Science & Pipeline

Overview

DemeRx is committed to transforming the treatment of substance use disorders through innovative science, polypharmacology, and therapeutic strategies. Central to our approach is the concept of neuroplasticity, which refers to the brain’s remarkable ability to heal itself, reorganize, and form new neural connections.

Read on to delve deeper into the science of neuroplasticity, explore DMX-1001 as our lead program for alcohol use disorder (AUD), and gain insights into the urgent need for effective treatments for this pervasive public health challenge.

The Science of Neuroplasticity

DemeRx is dedicated to leveraging the transformative potential of neuroplasticity to create groundbreaking therapeutics for the treatment and management of substance use disorders.

The adage “neurons that fire together, wire together” encapsulates the mechanism by which the brain forms and strengthens neural pathways through repetition. As the brain engages in specific tasks, these neural networks become increasingly robust, enhancing the efficiency of those processes over time. However, chronic alcohol consumption or drug use can disrupt and hijack these natural brain functions.

This disruption is particularly critical in the context of alcohol use disorder (AUD), where sustained heavy drinking can impair normal cognitive function, resulting in compromised decision-making and weakened impulse control.

Neuroplasticity manifests in two primary forms: functional and structural. Functional plasticity allows the brain to adapt by reallocating tasks from damaged areas to healthier regions, compensating for lost functions. In contrast, structural plasticity involves the physical reorganization of the brain, including the growth, strengthening or weakening of synapses—the connections between neurons—based on our experiences and behaviors, both positive and negative.

By fostering neuroplasticity, we have the potential to counteract some of the harmful effects associated with AUD, allowing the brain to rewire its reward pathways. This could help reduce cravings and compulsive behaviors that often lead to relapse, paving the way for more effective recovery strategies.

DMX-1001 (oral noribogaine)

DMX-1001, an innovative neuroplastogen developed by DemeRx, represents a groundbreaking therapeutic advancement for alcohol use disorder (AUD).

DMX-1001 targets multiple areas if the central nervous system simultaneously, allowing for a rapid intervention that effectively reduces cravings and the compulsion to drink more.

What distinguishes DMX-1001 is its unique ability to promote enduring neural connections through neuroplasticity, potentially reversing the long-term detrimental effects of AUD and lowering the risk of relapse by normalizing neurotransmitter signaling.

This innovative approach redefines the landscape of medical treatment by moving beyond traditional pharmacological strategies that often focus on single, isolated chemical imbalances in the brain.

“By specifically targeting structural neuroplasticity within the brain’s addiction circuitry, DMX-1001 aims to facilitate lasting changes that empower individuals to overcome the challenges of alcohol and drug addiction.”

Deborah Mash, PhD, CEO and Founder

Clinical and Preclinical Pipeline

DMX-1001 shows promise not only for treating alcohol addiction but also for addressing a variety of substance use disorders. As the active metabolite of ibogaine, noribogaine offers therapeutic benefits without the euphoric effects or addiction risks typically associated with conventional psychedelics.

Initial Phase 1a studies suggest that DMX-1001 boasts a favorable safety profile and effective pharmacokinetics. Preclinical research further supports its efficacy against alcohol, opioid, and cocaine addictions.

DemeRx is committed to advancing DMX-1001 through clinical trials, with a Phase 1b trial currently underway to assess its pharmacokinetics, pharmacodynamics, and safety in healthy volunteers.

Intellectual property

Patents granted:
Composition of matter
Methods of use
Combination therapies
Synthetic processes & formulations

Understanding Alcohol Use Disorder

Alcohol use disorder is a chronic brain disorder characterized by an inability to control alcohol consumption despite the negative consequences it brings to an individual’s social, occupational, and health-related life. According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA), over 29 million people in the United States are affected by AUD, making it a significant public health challenge.

AUD can lead to severe physical and mental health problems, including liver disease, cardiovascular issues, and increased risk for mental health disorders such as depression and anxiety. It also has a profound impact on families and communities, contributing to economic burdens such as reduced workforce productivity and increased healthcare costs.

Despite the large number of individuals affected, less than 5% of those with AUD currently use medication as part of their treatment. Existing FDA-approved treatments have been available for many years, but relapse rates remain high. Approximately 60% of individuals treated for AUD will relapse within six months, with rates rising to 80% within a year.

Given the complexities of AUD and the limitations of current treatment options, there is an urgent need for new therapeutic approaches.

DemeRx is committed to addressing this need through our innovative research and the development of DMX-1001, which aims to provide a more effective solution for those struggling with alcohol addiction.

By promoting neuroplasticity and targeting the underlying issues of AUD, we hope to pave the way for sustainable recovery and improved quality of life for affected individuals.

1 M

people in the U.S. with AUD

10,000

people die yearly from alcohol related causes

$10 B

is the estimated yearly economic burden of AUD

Sources:

  1. 2023 National Survey on Drug Use and Health (NSDUH) SAMHSA, Center for Behavioral Health Statistics and Quality. 2022 National Survey on Drug Use and Health. Table 5.9A—Alcohol use disorder in past year: among people aged 12 or older; by age group and demographic characteristics, numbers in thousands, 2022 and 2023. [cited 2024 Aug 2]. Available from: https://www.samhsa.gov/
  2. CDC. Alcohol and Public Health: Alcohol-Related Disease Impact. [Table], Annual average for United States 2020–2021 alcohol-attributable deaths due to excessive alcohol use, all ages. [cited 2024 Mar 13]. Available from: https://nccd.cdc.gov/
  3. CDC: https://www.cdc.gov/alcohol/
  4. NIAAA: https://www.niaaa.nih.gov/alcohols-effects-health/
  5. Stillman M, Sutcliff J. Predictors of relapse in alcohol use disorder: identifying individuals most vulnerable to relapse. Addict Subst Abus. 2022;1(1):3–8. doi: 10.46439/addiction.1.002.
  6. Burnette EM, Nieto SJ, Grodin EN, Meredith LR, Hurley B, Miotto K, Gillis AJ, Ray LA. Novel Agents for the Pharmacological Treatment of Alcohol Use Disorder. Drugs. 2022 Feb;82(3):251-274. doi: 10.1007/s40265-021-01670-3. Epub 2022 Feb 8. PMID: 35133639; PMCID: PMC8888464.

Publications

Mash, D.C. (2023). IUPHAR – invited review – Ibogaine – A legacy within the current renaissance of psychedelic therapy. Pharmacological Research, 190, 106620. https://doi.org/10.1016/j.phrs.2022.106620.

Mash DC, Duque L, Page B, Ferdinand KA Ibogaine detoxification transitions opioid and cocaine abusers between dependence and abstinence: Clinical observations and treatment outcomes.  Frontiers Psychopharmacology published: 05 June 2018 doi: 10.3389/fphar.2018.00529

Am J Drug Alcohol Abuse. 2018;44(1):1-3. doi: 10.1080/00952990.2017.1357184. Epub 2017

Mash DC Breaking the cycle of opioid use disorder with Ibogaine.

Mash DC, Ameer B, Prou D, Howes JF, Maillet EL Oral noribogaine shows high brain uptake and anti-withdrawal effects not associated with place preference in rodents. J Psychopharmacol. 2016 Jul; 30(7):688-97. doi: 10.1177/0269881116641331. Epub 2016 Apr 4. PMID: 27044509

Maillet EL, Milon N, Heghinian MD, Fishback J, Schurer SC, Garamszegi N, Mash DC. Noribogaine is a G-protein  biased k-opioid receptor agonist. Neuropharmacology. 2015 Dec; 99:675-88. DOI: 10.1016.

Maillet E, Chang Q, Milon N, Hanania T, Heghinian M, Garamszegi N, Mash DC. Characterization of Noribogaine at nAChRs and Effect on Nicotine Self-Administration in Rats. J. Psychopharmacol. (6): 704-11. DOI: 1019.2. 2015.

Chang Q, Hanania T, Mash DC, Maillet E. Noribogaine reduces nicotine self-administration in rats. J  Psychoparmacol. 29(6): 704-711. DOI: 10.1177/026988115584461. 2015.

Mash DC. Ibogaine therapy for substance abuse disorders: Clinical Addition Psychiatry: (Part 1, Chapter 6). Editors: Brizer, D. and Castaneda, R., Cambridge University Press, 2010.

Passarella, D., Barilli, A., Efange, S.M.N., Elisabetsky, E., Leal, M.B., Lesma, G., Linck, V.M., Mash, D.C., Martinelli, M., Peretto, H., Silvani, A., Danieli, B. Nature-inspired indolyl-2-azabicyclo [2.2.2] act-7-ene derivatives as promising agents for the attention of withdrawal symptoms. Synthesis of 20-desethyl-20-hydroxymethyl-11-demethoxyibogaine. Nat Prod Res 20(8):758-65, 2006.

Mash, D.C. Ibogaine Therapy. Euro Neuropsychopharm 15(3):S322, 2005.

Pasarella, D., Favia, R., Giardini, A., Lessma, G., Martinelli, M., Silvani, A., Danieli, B., Efange, S.M.N., and Mash, D.C. Ibogaine analogues. Synthesis and preliminary pharmacological evaluation of 7-heteroaryl-2-azabicyclo [2.2.2] Oct-7-enes. Biorg. Med. Chem. 11(6):1007-14, 2003.

Baumann, M.H., Pablo, J., Ali, S.F., Rothman, R.B., Mash, D.C. Comparative neuropathology of ibogaine and its o-desmethyl metabolite, noribogaine. In: Ibogaine: Proceeding of the First International Conference., Alkaloid Series, Volume 56.  Editors: Dr. Kenneth Alper and Dr. Stan Glick. Academic Press, San Diego, California pp 80-109, 2001.

Mash, D.C., Kovera, C.A., Pablo, J., Tyndale, R., Ervin, F.R., Kamlet, J.D., Hearn, W. L. Ibogaine in the treatment of heroin withdrawal. In: Ibogaine: Proceeding of the first International Conference., Alkaloid Series, Volume 56. Editors: Dr. Kenneth Alper and Dr. Stan Glick. Academic Press, San Diego, California pp 156-170, 2001.

Baumann, M.H., Rothman, R.B., Pablo, J.P., Mash, D.C. In vivo neurobiological effects of ibogaine and its o-Des-methyl metabolite, 12-hydroxyibogamine (Noribogaine), in rats. J. Pharm. Exp. Ther. 297(2):531-539, 2001.

Mash, D.C., Kovera, C.A., Pablo, J., Tyndale, F.R., Ervin, F.D., Williams, I.C., Singelton, E.G., Mayor, Manny. Ibogaine: complex pharmacokinetics, concerns for safety, and preliminary efficacy measures.  Ann New York Acad Science, 914:394-401, 2000.

Zubaran, C., Shoaib, M., Stolerman, I.P., Pablo, J., Mash, D.C., Noribogaine generalization to the ibogaine stimulus: Correlation with noribogaine concentration in rat brain. Neuropsychopharmacology 21: 119-126, 1999.

Mash, D.C., Kovera, C. A., Buck, B.E., Norenberg, M.E., Shapshak, P., Hearn, W.L. and Sanchez-Ramos, J. Medication development of Ibogaine as a pharmacotherapy for drug dependence,  (ed. Sayed Ali),  Ann. New York Academy of Sciences, 844:274-292, 1998.

Obach, R. S., Pablo, J. and Mash, D.C. Cytochrome P4502D6 catalyzes the O-demethylation of the psychoactive alkaloid ibogaine to 12-hydroxyibogamine. Drug Metabolism and Disposition 25(12):1359-69, 1998.

Pablo, J. and Mash, D.C. Noribogaine stimulates naloxone-sensitive [35S]GTPgS binding. NeuroReport 9:109-114, 1998.

Efange, S.M.N., Mash, D.C., Khare, A.B., Ouyang, Q. Modified ibogaine fragments: synthesis and preliminary pharmacological characterization of 3-ethyl-5-phenyl-1,2,3,4,5,6 hexahydroazepino [4,5-b] benzothiophenes.  J. Med. Chem. 41(23):4486-91, 1998.

Sanchez-Ramos, J. and Mash, D. C. Pharmacotherapy of drug dependence with Ibogaine, IN: Constructive Potential of Psychedelics: Cross-Cultural Perspectives, (Winkelman, M., and Andritzky, W., eds.) Yearbook of Cross-Cultural Medicine and Psychotherapy, Berlin, pp. 353- 367, 1996.

Staley, J.K., Ouyang, Q, Pablo, J., Hearn , W.L., Flynn, D.D., Rothman, R.B.,  Rice, K.C. Mash, D.C., Pharmacological screen for activities of 12-hydroxyibogamine: A primary metabolite of the indole alkaloid ibogaine. Psychopharm 127:10-18, 1996.

Mash, D.C., Douyan, R., Hearn, W.L., Sambol, N.C., Sanchez-Ramos, J.  A preliminary report on the safety and pharmacokinetics of ibogaine. Biol. Psych.  37: 652, 1995.

Hearn, W.L., Pablo, J., Hime, G. and Mash, D.C. Identification and quantitation of ibogaine and an o-demethylated metabolite in brain and biological fluids using gas chromatography/mass spectrometry. J. Anal. Tox. 19:427-434, 1995.

Mash, D.C., Pablo, J., Staley, J. K., Holohean, A.M., Hackman, J.C., and Davidoff, R.A., Properties of Ibogaine and a principal metabolite (12-Hydroxyibogamine) at the MK-801 binding site on the NMDA- receptor complex. Neurosci. Letters 192:53-56, 1995.

Mash, D.C., Staley, J.K., Baumann, M., Rothman, R.P., and Hearn, W.L., Identification of a primary metabolite of ibogaine that targets serotonin transporters and elevates serotonin. Pharmacol. Letters 57: 45-50, 1995.

Hearn, W. L., Mash, D.C., Pablo, J., Hime, G., Sambol, N.C., and Doepel, F.M. Pharmacokinetics of Ibogaine: Analytical method, animal-human comparisons, and the identification of a primary metabolite. Proceedings of the TIAFT-SOFT Joint Congress, Oct. 21 – Nov. 4, 1994 (Spiehler, V. ed.) Omnipress, Ann Arbor, MI, pp. 325 – 334, 1995.