Xanax Alternative? New Anxiety Drug Without Sedation in Trials

Background: Why alternatives to Xanax (alprazolam) are needed

Xanax (alprazolam) is a benzodiazepine. It acts by enhancing GABA-A (gamma-aminobutyric acid) inhibitory neurotransmission, producing anxiolysis, sedation, muscle relaxation, and anticonvulsant effects. But the very properties that make benzodiazepines effective—rapid onset, central GABA modulation—also bring problems: sedation, cognitive slowing, tolerance, dependence, withdrawal, risk of falls (especially in older adults), and potential for misuse.

Because of these risks, clinicians and researchers have long sought alternative anxiolytics that retain efficacy but with less sedation, lower abuse potential, and better safety for longer-term use.

Historically, many non-benzodiazepine options exist (SSRIs, SNRIs, buspirone, propranolol, hydroxyzine, etc.), but most of these are slower in onset (weeks) or limited in effect on acute anxiety, or still carry side effects. Recent research is now exploring entirely new molecular targets, “psychoplastogens,” receptor modulators, and more selective approaches to uncouple anxiolysis from sedation. Below I review some of the most promising candidates or approaches in trials or preclinical stages.

Emerging or Experimental Approaches / Drugs

Soclenicant (BNC210 / IW-2143 / “α7-nAChR negative allosteric modulator”)

One of the better-known experimental compounds is Soclenicant (developmental code BNC210, also IW-2143). Soclenicant acts as a negative allosteric modulator (NAM) of the α7 nicotinic acetylcholine receptor (α7-nAChR). https://en.wikipedia.org

• The rationale: α7 nicotinic receptors are implicated in modulating stress responses, cholinergic transmission, and circuits of uncertainty and arousal. By dampening over-excitation in these circuits (rather than globally enhancing inhibition like benzodiazepines do), the goal is to reduce anxiety without suppressing alertness.https://www.maudsleybrc
• In early human trials (small pilot studies in people with generalized anxiety disorder [GAD]), Soclenicant showed reductions in anxiety metrics during stress tasks, with reportedly minimal sedation, memory impairment, or motor impairment.https://www.maudsleybrc
• Current status: As of late 2024, Soclenicant is in Phase 3 trials for anxiety disorders, and in Phase 2 for agitation and PTSD.https://en.wikipedia.org
• Strengths & challenges: The main strength is that it seems to “decouple” anxiolysis from sedation in early data. However, large-scale efficacy, safety over long-term use, dose optimization, and side effects (e.g. cholinergic or nicotinic system effects) remain to be fully established.

Thus, Soclenicant is among the front-runner candidates for a potentially non-sedating alternative to benzodiazepines.

FKW00GA / TGW00AA (5-HT₁A receptor partial agonist / 5-HT₂A antagonist)

Another novel compound is FKW00GA (also called TGW00AA). It is a dual-acting agent: partial agonist at 5-HT₁A and antagonist (or weak antagonist) at 5-HT₂A receptors. https://en.wikipedia.org

• This mechanism is distinct from benzodiazepines; it works via serotonin receptor modulation rather than GABA.
• As of current reports, FKW00GA is in Phase 2 clinical trials for generalized anxiety disorder (GAD), social anxiety disorder, and sexual dysfunction. https://en.wikipedia.org
• Potential: Because 5-HT1A agonism is a well-known anxiolytic mechanism (e.g. buspirone acts here), combining it with 5-HT2A antagonism may increase efficacy and reduce side effects (e.g. removing pro-anxiety effects of 5-HT2A stimulation).
• Unknowns: Whether FKW00GA will truly avoid sedation or cognitive impairment, and how potent its anxiolytic effects will be relative to benzodiazepines, is not yet known in published large trials.

Psychoplastogens & Novel Neuroplasticity Agents (e.g. GM-5022, XYL-3001)

A more radical approach is to design drugs that foster beneficial neural plasticity (rewiring, synaptogenesis) rather than simply modulating inhibition or excitation acutely. These are sometimes called psychoplastogens (inspired by psychedelic-like compounds but without hallucinogenic effects).

• GM-5022: This is a non-hallucinogenic psychoplastogen under development by Gilgamesh Pharmaceuticals, intended for depressive, anxiety, and other neurologic disorders. It is currently in preclinical development (i.e. not yet in humans). https://en.wikipedia.org
• XYL-3001 (also called PSYLO-3001): This compound is a non-hallucinogenic 5-HT₂A receptor agonist (or modulator) being developed for GAD, social anxiety, and depression. As of early 2025, it is still in preclinical stages.https://en.wikipedia.org
• Rationale: The idea is that by promoting healthy connectivity and circuit resilience, these drugs may reduce baseline anxiety (or retrain circuits) and perhaps make individuals less reactive to stress, rather than simply suppressing symptoms.
• Risks/challenges: Preclinical to human translation is uncertain. Safety, dosing, off-target effects, and ensuring no hallucinations or abuse potential are big hurdles. Also, onset time may not match the rapid relief of benzodiazepines.

mGluR / Glutamate-modulating Compounds (e.g. Eglumetad / LY354740 family)

Another interesting target is the glutamatergic system, especially metabotropic glutamate receptors (mGluR2/3, group II receptors).

• Eglumetad (also called LY354740): This is a selective group II mGluR agonist. In animal models, it showed anxiolytic effects comparable to diazepam (a benzodiazepine) without the sedative or memory-impairing effects. Human trials also suggested anxiolysis with minimal sedation. https://en.wikipedia.org
• However, clinical development has been challenging: issues of bioavailability, tolerability, and translation to robust human evidence have slowed progress. For example, a prodrug (LY544344) was trialed in GAD but safety concerns (“convulsive activity” in preclinical models) forced halting. https://www.frontiersin.org
• Nonetheless, the mGluR/glutamate modulation avenue remains of interest for designing anxiolytics that don’t use GABAergic sedation.

Hydroxyzine (antihistamine) and as-needed / intermittent use

While not entirely new, hydroxyzine is a first-generation antihistamine with anxiolytic properties and relatively low dependence risk compared to benzodiazepines. It is sometimes used off-label for acute anxiety.https://www.frontiersin.org

• Advantages: Can produce anxiolysis within 15–30 minutes; no significant risk of benzodiazepine-type dependency (not a controlled substance).https://www.frontiersin.org
• Limitations: It is sedating (especially at higher doses) and tolerability for daytime use is limited. Also, the literature on its use beyond generalized anxiety disorder is limited. https://www.frontiersin.org
• Some research suggests that tolerance to its sedative effect may develop quickly (in ~7 days), which limits repeated usage.https://www.frontiersin.org
• Because hydroxyzine still causes sedation, it is not a perfect “non-sedating” alternative—but in some cases it is considered the “least bad” among acute agents with lower abuse risk.

Other agents in development / under discussion

Beyond those above, there are additional “next-generation” or second-line approaches being explored:

• Gepirone ER (a new azapirone): an extended-release azapirone with 5-HT₁A agonist action is under study for anxiety and depression.
  
• Tandospirone and other azapirones: older compounds with partial agonism at 5-HT1A, considered safer than benzodiazepines in some settings.https://www.frontiersin.org
• Selective 5-HT₆ receptor antagonists (e.g. AVN-101) have shown anxiolytic potential in animal models and were tolerable in Phase 1 trials; their utility in anxiety disorders is under investigation.https://www.frontiersin.org
• Ondansetron (a 5-HT₃ antagonist): in small trials in GAD, has shown some anxiolytic benefit, although further work is sparse.https://www.frontiersin.org
• “PanX”: a patented combination that combines a β-blocker (atenolol) with an anticholinergic (scopolamine), proposed as a non-addictive anxiety drug, but it is early stage, with limited human data.https://www.therecoveryvillage.com

Each of these has potential, but most remain in early trial phases or animal/preclinical testing.

How promising are these in practice, and what are the hurdles?

Advantages of newer approaches:

• Better separation of anxiolysis vs sedation: The main aim is to preserve wakefulness, cognition, memory, alertness while reducing excessive emotional reactivity or worry.
• Lower dependence/addiction potential: Because many of these do not act on GABA in the same way as benzodiazepines, the hope is that they will not engender tolerance or withdrawal syndromes comparable to benzos.
• Novel mechanisms, broader effects: Some also aim to promote neural resilience, reduce maladaptive circuits, or change brain plasticity (psychoplastogens), rather than just symptomatic suppression.

Key challenges and risks:

• Translational gap: Many compounds show promise in animals or small human trials, but fail in larger, controlled studies due to limited efficacy, side effects, or safety issues.
• Onset speed: One of the advantages of benzodiazepines is rapid onset (minutes). Newer drugs often have slower therapeutic onset (days to weeks), which limits their utility for acute panic episodes.
• Side effects / off-target effects: Any novel compound may cause unforeseen adverse effects, especially when modulating neurotransmitter systems less well understood (e.g. cholinergic, nicotinic, glutamatergic, plasticity circuits).
• Dose optimization and individual variability: Anxiety is heterogeneous; what works in one subgroup may not in another (GAD vs panic vs social anxiety).
• Regulatory hurdles, cost, and long development timelines: Even promising drugs may take many years before approval, and many never make it to market.

What about “right now” alternatives?

While the above focus on future/designed drugs, in current clinical practice the common alternative strategies include:

• SSRIs / SNRIs (e.g. sertraline, escitalopram, venlafaxine) — first-line for many anxiety disorders, though slow onset (weeks) and side effects (sexual dysfunction, GI upset) are limitations. 
• Buspirone — a non-benzodiazepine anxiolytic with moderate efficacy in generalized anxiety, less sedation, no dependence risk.
• Beta-blockers (e.g. propranolol) — used for somatic symptoms (tremor, palpitations) in situational anxiety (e.g. performance anxiety); less effective on cognitive worry. 
• Hydroxyzine — as noted earlier, used off-label for acute anxiety though sedation is still an issue. 
• Psychotherapy / cognitive behavioral therapy (CBT), mindfulness, lifestyle interventions — while not “drugs,” these are key supporting modalities and sometimes sufficient by themselves for mild to moderate anxiety. https://neurowellnessspa.com

These don’t perfectly match the rapid relief of Xanax, but are safer for long-term use in many patients.

Conclusion & Outlook

The quest for a “Xanax alternative” that provides potent, fast anxiety relief without sedation or dependence is one of the holy grails of psychopharmacology. The most promising candidate currently in advanced trials is Soclenicant (BNC210), which targets α7-nicotinic receptors and has shown anxiolytic effects without sedation or cognitive impairment in early data. If the Phase 3 trials succeed, it could represent a paradigm shift.

Other interesting leads include FKW00GA (a serotonin 5-HT₁A/5-HT₂A modulator) and psychoplastogens like GM-5022 or XYL-3001 that aim to remodel neural circuits rather than suppress activity. Glutamate-modulating agents like Eglumetad also remain scientifically intriguing.

However, caution is warranted: many drugs that look good in animals fail in humans; achieving rapid onset and adequate potency without side effects is very difficult. Even if a non-sedating anxiolytic reaches the market, it will need years of clinical validation, head-to-head trials with established treatments, and real-world safety monitoring.

In the meantime, patients and clinicians must rely on a combination of safer pharmacotherapies (SSRIs, buspirone, hydroxyzine in limited cases), psychotherapy, and lifestyle interventions, while being alert to the risks of benzodiazepine overuse.