CLINICAL TRIALS PROFILE FOR TACRINE HYDROCHLORIDE

All Clinical Trials for tacrine hydrochloride

Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
NCT00006187 ↗	The Safety and Efficacy of an Investigational Drug in Delaying the Progression of Alzheimer's Disease	Terminated	Merck Sharp & Dohme Corp.	Phase 3	1969-12-31	This is a 15-month study with two phases. During the first 12-month phase of this study, patients will be randomly assigned to receive either active study drug or placebo (approximately half of all patients will be on active study drug, the other half on placebo). The second phase is a 3-month randomized withdrawal period. For this phase approximately 10% of the patients will remain on the active drug.
NCT00190021 ↗	Donepezil Treatment of Psychotic Symptoms in Dementia Patients	Unknown status	Beersheva Mental Health Center	Phase 3	1969-12-31	Conventional psychotropic medications may be used to treat behavioral disturbances and psychotic symptoms in patients with dementia and they are the drugs of choice for treating delusions and hallucinations. However the sensitivity to side effects in these patients often restricts the use of these agents (2, 3). Although, atypical antipsychotics have some advantages compared with conventional neuroleptics, they also are associated with side effects (5, 6). Cholinesterase inhibitors (ChEIs) enhance neuronal transmission by increasing the availability of acetylcholine in muscarinic and nicotinic receptors. According to findings of some researchers ChEIs have psychotropic effects and may play an important role in controlling neuropsychiatric and behavioral disturbances in patients with Alzheimer's disease (7-10). These agents may also contribute to the management of other disorders with cholinergic system abnormalities and neuropsychiatric symptoms such as visual hallucinations (11). Donepezil is a piperidine-based reversible, noncompetitive ChEI, which is indicated in the management of patients with Alzheimer's disease of mild to moderate severity (12-14). Preliminary observations suggest the possible value of ChEIs in the amelioration of psychotic symptoms in patients with dementia of the Alzheimer's type (DAT), dementia with Lewy bodies and patients suffering from Parkinson's disease (11-18). The results of our study (18) indicate that the addition of donepezil to perphenazine resulted in qualitatively superior clinical gains compared to higher doses of neuroleptic therapy without donepezil. The finding of the pilot study although impressive, stem from data regarding a rather small sample. The present (second) phase of the study will include a larger sample of patients. We now intend to examine 80 inpatients, aged 65-90 years old, suffering from DAT.
NCT00551161 ↗	Magnetic Resonance Spectroscopy Study of Memantine in Alzheimer's Disease	Completed	Forest Laboratories	Phase 4	2007-08-01	We are studying subjects with mild to moderate Alzheimer's disease who have been on a stable dose of any cholinesterase inhibitor [donepezil (Aricept), rivastigmine (Exelon), or galantamine (Razadyne)] for at least 3 months, and have not previously taken memantine (Namenda). This is an open-label study, with magnetic resonance spectroscopy (MRS) as the primary outcome measure, along with neuropsychological testing, and optional lumbar puncture, evaluating patients on their stable dose of a cholinesterase inhibitor over 24 weeks, followed by another 24 weeks on memantine in combination with stable dose of cholinesterase inhibitor. The purpose of this study is to characterize the progression of disease using MRS, cerebrospinal fluid (CSF) biomarkers, and cognitive outcome measures, and to determine whether changes in cognitive function on neuropsychological testing are correlated to changes in MR spectroscopic and/or CSF biomarkers.
NCT00551161 ↗	Magnetic Resonance Spectroscopy Study of Memantine in Alzheimer's Disease	Completed	Northwell Health	Phase 4	2007-08-01	We are studying subjects with mild to moderate Alzheimer's disease who have been on a stable dose of any cholinesterase inhibitor [donepezil (Aricept), rivastigmine (Exelon), or galantamine (Razadyne)] for at least 3 months, and have not previously taken memantine (Namenda). This is an open-label study, with magnetic resonance spectroscopy (MRS) as the primary outcome measure, along with neuropsychological testing, and optional lumbar puncture, evaluating patients on their stable dose of a cholinesterase inhibitor over 24 weeks, followed by another 24 weeks on memantine in combination with stable dose of cholinesterase inhibitor. The purpose of this study is to characterize the progression of disease using MRS, cerebrospinal fluid (CSF) biomarkers, and cognitive outcome measures, and to determine whether changes in cognitive function on neuropsychological testing are correlated to changes in MR spectroscopic and/or CSF biomarkers.
NCT01406522 ↗	Tacrine Effects on Cocaine Self-Administration and Pharmacokinetics	Withdrawn	Midwest Biomedical Research Foundation	Phase 2	2012-10-01	No medications are currently available for treatment of psychostimulant addiction, a compulsive preoccupation with use of cocaine and related compounds. Tacrine, a medication that is currently prescribed for Alzheimer's disease, can decrease the amount of cocaine injections that laboratory animals choose to inject by vein. This project will determine if tacrine can also decrease cocaine-motivated behavior for human subjects in a laboratory setting.
NCT01495195 ↗	Combined Donepezil and Selegiline Effects on Cocaine-Reinforced Behavior	Completed	National Institute on Drug Abuse (NIDA)	Phase 2	2012-02-01	No medications are currently available for treatment of psychostimulant addiction, a compulsive preoccupation with use of cocaine and related compounds. Donepezil is a medication that is currently prescribed for Alzheimer's disease, and selegiline is a medication used for treatment of Parkinson's Disease. Both of these medications can decrease the amount of cocaine injections that laboratory animals choose to inject by vein. This project will determine if combined treatment with donepezil and selegiline can also decrease cocaine-motivated behavior for human subjects in a laboratory setting.
NCT01495195 ↗	Combined Donepezil and Selegiline Effects on Cocaine-Reinforced Behavior	Completed	Midwest Biomedical Research Foundation	Phase 2	2012-02-01	No medications are currently available for treatment of psychostimulant addiction, a compulsive preoccupation with use of cocaine and related compounds. Donepezil is a medication that is currently prescribed for Alzheimer's disease, and selegiline is a medication used for treatment of Parkinson's Disease. Both of these medications can decrease the amount of cocaine injections that laboratory animals choose to inject by vein. This project will determine if combined treatment with donepezil and selegiline can also decrease cocaine-motivated behavior for human subjects in a laboratory setting.

Clinical Trial Conditions for tacrine hydrochloride

Condition Name

Condition Name for tacrine hydrochloride
Intervention	Trials
Alzheimer Disease	2
Cocaine Use Disorders	1
Dementia of Alzheimer Type	1
Cocaine Dependence	1

Condition MeSH

Condition MeSH for tacrine hydrochloride
Intervention	Trials
Alzheimer Disease	3
Cocaine-Related Disorders	1
Dementia	1

Clinical Trial Locations for tacrine hydrochloride

Trials by Country

Trials by Country for tacrine hydrochloride
Location	Trials
United States	19
Israel	1

Trials by US State

Trials by US State for tacrine hydrochloride
Location	Trials
Missouri	2
New York	2
Wisconsin	1
Washington	1
Utah	1

Clinical Trial Progress for tacrine hydrochloride

Clinical Trial Phase

Clinical Trial Phase for tacrine hydrochloride
Clinical Trial Phase	Trials
Phase 4	1
Phase 3	2
Phase 2	2

Clinical Trial Status

Clinical Trial Status for tacrine hydrochloride
Clinical Trial Phase	Trials
Completed	2
Terminated	1
Unknown status	1

Clinical Trial Sponsors for tacrine hydrochloride

Sponsor Name

Sponsor Name for tacrine hydrochloride
Sponsor	Trials
Midwest Biomedical Research Foundation	2
National Institute on Drug Abuse (NIDA)	1
Merck Sharp & Dohme Corp.	1

Sponsor Type

Sponsor Type for tacrine hydrochloride
Sponsor	Trials
Other	4
Industry	2
NIH	1

Tacrine Hydrochloride: Clinical Trials Update, Market Analysis, and Future Projections

Last updated: November 1, 2025

---

Introduction

Tacrine hydrochloride, historically recognized as the first approved acetylcholinesterase inhibitor for Alzheimer’s disease (AD), holds a significant place in neuropharmacology. While its commercial use has waned due to safety concerns and the advent of more effective agents, ongoing research and market dynamics continue to influence its positioning. This report provides an in-depth update on clinical trials, conducts a comprehensive market analysis, and projects future opportunities for tacrine hydrochloride.

---

Clinical Trials Landscape

1. Historical Context and Early Approvals
Tacrine hydrochloride was approved by the U.S. Food and Drug Administration (FDA) in 1993 for the treatment of mild to moderate Alzheimer’s disease. Its mechanism involves increasing central cholinergic transmission by inhibiting acetylcholinesterase, thereby improving cognitive symptoms [[1]].

2. Clinical Limitations and Safety Concerns
Progressively, the clinical use declined owing to hepatotoxicity concerns. Approximately 20% of patients experienced elevated liver enzymes leading to discontinuation. Consequently, the drug was withdrawn from many markets, particularly in North America, by the early 2000s.

3. Current Clinical Trials and Research

• Repurposing and Combination Strategies: Several small-scale investigations explore tacrine’s potential in combination therapies or alternative indications.
• Novel Formulations: Attempts to develop targeted, lower-dose formulations aim to minimize toxicity [[2]].
• Regenerative Medicine Fusion: Some early-stage studies are examining tacrine derivatives and analogs with improved safety profiles.

Despite the limited number of active clinical trials, recent databases indicate minimal ongoing research. Notably:

• Phase I/II Initiatives: A few experimental compounds derived from tacrine are under investigation for neurodegenerative diseases beyond AD, such as Parkinson's disease and vascular dementia.
• Biomarker Research: Explorations focus on assessing predictive responses to cholinesterase inhibitors, including tacrine-based variants.

4. Regulatory Status and Future Trials
No recent pivotal trials involving tacrine hydrochloride pristine formulations are registered on ClinicalTrials.gov. However, the investigative focus has shifted toward hybrid molecules—combining tacrine’s acetylcholinesterase inhibition with neuroprotective or anti-inflammatory agents—to enhance efficacy and toxicity profiles [[3]].

---

Market Analysis

1. Historical Market Dynamics
Tacrine hydrochloride was among the earliest pharmacotherapies targeting AD, with peak sales estimated at over $100 million annually in the late 1990s globally. However, safety issues rapidly curtailed its market penetration [[4]].

2. Current Market Status

• Market Exit: Major pharmaceutical firms withdrew tacrine due to adverse effects and superior alternatives like donepezil, rivastigmine, and galantamine.
• Niche Applications: Limited research suggests minimal niche application in experimental or geriatric settings, but commercial use remains negligible.

3. Competitive Landscape
The Alzheimer's therapeutics market is now dominated by cholinesterase inhibitors (donepezil, rivastigmine) and NMDA receptor antagonists (memantine). Novel agents targeting amyloid beta and tau protein pathologies, such as aducanumab and lecanemab, have gained accelerated approvals, overshadowing older cholinergic drugs [[5]].

4. Regulatory and Market Barriers

• Toxicity Profile: Hepatotoxicity remains the paramount barrier hindering re-entry into the mainstream market.
• Market Preference: A shift toward disease-modifying therapies reduces demand for symptomatic agents like tacrine.
• Patent and Pricing Dynamics: The drug’s patent status expired long ago, and generic versions lack commercial viability due to safety concerns.

5. Future Market Opportunities
Despite the unfavorable historical trajectory, specific niche markets could emerge:

• Research Tools: Tacrine derivatives could serve as valuable molecular probes in neurobiological research.
• Hybrid Molecules: Development of tetramers or conjugates combining tacrine with neuroprotective compounds might pave the way for safer, more effective treatments.

---

Projection and Future Outlook

1. Short-Term Outlook (Next 3–5 Years)

• Market absence: Tacrine hydrochloride is unlikely to regain commercial prominence without significant reformulation efforts.
• Research Focus: Emphasis on derivative compounds and analogs with better safety profiles will continue.
• Regulatory Environment: Stringent safety standards will impede revival of original compounds in their existing forms.

2. Long-Term Outlook (Beyond 5 Years)

• Potential for Hybrid Molecules: Innovative conjugates and nanocarrier systems could improve delivery and safety, opening possibilities for niche therapeutic and research applications.
• Biomarker-Driven Drug Development: Future studies may leverage the molecular insights from tacrine-based research to formulate next-generation cholinergic agents.
• Personalized Medicine: Discovery of genetic markers predicting response could tailor therapy, possibly extending the utility of tacrine derivatives.

3. Impacts of Emerging Technologies

• Nanotechnology: Nanocarrier delivery systems may mitigate toxicity and enhance CNS penetration.
• Artificial Intelligence: AI-driven drug design could enable the development of tacrine analogs with minimized adverse effects, reinvigorating interest.

---

Key Takeaways

• Tacrine hydrochloride’s initial success was marred by safety issues, leading to market withdrawal and minimal ongoing clinical trials.
• Contemporary research focuses on derivates and conjugates attempting to outperform original formulations while maintaining safety and efficacy.
• The global market for cholinesterase inhibitors is dominated by newer, safer agents, making tacrine’s re-emergence unlikely without substantial reformulation.
• Future opportunities chiefly lie in research tools, hybrid molecules, and innovative delivery systems rather than standard therapeutic indications.
• Advancements in nanotechnology and AI could facilitate the development of improved tacrine-based compounds, potentially renewing interest in its pharmacology.

---

FAQs

1. Why was tacrine hydrochloride withdrawn from the market?
Because of hepatotoxicity concerns, with approximately 20% of patients experiencing liver enzyme elevations, leading to safety-related discontinuations.

2. Are there any ongoing clinical trials involving tacrine hydrochloride?
Currently, no significant phase III or pivotal trials are active. Research is mainly focused on derivatives, analogs, or hybrid compounds.

3. Could tacrine hydrochloride make a clinical comeback?
Unlikely in its original form due to safety issues. Future prospects depend on developing safer formulations or conjugations that retain efficacy while reducing toxicity.

4. What are the main competitors to tacrine in Alzheimer’s disease?
Donepezil, rivastigmine, and galantamine—a class of safer, approved cholinesterase inhibitors with better tolerability profiles.

5. What is the future of tacrine derivatives?
Potential exists for hybrid compounds or nanoparticle delivery systems that could mitigate toxicity, opening avenues for research and niche applications.

---

References

[1] Birks, J. (2006). Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database of Systematic Reviews, (1).
[2] Danysz, W., & Szyndler, M. (2010). New strategies for management of Alzheimer’s disease: hybrid molecules based on tacrine. Pharmacological Reports, 62(5), 943-951.
[3] Zhang, Q., et al. (2018). Novel Tacrine Derivatives with Improved Safety Profiles: Synthesis and Biological Evaluation. Bioorganic & Medicinal Chemistry Letters, 28(10), 1630-1634.
[4] Berson, A., et al. (2000). Market and therapeutic development of cholinesterase inhibitors. Drugs of the Future, 25(4), 323-332.
[5] Katz, M. J., et al. (2020). Innovation in Alzheimer’s Disease: From Blood Biomarkers to Disease-Modifying Therapies. The Journal of Clinical Investigation, 130(4), 1620–1624.