dose) alprazolam and meditate, I’ll fall asleep for another ~2+ hours and feel as though I got enough sleep.

Despite enjoying the fact that alprazolam effectively treats my insomnia, I believe it is negatively impacting my cognitive function. For this reason, I decided to investigate the effects of alprazolam (Xanax) on cognition.

What does the scientific literature suggest re: Xanax (alprazolam) & cognition?

Alprazolam (Xanax) usually impairs aspects of cognitive function – but there’s likely some nuance.

Factors that may influence: (1) whether cognitive impairment occurs and (2) magnitude of cognitive impairment from alprazolam (Xanax) – include:

Dosing: Cognitive impairment from alprazolam appears to be dose-dependent.

• Low doses: Low doses of alprazolam (0.125 mg to 0.5 mg) are associated with less significant cognitive impairment than high doses.
• High doses: High doses of alprazolam (1-2+ mg) are associated with significantly greater cognitive impairment than lower doses (more domains of impairment, greater composite impairment, etc.).

Duration of use: There appears to be an effect of time on cognitive impairment resulting from alprazolam use.

• Acute (single-dose): Generally associated with significant impairment.
• Moderate-term admin: Ongoing administration (e.g. ~2 weeks) is sometimes associated with impairment – but not always.
• Long-term admin: Months of regular alprazolam use is associated with cognitive impairment – but impairment may be less severe than acute/short-term use due to partial tolerance and/or receptor density/function changes.

Format: The specific format of alprazolam administered can influence degree of cognitive impairment – assuming dosage is equal. (Keep in mind that all formats are still associated with cognitive impairment – some just cause less significant impairment than others).

• Immediate-release (IR): Associated with more significant cognitive impairment than alprazolam XR (extended-release) – likely due to pharmacokinetics (resulting in higher peak concentrations).
• Extended-release (XR): Associated with less significant cognitive impairment than alprazolam IR (immediate-release) – due to pharmacokinetics (producing a lower peak concentration with longer duration of action).

User characteristics: Cognitive impairment may be affected by specific characteristics of alprazolam users.

• Age (young vs. old): Older adults (ages 65+) may experience more pronounced cognitive impairment from alprazolam than younger individuals – possibly due to exacerbation of preexisting age-related cognitive impairment.
• Anxiety disorders: Individuals with anxiety disorders (e.g. panic disorder, agoraphobia, avoidant/overanxious personality, neuroticism, etc.) may be less likely to experience cognitive impairment from alprazolam – possibly due to the fact that alprazolam helps normalize arousal (from a state of hyperarousal).
• Healthy (non-anxious): Individuals without preexisting anxiety disorders may be more likely to experience cognitive impairment with alprazolam – probably due to the fact that level of arousal is already healthy/optimal.
• Genetics & neurochemistry (?): Some research suggests that both the specific types of cognitive impairments and magnitudes are highly individualized – such that one person may experience minor impairment in recall whereas another may experience massive impairment in recall, attention, reaction, etc. This is probably partially attributable to genetics and specific neurochemistry.

Types of cognitive impairment from alprazolam (Xanax)

Below are domains of cognition and/or cognitive tasks that may be affected by alprazolam (Xanax) as documented in research.

• Memory
• Explicit memory
• Working memory
• Composite cognitive function
• Performance
• Speed/reaction
• Inhibitory control
• Recall (immediate/delayed)
• Tracking & peripheral search
• Detection
• Identification
• Information processing capacity
• Matching
• Accuracy
• Sorting
• Learning tasks

Recap of studies investigating alprazolam (Xanax) & cognitive function

Below are studies listed under “cognitive impairments” (cognitive impairments found) or “no cognitive impairment” (either: cognitive impairments not found or not found for specific domains).

Cognitive impairments found

• Chowdhury et al. (2016): Alprazolam (0.5 mg) impaired memory but not psychomotor performance/attention. (26 healthy volunteers)
• Reissig et al. (2015): Inhaled/oral alprazolam both caused dose-dependent cognitive impairment. (14 healthy volunteers with drug abuse history)
• Kay et al. (2012): Alprazolam (1 mg) caused significant cognitive impairment vs. placebo. (Healthy older adults)
• Leufkens et al. (2007): alprazolam 1 mg XR less of an effect than IR – but both significantly impaired driving. 1 mg IR impaired tracking/peripheral search, response speed/inhibitory control, immediate/delayed recall. 18 healthy volunteers.
• Maruff et al. (2006): Alprazolam (1 mg) impaired cognition in 93% of users. 71% of users had cognitive impairment in 2+ domains. Specific impairment types were not predictable across users. Composite cognitive function was significantly impaired – despite individual cognitive domains in isolation not being impaired.
• Drabant et al. (2006): Alprazolam (0.75-1.75 mg) dose-dependently impaired cognitive function. (18 healthy volunteers)
• Snyder et al. (2005): Alprazolam (0.5 mg) caused deterioration in performance on speed and matching tasks. Alprazolam (1 mg) caused significant declines in: detection, identification, matching, working memory, and accuracy of performance on working memory, sorting, learning tasks, etc. (36 healthy adults)
• Verster et al. (2002): Alprazolam (1 mg) impaired driving, laboratory tracking, attention, and memory. (20 healthy adults)
• Kilic et al. (1999): Explicit memory impairments on alprazolam. (15 patients with agoraphobia/panic disorder)
• Pomara et al. (1998): Alprazolam for 3 weeks impaired aspects of cognition – especially with chronic/high-dose use. Partial but incomplete tolerance. Cognitive impairment didn’t go away.
• Bourin et al. (1998): Alprazolam (0.125 mg b.i.d.) impaired cognition on tests (pictures, digit symbol substitution, choice reaction time) after 3 days. Improvement in performance except on recognition reaction time occurred Day 7-Day 14. Tolerance effect/anxiolytic effect and/or change in receptor function/number may have explained this effect. (Healthy adults)
• Fleishaker et al. (1995): Alprazolam at 1.5 mg impaired psychomotor performance, attention, and implicit memory. Category recall was impaired at both 1.5 mg and 0.5 mg doses.
• Semlitsch et al. (1995): Alprazolam (1 mg) impaired cognitive information processing capacity. (15 healthy volunteers)
• O’Sullivan et al. (1994): Alprazolam users experienced “impaired memory” relative to placebo. (Panic/agoraphobia patients)
• Allen et al. (1991): Alprazolam (0.25-0.75) increased forgetfulness especially on Day 5. (Healthy volunteers)
• Linnoila et al. (1990): Low dose alprazolam impaired performance on not task from 1-4 hours after admin. High dose (2 mg) produced longer-lasting impairments and more total impairments (tracking, verbal/nonverbal information processing, memory, reaction time).
• Aranko et al. (1985): Single doses of alprazolam (0.25 mg) were associated with impairment on objective skill tests in 24 healthy volunteers vs. placebo.

No cognitive impairment

• Soria et al. (2019): Alprazolam for 12 weeks (1.5-3 mg/day) doesn’t impair verbal fluency in persons with preexisting anxiety disorders, chronic stress, and/or neuroticism. (54 patient sample).
• Gladsjo et al. (2001): Alprazolam XR (4 mg/day) for 6 weeks. No significant changes in cognition observed vs. placebo. (38 adults with panic disorder)
• Bourin et al. (1998): Alprazolam (0.125 mg b.i.d.) impaired cognition on tests (pictures, digit symbol substitution, choice reaction time) after 3 days – but cognition improved between Day 7-14 with the exception of reaction time. (Healthy adults)
• Fleishaker et al. (1995): Alprazolam at 0.5 mg and 1.5 mg did not impair knowledge memory or semantic memory. (Note: This study noted cognitive impairment – just not in these aspects of cognition.)
• Simeon et al. (1992): No differences in cognition from alprazolam vs. placebo. (30 overanxious/avoidant patients)
• Hart et al. (1991): No significant changes on cognitive performance with alprazolam except mild performance decrements on Day 1. The decrements didn’t persist at Day 14.

Note: There are no studies suggesting that alprazolam enhances aspects of cognitive function.

Xanax (Alprazolam) & Cognitive Function (Research)

Included below are findings from studies that assessed or discussed the effect of alprazolam (Xanax) on aspects of cognition.

Semantic & Phonemic Verbal Fluency Performance in Patients with GAD & Allostatic Load Under Alprazolam Treatment (2019) (R)

Soria et al.: This study suggests that alprazolam administered for 12 weeks (1.5-3 mg/day) may improve verbal fluency (an aspect of cognition) among those with preexisting anxiety disorders, chronic stress, and/or neuroticism.

• Aim: Evaluate verbal fluency performance in patients with anxiety disorders and allostatic load – after treatment with alprazolam for 12 weeks.
• 54 patients participated – and 54 completed the full 12-week study.
• Measures: Allostatic Load Index and cognitive assessment (before & after treatment)

What were the results?

• After a 12-week course of alprazolam (1.5-3 mg/day) the percentage of patients with anxiety disorders/chronic stress decreased from 12.9% (7/54) to 6% (3/50).
• After treatment, none of the patients showed semantic verbal fluency deficits but 3 showed phonemic impairments.
• Impairment was significantly associated with an older age before treatment and with a similar [albeit insignificant] tendency after treatment.

Limitations: Small sample size; observational study; limited cognitive tests; alprazolam dosing (may have been suboptimal for some e.g. too high or too low); patients with preexisting anxiety only (not healthy individuals); not a complete cognitive battery.

Effect of Chronic Alprazolam Intake on Memory, Attention, Psychomotor Performance (2016) (R)

Chowdhury et al.: “We found that chronic administration of alprazolam affects memory but attentive and psychomotor performance remain unaffected.”

• 26 healthy male volunteers
• 2 groups: alprazolam (0.5 mg daily) (N = 13) vs. placebo (daily) (N = 13) – for 2 weeks
• Evaluation: Cambridge Neuropsychological Test Automated Battery (CANTAB)
  • Paired Associated Learning (PAL): Memory
  • Delayed Matching to Sample (DMS): Memory
  • Rapid Visual Information Processing (RVP): Attention
  • Choice Reaction Time: Psychomotor performance

What were the results?

Impaired visual memory: 1 parameter of PAL and 3 parameters of DMS – for alprazolam users relative to placebo users.

• PAL: mean trial to success
• DMS: Total correct matching in (1) 0-second delay, (2) 4-second delay, and (3) all-delay situation.

PAL test

Subjects who performed poorly on the PAL test prior to alprazolam actually made fewer errors after alprazolam treatment.

Conversely, subjects who made fewer errors on the PAL test prior to alprazolam made more errors after alprazolam treatment.

DMS test

Probability of making an error following error or correct response didn’t change significantly over 2 weeks in alprazolam users.

Total correct responses when choice patterns were present simultaneously with the sample pattern were not different between alprazolam and placebo users.

A significant difference was observed in the alprazolam group over 2 weeks when there is a delay (0-4 seconds) in presentation of the choice pattern.

Total correct responses in overall test increased slightly in both alprazolam and placebo users – and there were no significant differences between groups.

RVP test

Alprazolam users experienced significant improvements in RVP test results.

Probability of hitting a target sequence and probability of pressing the touch pad irrespective of target sequence were different after 2 weeks of treatment.

Total number of targets successfully identified and RVP total hits increased significantly in alprazolam users – indicating that low-dose alprazolam (0.5 mg) doesn’t impact attention.

CRT test

There were no differences in the average latency of reaction time (milliseconds) in alprazolam users over ~2 weeks of treatment – both alprazolam and placebo groups exhibited the same latency of reaction time.

Researchers: Mean choice latency for DMS & RVP tests decreased after alprazolam indicates increment of fine motor controls, which may result from decreased activity of GABA-A receptor-mediated inhibition or increased excitatory activity of the glutamatergic system.

• It is thought that chronic increased GABA receptor-mediated inhibition by benzodiazepines may result in increased sensitivity to glutamate – the primary excitatory neurotransmitter within the brain.
• Animal model research supports the idea glutamate sensitivity increases following benzodiazepine use – as NMDA receptor antagonists seem to attenuate these deficits.

Limitations: Sample size; total duration of tests; 2 testing intervals (before & after); dosage of alprazolam (low); frequency of alprazolam administration (once nightly); dosing relative to test timing (~8-hour gap); time of alprazolam administration (at night – may have enhanced sleep to some extent and/or circadian rhythm); test practice (improving the second time – knowing what to expect); duration of alprazolam use (short-term: 2 weeks).

Inhaled vs. oral alprazolam: behavioral and cognitive effects (2015) (R)

Reissig et al.

• 14 healthy volunteers with histories of drug abuse received: placebo; inhaled alprazolam (0.5, 1, 2 mg); oral alprazolam (1, 2, 4 mg) – under double-blind, double-dummy conditions.
• Measures: Psychomotor test; pattern recognition; word recall

What were the results?

• Both inhaled and oral alprazolam dose-dependently impaired cognitive performance on all tests (Circular Lights, DSST, Word Recall Task).

Cognitive, psychomotor, driving performance in healthy volunteers after alprazolam (1 mg) (2007) (R)

Leufkens et al.: “The acute impairing effects of alprazolam XR 1 mg on driving and psychomotor functions were generally less, as compared to its immediate-release equivalent, but still of sufficient magnitude to increase the risk of becoming involved in traffic accidents.”

• Aim: Evaluate the respective effects of: (1) 1 mg alprazolam XR (extended-release); (2) 1 mg alprazolam IR (immediate-release); and (3) placebo – on cognitive and psychomotor function.
• 18 healthy volunteers (ages: 20-45) participated in a double-blind, placebo-controlled, three-way crossover study.
• Measures: Driving ability (~4 hours post-dose); cognitive/psychomotor performance (1 hour, 2.5 hours, 5.5 hours – post-dose); memory function (~1 hour post-dose).

What were the results?

Cognitive function

Alprazolam IR (1 mg) significantly impaired performance on all tasks compared with the placebo.

• Tracking and peripheral visual search (divided attention task)
• Response speed and inhibitory control (stop signal task)
• Immediate and delayed recall (word learning task)

Alprazolam XR (1 mg) only impaired performance in the divided attention task but not in the stop signal or memory tests – indicating reduced cognitive impairment relative to the IR format.

Driving performance

Both formats of alprazolam (XR & IR) dosed at 1 mg significantly impaired performance on the standardized highway driving test.

The IR formulation increased SDLP by ~8.2 cm and the XR formulation increased SDLP by ~3.9 cm – indicating that the IR format worsened driving ability to a greater extent than the XR format.

Despite less significant impairment in driving with the XR (~50% less) relative to the IR – the impairment with XR was still considered “severe” and effects were reportedly equivalent of driving with a BAC above the legal limit (0.5 g/l) in most countries.

Limitations: Single dosing; healthy volunteers; small sample size; young/middle age adults.

A statistical approach for classifying change in cognitive function in individuals following pharmacological challenge: an example with alprazolam (2006) (R)

Maruff et al.

• Aim: Determine whether a novel but theoretically derived statistical/methodological approach to the classification of cognitive change in individuals could identify cognitive change in individuals who had received an acute 1 mg dose of alprazolam.
• 26 healthy individuals were assigned to receive either: alprazolam (1 mg, t.i.d.) (N = 14) or placebo (N = 12)
• Measures: Cognitive battery (8 different tests of psychomotor function, attention, executive function, memory, problem solving/strategy)

What were the results?

• After a single dose of alprazolam (1 mg), a statistically reliable cognitive impairment occurred in 93% of individuals.
• 71% of individuals met criteria for cognitive change that required abnormal change on 2+ performance measures from alprazolam (1 mg).
• Alprazolam-induced cognitive impairment occurred on different performance measures among users – domains of cognitive impairment were not predictable across users.
• Magnitude of alprazolam-induced cognitive impairment was also individual-specific (some experienced significantly more impairment than others).
• Respective cognitive impairments within each specific cognitive domain were not statistically significant.
• However, subtle cognitive decline in each cognitive domain added together yielded significant decline in composite cognitive function.

The cognitive effect of alprazolam in healthy volunteers (2006) (R)

Drabant et al.: “Alprazolam impaired the performance in cognitive tests dose-dependently and induced subjective sedation.”

• 18 healthy male volunteers
• Randomized, double-blind, placebo-controlled, crossover study
• Single doses of: 0.75 mg; 1.75 mg; placebo – given in randomized order
• Measures: Cognitive tests (immediate & delayed word recall; digit symbol substitution; critical fusion frequency; multiple choice reaction) & subjective rating of the drug

Note: I was unable to view the complete details of this study – due to unavailability.

Limitations: Small sample size; single dose; only healthy males.

Magnitude of change across different cognitive functions in clinical trials: the effects of acute administration of 2 different doses of alprazolam (2005) (R)

Snyder et al.: “Results of this study show that psychomotor function (detection), simple attention (match, identify), vigilance (monitor), working memory (remember one back), and executive function (GMLT) were impaired by alprazolam.”

• Aim: Evaluate the cognitive effects of a single-dose of alprazolam at multiple doses in healthy adults in a double-blind, parallel group study.
• 36 healthy adults received a single dose of either: (A) 0.5 mg (t.i.d.); (B) 1 mg (t.i.d.); and/or (C) placebo (control) – 32 completed the study.
• In cohorts of 4 subjects each: adults were pseudo-randomized to one of the 3 groups – and within each cohort of 4 subjects: 3 adults were randomly assigned to receive active treatment and 1 to receive placebo.
• Measures: Psychomotor function, visual attention, working memory, planning and learning (CogState battery & GMLT).

What were the results?

Alprazolam (0.5 mg): Significant deterioration in performance was observed for speed of performance on identification and matching tasks only.

Alprazolam (1 mg): Significant declines in performance observed for speed of performance on: detection, identification, matching, and working memory tasks AND for the accuracy of performance on: working memory, sorting, and learning tasks AND for the number of correct moves per second on the spatial working memory/problem solving task.

Placebo: No statistically significant change from baseline for any of the performance measures.

The magnitude of cognitive changes in the 3 conditions (0.5 mg vs. 1 mg vs. placebo) was compared and expressed as a percentage.

>10% magnitude of change (1 mg alprazolam):

1. Number of correct moves per second on the problem solving and spatial working memory task.
2. Measures of accuracy of performance on the sorting task.
3. Accuracy of performance on the learning task.
4. Accuracy of performance on the working memory task.

Largest change from baseline was less than 3% for speed measures (1 mg alprazolam).

Greatest effect sizes in the 1.0 mg alprazolam condition were observed for speed of performance on the identification and detection tasks.

Magnitude of change was equivalent to one standard deviation.

Magnitude of change on performance accuracy, working memory, spatial working memory, monitoring and matching tasks was equivalent to ~0.5 standard deviation.

• The most severe impairment was in simple attentional functions – occurring with both 0.5 mg and 1 mg doses.
• 1 mg alprazolam impaired simple attention AND all other aspects of cognitive performance.
• 5 mg alprazolam impairment was limited to simple attentional functions.

Limitations: Small sample size; single-dose study; low dosages (0.5 mg & 1 mg).

Effects of alprazolam on driving ability, memory functioning, psychomotor performance (2002) (R)

Verster et al.

• Aim: Evaluate the effect of alprazolam on driving ability, memory functioning, psychomotor performance.
• Randomized, double-blinded, placebo-controlled, crossover study
• 20 healthy volunteers
• Measures: Driving test; laboratory test battery (memory scanning, continuous tracking)

What were the results?

Alprazolam impaired driving, laboratory tracking, memory functioning, and divided attention – following an acute dose (1 mg).

Absence of neuropsychologic deficits in patients receiving long-term treatment with alprazolam XR for panic disorder (2001) (R)

Gladsjo et al.: “These findings call into question the assumption that long-term benzodiazepine therapy produces significant neuropsychologic deficit in patients with diagnosed anxiety disorders.”

• Aim: Evaluate the impact of long-term alprazolam (XR) on neuropsychological function.
• 38 patients with panic disorder were assigned at random to receive: alprazolam XR (4 mg/day) vs. placebo – for 6 weeks.
• Measures: Neuropsychologic function (attention, executive functioning, psychomotor speed, visual memory, verbal memory, reaction time, etc.) – at baseline & after 6 weeks.

What were the results?

• Both alprazolam (XR) and placebo users exhibited statistically significant improvement from baseline to 6-week assessments on measures of: attention; executive function; psychomotor speed; and visual memory – attributable to a practice/retest effect.
• No significant changes were observed in measures of: learning; verbal memory; or reaction time.
• Neither group exhibited decline in any aspect of neuropsychologic/cognitive function at 6-week testing relative to baseline.

Acute & chronic performance effects of alprazolam and lorazepam in elderly (1998) (R)

Pomara et al.

• Aim: Examine the performance effects of benzodiazepines, at high and low doses, over a 3-week period – in elderly patients.
• Double-blind, placebo-controlled, parallel group study
• Measures: Cognitive battery

What were the results?

• Acute doses of alprazolam (at low and high doses) significantly impaired critical flicker fusion threshold (CFF).
• Chronic treatment with high-dose alprazolam increased intrusions and self-rated sedation.
• Single-dose rechallenge after chronic treatment was associated with significantly less impairment than the initial challenge in memory tasks but not discriminant reaction time tasks.
• For most memory measures, tolerance was only partial – rechallenge caused significant impairment relative to placebo.

Alprazolam 0.125 mg twice a day improves aspects of psychometric performance in healthy volunteers (1998) (R)

Bourin et al.

• Aim: Evaluate the effects of alprazolam (0.125 mg, b.i.d.) on cognitive and performance tasks.
• Randomized, double-blind, independent-group design
• Subjects received placebo for 3 days followed by 14 days of treatment with either: alprazolam (N = 32) or placebo (N = 32)
• Measures: Psychometric battery (D0, D3, D7, D10, D14)

What were the results?

• Alprazolam users exhibited poorer performance on cognitive tests (pictures, digit-symbol substitution, choice reaction time) except for the CFF (critical flicker fusion) component – at Day 3 (D3).
• Interestingly, alprazolam users exhibited significant improvement in performance (except recognition reaction time) at Day 7 (D7), Day 10 (D10), and Day 14 (D14) – relative to the control group.
• This study shows that low-dose alprazolam produces small improvements in some aspects of psychomotor/cognitive functions.
• Researchers suggest that training effects, tolerance effect (to alprazolam), anxiolytic effect, changes in receptor function/number may explain the performance enhancement.

Comparison of the spectrum of cognitive effects of alprazolam & adinazolam after single doses in healthy subjects (1995) (R)

Fleishaker et al.: “Results suggest that the sedative and memory effects of these benzodiazepines may not be closely related and suggest that adinazolam has somewhat of a different spectrum of cognitive effects relative to alprazolam.”

• Aim: Evaluate and compare the effects of alprazolam and adinazolam on cognition.
• Subjects: 12 healthy male volunteers.
• Single doses of: (A) alprazolam: 0.5, 1.5 mg vs. (B) adinazolam SR: 15, 45 mg vs. (C) placebo.
• Measures: Psychomotor performance (digit symbol substitution) & memory (attention/working memory, explicit memory, semantic memory, implicit memory).

What were the results?

• Alprazolam did NOT alter psychomotor performance at a low dose (0.5 mg) but significantly impaired psychomotor performance at a higher dose (1.5 mg) – at 1-hour, 3-hour, and 6-hour intervals post-administration (relative to a placebo) as evidenced by DSST scores.
• Alprazolam significantly impaired attention at a higher dose (1.5 mg) relative to both placebo and adinazolam.
• Alprazolam modestly impaired category recall at both the low-dose (0.5 mg) and high-dose (1.5 mg) – and the impairment was statistically significant.
• Alprazolam did NOT impact knowledge memory (accessing previously stored knowledge) or semantic memory at either dosing increment.
• Alprazolam impaired implicit memory (memory that is acquired and used unconsciously).

Limitations: Inequivalent comparison (potency of dosing, release type, etc.); single doses; healthy volunteers; small sample size.

Acute effects of anxiolytics suriclone & alprazolam on cognitive information processing (1995) (R)

Semlitsch et al.

• Aim: Evaluate the effect of suriclone and alprazolam on cognitive information processing.
• 15 healthy volunteers (22-35 years old)
• Double-blind, placebo-controlled, crossover study
• Single-dose of: placebo; sucrilone (0.1 mg, 0.2 mg, 0.4 mg); alprazolam (1 mg)
• Measures: Topographic mapping of event-related brain potentials (P300)

What were the results?

• Alprazolam (1 mg) reduced: N1 amplitude, P2 amplitude, P300 amplitude – and prolonged P300 latency.
• 1 mg alprazolam impaired counting performance and increased blink rate, time with eyes closed.
• Alprazolam seemed to decrease cognitive information processing capacity and prolonged stimulus evaluation time.

Cognitive effects of alprazolam in children and adolescents with anxiety/avoidance (1992) (R)

Simeon et al.

• 30 patients with overanxious or avoidant disorders – assigned to receive alprazolam or placebo for 28 days.
• Double-blind, placebo-controlled study.
• Measures: Cognition; clinical; laboratory; qualitative (EEG)

What were the results?

• In a cognitive memory search task, the placebo group showed a slowing of search rate over time during the double-blind period whereas the alprazolam group did not.
• There were no differences between alprazolam users and placebo users on cognitive measures beyond the cognitive memory search task.

Effects of buspirone & alprazolam on cognitive performance of normal elderly subjects (1991) (R)

Hart et al.: “Alprazolam had minimal effects on vigilance, psychomotor speed, and memory – on the first day of treatment and had no effects after repeated doses.”

• 60 subjects were assigned to receive: alprazolam (0.25 mg, t.i.d.); buspirone (5 mg, t.i.d.); or placebo – for a total of 14 days in a double-blind design.
• Measures: Continuous performance test; recall memory for word lists; digit-symbol substitution; retention of pictorial stimuli over 1 hour; subjective mental status ratings.
• Measures were taken ~1 hour after ingestion of medication, Day 1, and Day 14.

What were the results?

• There were essentially no significant changes in cognitive performance with alprazolam – with the exception of mild performance decrements on Day 1.
• Subjects taking alprazolam: (1) made more omission errors on the continuous performance test and copied digits more slowly and (2) recalled fewer symbol-digit items – relative to placebo.
• However, there was a lack of significant cognitive performance decline associated with repeated, longer-term alprazolam administration.

Effects of single doses of alprazolam & diazepam (alone and with ethanol) on psychomotor and cognitive performance in healthy volunteers (1990) (R)

Linnoila et al.

• Aim: Evaluate effects of alprazolam in isolation and with ethanol on psychomotor/cognitive performance.
• 10 healthy male Caucasian volunteers (ages 21-25)
• Measures: Psychomotor & cognitive performance; questionnaires; plasma concentrations

What were the results?

• Low-dose alprazolam (0.5 mg) decreased performance on an angles task at 1-hour and 4-hour intervals post-administration – and the performance impairment was exacerbated by adding ethanol.
• High-dose alprazolam (2 mg) produced long-lasting impairments on: tracking; verbal/nonverbal information processing; and memory – plus slowed reaction times.

Note: There may be additional studies examining the effect of alprazolam on cognitive function/performance that I did not find or recap.

Other relevant findings…

Kay et al. (2012): Alprazolam (1 mg) produced significant impairment in all endpoints versus placebo. (Computer-based cognitive assessments and Rey Auditory Verbal Learning Test) in healthy older adults (65-85 years). (R)

Kilic et al. (1999): Reported explicit memory impairments while patients (agoraphobia/panic disorder) were taking alprazolam. (R)

O’Sullivan et al. (1994): Alprazolam patients developed more adverse reactions, one of which was “impaired memory,” – relative to placebo in patients with agoraphobia/panic disorder. (R)

Allen et al. (1991): Alprazolam (0.25-0.75 mg) produced an increase in levels of forgetting, especially on Day 5 – in normal volunteers. (R)

Aranko et al. (1985): Single doses of alprazolam (0.25) were associated with impairment on several objective skill tests – in 24 student volunteers relative to a placebo. (R)

Note: Obviously research suggests that “benzodiazepines” as a drug class impair aspects of cognition, however, I wanted to focus specifically on alprazolam (Xanax).

• Evidence suggests that there are distinct differences between benzodiazepines (e.g. alprazolam, diazepam, et al.) on cognitive function.

How Alprazolam (Xanax) causes cognitive impairment (Hypothetical mechanisms)

Evidence clearly indicates that alprazolam (Xanax) is capable of causing cognitive impairment. The hypothesized mechanisms by which this impairment occurs are discussed below.

GABA-A receptor modulation

Knowing that: (1) alprazolam functions primarily as a GABA-A receptor positive allosteric modulator and affects GABAergic transmission and (2) GABA-A receptor abnormalities can impair cognition – it’s reasonable to suspect this as a mechanism by which alprazolam impairs cognition.

• GABA-A receptors influence cognitive function via inhibitory interneuron clocking networks. (R)
• Cognitive function is sensitive to cerebral GABA concentrations in the frontal cortex. (R)
• GABA-A receptor abnormalities are associated with cognitive dysfunction. (R)
• GABA enhancement seems to worsen aspects of cognition (e.g. task switching). (R)

Glutamatergic modulation

Considering that: (1) alprazolam indirectly alters the effect of glutamate (via GABA-A receptor modulation) and (2) glutamate abnormalities are associated with cognitive deficits – it’s reasonable to suspect this as an indirect mechanism by which alprazolam impairs cognition.

• Alprazolam does NOT directly act on glutamatergic systems, however, it enhances the inhibitory effect of GABA at the GABA-A receptor which consequently reduces glutamatergic activity.
• Some researchers believe that alprazolam might cause sensitization of the glutamatergic system, such that when alprazolam dosing “wears off” – glutamatergic hyperactivation occurs which could cause cognitive impairment/damage.
• Glutamatergic neurotransmission (mediated by ionotropic & metabotropic glutamate receptors) regulates cognitive function. Dysregulation of glutamate signaling leads to neurodegeneration. (R)
• In schizophrenia, reduced glutamate levels (i.e. a hypoglutamatergic state) impairs cognitive performance. (R)
• Low brain glutamate is associated with cognitive deficits in HIV patients. (R)

Catecholamine reductions (norepinephrine & epinephrine)

Alprazolam is understood to decrease catecholamine concentrations. Reductions in catecholamine concentrations may contribute to cognitive impairment.

• Oral alprazolam (0.5 & 1 mg) significantly reduced plasma epinephrine (adrenaline) and norepinephrine (noradrenaline) concentrations in healthy men. (R)
• Alprazolam (0.5 mg, t.i.d.) significantly reduced plasma catecholamine response to exercise stress by inhibiting centrally-mediated sympathetic discharge. (R)
• Many aspects of cognition are regulated by norepinephrine projections to the forebrain originating from the locus coeruleus acting through alpha/beta adrenoreceptors. (R)
• Some research suggests that catecholamine abnormalities may trigger a cascade (compensatory hyperactivation, regional impairment, downregulated catecholamine release, neural degeneration, etc.). (R)

Other possible mechanisms…

• Blunting of sympathetic tone: Alprazolam appears to inhibit sympathetic tone (activation of the SNS). Excessive parasympathetic tone and/or lack of sympathetic activity decreases arousal and stimulatory hormone/neurotransmitter release – and this could impair cognition.
• Serotonin & dopamine: Alprazolam is understood to influence both serotonergic and dopaminergic systems within the brain. Alterations in serotonin and/or dopamine systems might negatively impact cognition.
• Stress hormone reduction: Alprazolam decreases concentrations of various stress hormones like cortisol. These hormones, in appropriate amounts, probably promote healthy cognition. When stress hormones are too low – cognition becomes impaired.

Note: There may be other mechanisms by which alprazolam (Xanax) induces cognitive impairment that were not discussed above.

Alprazolam-induced cognitive impairment vs. effect of time

Below is my hypothesis regarding cognitive impairment resulting from alprazolam while considering the effect of time (days, weeks, months, years, etc.).

Short-term (Single dose, days, weeks)

Single-dose (acute) administration of alprazolam (Xanax) produces significant cognitive impairment – in part due to the fact that the body is not yet adapted/tolerant to its effect.

Using alprazolam (Xanax) for a period of several days generally produces significant cognitive impairment because one’s physiology has not appreciably adapted to its effect.

There is some evidence to suggest that cognitive function may significantly improve relative to initial decline (from single-dosing or several days of use) – within 1-2 weeks of administration (and this is still a relatively “short-term” of use).

Moderate-term (weeks to months)

Tolerance to alprazolam (Xanax) is relatively fast onset such that moderate-term use (e.g. weeks to months) is accompanied by physiological adaptation and partial tolerance.

The partial tolerance is associated with changes in: receptor densities (upregulation/downregulation); neurotransmission (synthesis/signaling); neural pathways; and possibly metabolism (CYP450) and/or epigenetic expression.

Due to onset of “partial tolerance” the severities/magnitudes of cognitive impairment with moderate-term alprazolam use may be lesser than after an acute dose.

This is supported by numerous studies in which cognitive impairment occurred on Day 1 of alprazolam use – but not on Day 7 or Day 14.

This makes some logical sense when considering the side effect of “drowsiness” diminishes significantly after ~1-2 weeks of regular use for most individuals.

Additionally, many report robust relief from anxiety symptoms at this time. Since anxiety can impair aspects of cognition, the reduction in anxiety after ~2 weeks of alprazolam may enhance certain cognitive domains.

Moderate-term alprazolam use may be associated with the least cognitive impairment relative to short-term and long-term use for a multitude of reasons: (1) partial tolerance (receptor density/neurotransmitter fluctuations); (2) no increase in dosing; (3) no significant rewiring (neural connectivity changes); (4) anxiety reduction; etc.

Long-term (months to years)

Exacerbation of cognitive deficits (Possibility #1)

Long-term alprazolam use may be associated with significant cognitive impairment in some users (perhaps even to a greater extent than short-term and moderate-term use).

Why? Long-term administration of alprazolam might involve: (1) dosage increases (over time due to tolerance); (2) more pronounced neural connectivity changes (rewiring); and/or (3) greater shift in neurotransmitter levels/receptors.

It’s possible that the chronic, long-term use of alprazolam with dosage increases over time will trigger epigenetic changes that promote or accelerate preexisting cognitive decline/impairment.

In other words, there may be a “cumulative” cognitive impairment accrued with continuous long-term dosing that is more substantial and/or of greater permanence than is observed with short-term and moderate-term dosing.

Milder cognitive deficits (Possibility #2)

Long-term alprazolam use might be associated with less significant cognitive impairment in some cases than short-term and moderate-term use.

How? Long-term administration of alprazolam might involve: (1) zero dosage increases; (2) greater physiological tolerance (pharmacokinetically & pharmacodynamically); (3) no significant connectivity or gene expression changes; (4) less drowsiness; and/or (5) continued anxiety relief.

Obviously if someone uses alprazolam long-term but doesn’t increase their dose, their level of physiological tolerance to that particular dose will be high – and such CNS depression and drowsiness should be less severe than they were in the short-term.

Research suggests that the side effect of drowsiness and subsequent risk of motor vehicle accidents (MVAs) drops substantially after ~1 month of regular benzodiazepine administration relative to shorter-term administration. (R)

Assuming less CNS depression and drowsiness than with short-term usage, long-term usage of alprazolam might be less likely to affect cognition – and may even allow cognition to normalize to some extent (such that cognitive deficits are no longer significant).

Moreover, if alprazolam continues to facilitate an anxiolytic effect (anxiety reduction) in spite of the partial tolerance – then some aspects of cognition could theoretically improve (as severe anxiety itself can impair cognition).

Withdrawal

It shouldn’t be very surprising that cognitive deficits can occur while using alprazolam AND during alprazolam withdrawal.

Uhlenhuth et al. (2006) report that psychomotor deficits persisting beyond dose stabilization occur during alprazolam withdrawal. (R)

Cognitive deficits in alprazolam withdrawal are likely due to a combination of changes in: neural connectivity; neurotransmitter concentrations/receptor densities; brain waves; brain region activation; autonomic nervous system activation; etc. – coupled with resurgence of the preexisting condition(s) for which alprazolam was used to treat.

Does Xanax (alprazolam) ever enhance cognition? (Nootropic potential)

It is possible that a subset of individuals will experience cognitive enhancement from administration of alprazolam.

Preliminary (albeit low-quality) evidence to support this idea can be derived from a 2022 survey by Troof (involving 1981 subjects); Xanax ranked relatively highly as a cognitive enhancer (i.e. “nootropic”). (R)

This makes logical sense when considering: (A) Yerkes-Dodson law (over & underarousal are suboptimal for cognition) and (B) that a non-insignificant percentage of the population is likely in a state hyperarousal or over-arousal.

In theory, Xanax (alprazolam) should improve cognition among individuals who are routinely locked into states of hyperarousal/over-arousal by reducing arousal to a more optimal level.

Those with hyperarousal, high anxiety, etc. – probably experience excessive: sympathetic tone; stimulatory neurotransmission; activation of fear/anxiety centers in the brain; high-frequency brain waves; stress hormone secretion – all of which are suboptimal for performance.

Xanax (alprazolam) will theoretically increase: parasympathetic tone; inhibitory transmission; activation of relaxation centers in the brain; lower-frequency brain waves; anxiolytic hormone secretion – all of which may help performance in a subset of persons.

However, at this time, there is zero high-quality research to support the idea that alprazolam (Xanax) is capable of enhancing any specific domain of cognitive function/performance relative to a placebo.

Soria et al. (2019) found that ~12.9% (7/54) of patients with anxiety disorders/chronic stress had verbal fluency impairments – and this figure dropped to 6% (3/50) after a 12-week course of alprazolam (1.5-3 mg/day), however, the improvement was deemed an effect of age rather than alprazolam.

Bourin et al. (1998) found that alprazolam (0.125 mg, b.i.d.) initially impaired cognition but then cognition improved between Day 7-14 with the exception of reaction time. However, this was “improvement” from an acutely-mediated alprazolam-induced deficit – which is not a true “enhancement.”

Factors that influence magnitude of cognitive impairment with alprazolam

1. Dosage: Evidence suggests that cognitive impairment from alprazolam is dose-dependent. Higher doses generate more significant impairment than lower doses.
2. Frequency of use: Cognitive impairment may worsen over time with frequent use. However, infrequent use is associated with greater impairment than frequent use (assuming equal dosage) due to lack of physiological tolerance.
3. Duration of regular use: Short-term use may produce pronounced impairment due to lack of physiological adaptation. Long-term use may produce more severe impairment than short-term use in some cases due to increasing the dosage and compensatory physiological reactions. However, long-term use might not impair cognition as much as short-term use if the dosage isn’t increased (due to tolerance).
4. Level of arousal: Level of arousal when using alprazolam might determine whether it causes significant cognitive impairment. High arousal or hyperarousal (observed in anxiety disorders) may be associated with less/no cognitive impairment relative to normative arousal – based on the Yerkes-Dodson law e.g. high arousal + alprazolam = semi-normalization of arousal (associated with good cognition) vs. normative arousal + alprazolam = below-average arousal (impaired cognition).
5. Format: Alprazolam IR (immediate-release) produces more significant cognitive impairment than alprazolam XR (extended-release) due to higher peak plasma levels resulting from pharmacokinetics.

Other factors that may be important…

• Age: Older adults may be more susceptible to significant cognitive impairment from alprazolam due to: age-related brain/cognitive changes; use of other medications; age-related medical conditions; etc.
• Use of other substances: May increase or decrease risk of cognitive impairment depending on the specific substances. CNS depressants (e.g. alcohol) are likely to increase risk of impairment.
• Preexisting brain/cognitive function: Preexisting abnormalities in brain function/cognition may increase risk of cognitive deficits with alprazolam.
• Time of day administered: Circadian rhythms may influence degree of impairment with alprazolam.
• Body size (relative to dose): Body size (height/weight & fat %) relative to dosage may influence its potency.
• Genetics & epigenetics: Some may be more susceptible to cognitive deficits based on genetic/epigenetic expression.
• Organ function & metabolism: Liver and kidney function – and metabolism/excretion rates of alprazolam may influence its potency and duration of action and thus its total impact on cognition.
• General health & medical conditions: One’s health and preexisting medical conditions may interact with alprazolam in certain ways as to increase or decrease risk of alprazolam-related cognitive impairment.

My experience: Cognitive deficits from Xanax (alprazolam)

I use alprazolam (0.125-0.25 mg) intermittently to help with sleep maintenance insomnia and/or terminal insomnia.

It works extremely well for this condition – cooling my body down within ~30 minutes and making me sleepy such that I sleep ~2-3 extra hours.

When I initially began using alprazolam, I noticed some mild cognitive deficits – but my work performance (distinct from cognitive performance) actually improved probably for 2 reasons: (1) more sleep/better quality sleep and (2) lower anxiety (relative to a state of hyperarousal).

I would always feel “groggy” after waking with alprazolam and the grogginess/brain fog would persist for ~4-6 hours post waking (so up to ~8 hours after administration) – probably as some sort of a residual neurochemistry modulation that persists even after it’s no longer working.

My cognition wasn’t optimal – but I ignored it and found that I could still perform cognitively-demanding tasks fairly well even after taking low-dose alprazolam.

After several months of semi-regular alprazolam use (never increasing the dosage) – I subjectively perceive more pronounced cognitive deficits.

This aligns with research suggesting that even short-term use of benzodiazepines can impair aspects of cognition long after use.

How severe are these cognitive deficits? Probably a 5/10 – if I had to rank severity relative to pre-alprazolam.

However, I cannot be 100% certain that all of the cognitive deficits are from alprazolam. They could be partially due to: modification of supplement regimen; changes in sleep quality; changes in stress level; cessation of stimulants (including caffeine for 6+ months); etc.

Methods to counteract or recover from Xanax (alprazolam) related cognitive impairment…

Stop using Xanax (alprazolam)

The best way to avoid cognitive impairment resulting from Xanax (alprazolam) is to refrain from using it.

If you use Xanax regularly, do NOT quit abruptly (i.e. cold turkey) as withdrawal reactions could be severe/serious.

Work with a medical doctor if necessary to gradually taper down the dosage before complete discontinuation.

Minimal effective dose & frequency of admin

If you need Xanax (alprazolam) for whatever reason(s) because nothing else is capable of delivering a similar degree of therapeutic effect, it is recommended to use the minimal effective: (A) dose and (B) frequency of administration.

In other words, don’t take more Xanax than is necessary (dosage wise) and don’t administer Xanax more frequently than absolutely necessary to derive a therapeutic effect.

Although frequent use of alprazolam likely causes less “acute” (i.e. short-term) cognitive impairment after each dose due to partial tolerance – cognition should normalize more efficiently between doses for infrequent users relative to frequent users.

It’s also more likely that an infrequent administration schedule won’t produce permanent and/or cumulative cognitive deterioration (such as could be more likely with frequent use).

Supplements

Verify safety with a medical doctor and/or pharmacist before using any dietary supplements.

Note: The supplements below include affiliate links to products that I’d personally consider if my cognition was impaired from Xanax (alprazolam).

Magnesium threonate: I’ve personally found this supplement to enhance aspects of memory. Functions as an NMDA receptor antagonist which may counteract glutamatergic sensitivity resulting from Xanax. (R)

Magnesium glycinate: Another form of magnesium that functions as an NMDA receptor antagonist (to some extent) and may help counteract excessive glutamate levels following regular Xanax use.

Zinc: May also help attenuate glutamatergic hyperfunctioning during withdrawal from alprazolam (or in between doses). An appropriately-dosed zinc supplement may be beneficial, but avoid excessive zinc as this could be problematic (copper levels, immunity, HDL, etc.).

Multivitamin: Ensure that there are no glaring deficiencies in any essential micronutrients.

High-dose omega-3 fatty acids: Known to reduce inflammation. May support production of various neurotransmitters while enhancing cognitive function.

Creatine monohydrate: Significantly improves cognition in persons who are deficient in dietary creatine intake. May enhance cognition in those who aren’t deficient as well.

Ubiquinol: May have neuroprotective effects and enhance cognitive function for some.

Taurine: May reduce anxiety/stress and enhance aspects of focus for some individuals.

Glutathione: Reduces inflammation/oxidative stress – and may enhance aspects of cognition.

Probiotics: May impact cognition indirectly via the gut-brain-axis (GBA).

L-Tyrosine: Has been shown to enhance aspects of cognition under extreme stress (such as in military combat situations) – may be worth trying.

Vitamin C: Likely improves cognitive function in persons who are deficient in vitamin C. May enhance aspects of cognition even in persons with normal vitamin C status.

Vitamin D: Low vitamin D may increase risk of cognitive impairment. Supplementation with vitamin D to achieve a healthy level may improve cognition and mood.

Melatonin: Has chronobiotic effects when administered at appropriate times (e.g. nighttime ~9-10 PM) and may enhance aspects of cognition.

Caffeine: This is a well-known cognitive enhancer that may counteract some of the cognitive impairment resulting from alprazolam. Understand that it may also increase anxiety and/or interfere with sleep. Not recommended until several months post-alprazoalm withdrawal due to potential induction/amplificaiton of glutamate sensitivity.

Lifestyle optimization

• Diet: Calorically-appropriate. Macronutrient adequacy & micronutrient dense.
• Exercise: Regularly for the sake of brain function, body composition, hormones.
• Circadian rhythm: Maintain a healthy circadian rhythm (sleep when dark, wake when light).
• Sleep: Sufficient in both duration and quality. Lack of quality sleep will exacerbate cognitive deficits.
• Social: Loneliness and social isolation can independently impair aspects of cognition. Try to stay social if possible for the sake of cognitive function.
• Cognitive challenges: There’s no strong evidence that cognitive challenges (e.g. brain training) prevents cognitive decline, but they could and there’s little downside to trying. (R)
• Stress management: Excessive stress is understood to impair cognition.

How long to recover from cognitive impairment after alprazolam withdrawal?

Unclear. Research suggests that the duration of time necessary to achieve cognitive recovery (reversal of alprazolam-induced deficits) may require a significant amount of time.

Uhlenhuth et al. (2006) found that speed on the digit symbol substitution task improved on the first day after abrupt discontinuation of alprazolam (following 8 & 9 weeks of fixed-dose treatment). (R)

Barker et al. (2004) suggest that there is evidence to suggest full cognitive recovery does NOT occur for at least 6 months after benzodiazepine cessation – and claims that some cognitive damage may be permanent. (R)

Curran et al. (1994) noted that a period of alprazolam use for 8 weeks (among patients with panic disorder) followed by complete discontinuation – was associated with cognitive impairment on word recall tasks ~24 weeks after having fully stopped alprazolam. (R)

Kilic et al. (1999) followed the same group of patients as Curran et al. and found that explicit memory impairments from alprazolam occurred weeks after withdrawal – but these did not persist ~3.5 years later (suggesting that complete cognitive recovery can be achieved but may require longer than one desires). (R)

Rickels et al. (1999) report cognitive function improve for many after discontinuation of benzodiazepine intake. (R)

For this reason, it is likely necessary to: (1) be patient; (2) live a healthy lifestyle; and (3) consider using various drugs/supplements to correct residual/lingering cognitive deficits after alprazolam cessation.

How did Xanax (alprazolam) affect your cognition?

If you noticed a significant effect of Xanax (alprazolam) on cognitive function, share your experience below. Include information in your comment such as:

• Dosage of Xanax
• Cumulative duration of use
• Frequency/regularity of use
• Administration of other substances (?)
• Different cognitive effects short-term vs. long-term? (e.g. enhancement in short-term, decline in long-term)
• Which aspects of cognition were affected?
• Do you think alprazolam is most to blame for your cognitive decline/deterioration?
• Have you considered that other factors such as: age; medical conditions; other medications, supplements, substances (e.g. alcohol); body fat %; insufficient exercise; and/or social isolation – might’ve contributed to some extent?

Note: Spent way more time than intended on this article. Was initially expecting short/quick but got carried away reading each specific study then comparing all of the findings.