Bromantane

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Summary

Bromantane, marketed under the brand name Ladasten, is an unconventional psychostimulant and anxiolytic medication belonging to the adamantane family, sharing connections with amantadine and memantine. It finds usage in Russia for the treatment of neurasthenia. Although researchers have established that bromantane’s effects are tied to the dopaminergic and potentially serotonergic neurotransmitter systems, the precise mechanism of its action remains undisclosed. This sets it apart from typical psychostimulants like amphetamine. Due to its distinctive attributes, bromantane has, at times, been characterized as an adaptogen and actoprotector.

Identifiers
IUPAC name
CAS Number87913-26-6 
PubChem CID4660557
ChemSpider3849628 
UNIIN1ILS53XWK
CompTox Dashboard (EPA)DTXSID40405333
ECHA InfoCard100.213.907
Chemical and physical data
FormulaC16H20BrN
Molar mass306.247 g·mol−1

Medical uses

The therapeutic benefits of bromantane in treating asthenia are reported to become evident within a short timeframe, typically ranging from 1 to 3 days. This rapid onset of action is attributed to its unique combination of psychostimulant and anxiolytic properties, which may make bromantane particularly effective for managing asthenia.
In a large-scale, multi-center clinical trial involving 728 patients diagnosed with asthenia, bromantane was administered for 28 days at daily doses of either 50 mg or 100 mg. The results were remarkable, with 76.0% of patients showing improvement on the Clinical Global Impression-Severity (CGI-S) scale and 90.8% exhibiting positive changes on the Clinical Global Impression-Improvement (CGI-I) scale. These findings underscore the broad applicability and high effectiveness of bromantane in treating asthenia.
Significantly, the therapeutic benefits of bromantane persisted even one month after discontinuation of the drug, indicating its long-lasting positive effects. Patients experienced an enhanced quality of life, and this improvement remained evident after the withdrawal of bromantane. Side effects were minimal, with only 3% of patients reporting them, none of which were considered severe. Furthermore, only 0.8% of patients discontinued treatment due to side effects. Notably, bromantane was observed to normalize the sleep-wake cycle. In conclusion, the authors of the study recommended bromantane, in daily doses ranging from 50 to 100 mg, as a highly effective, well-tolerated, and safe drug for the treatment of asthenic disorders in neurological practice.
Effects:
Bromantane is primarily characterized as a mild psychostimulant and anxiolytic agent. It is also recognized for its antiasthenic properties. Users have reported improvements in both physical and mental performance, leading to its consideration as a potential performance-enhancing substance.
In addition to its psychostimulant and anxiolytic effects, bromantane has been found to lower the levels of pro-inflammatory cytokines such as IL-6, IL-17, and IL-4. It has shown promise in normalizing behavior in animal models of depression, suggesting potential clinical efficacy as an antidepressant.
Bromantane’s impact extends to enhancing sexual receptivity and proceptivity in rats of both sexes, an effect attributed to its dopaminergic actions. Additionally, it is proposed that bromantane may modulate prolactin levels due to its dopaminergic properties.
Furthermore, bromantane has been found to “agonize” amphetamine-induced stereotypies in vivo, implying that it may enhance certain effects of other psychostimulants.
The psychostimulant effects of bromantane are gradual in onset, typically becoming noticeable within 1.5 to 2 hours after administration and lasting for 8 to 12 hours.

Pharmacology

Pharmacodynamics:

Dopamine Synthesis Enhancement:

While often categorized as a psychostimulant, bromantane stands out in terms of its pharmacology and effects when compared to typical psychostimulants like phenethylamines (e.g., amphetamine and its derivatives) and structurally related analogs (e.g., methylphenidate, cocaine, mesocarb, etc.).

Unlike these conventional psychostimulants that directly target the dopamine transporter to inhibit reuptake or induce dopamine release, bromantane takes a different route. It operates through indirect genomic mechanisms, leading to rapid, substantial, and long-lasting upregulation of key enzymes involved in the dopamine biosynthesis pathway, such as tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AAAD), also known as DOPA decarboxylase. This upregulation occurs in various brain regions.

For example, a single dose of bromantane triggers a 2- to 2.5-fold increase in TH expression in the rat hypothalamus within 1.5- to 2 hours post-administration. As TH and AAAD expression rise, dopamine biosynthesis and release follow suit. This enhancement of dopaminergic neurotransmission occurs in regions including the hypothalamus, striatum, ventral tegmental area, and nucleus accumbens, among others. In essence, the primary mechanism driving the pharmacological activity and psychostimulant effects of bromantane is the activation of de novo dopamine synthesis via modulation of gene expression.

Here are some excerpts from medical literature that underscore the distinctions between bromantane and typical psychostimulants:

  • “Bromantane does not concede well-known psychostimulants of phenylethylamine structure and its analogs (amphetamine, mesocarb, methylphenidate, etc.) by specific activity. In contrast, bromantane has neither addictive potential nor reveals redundant and exhausting activation of the sympathoadrenergic system.”
  • “The use of the drug, in contrast to a typical psychostimulant, is not associated with hyperstimulation or functional exhaustion.”
  • “Bromantane administration in therapeutic doses is characterized by almost complete absence of side effects, including manifestations of withdrawal syndrome and hyperstimulation.”
  • “Bromantane has low peripheral sympathomimetic effects. Moreover, no signs of bromantane dependence and withdrawal symptoms were found.”

Bromantane is well-tolerated, producing minimal side effects, and does not appear to lead to tolerance, dependence, withdrawal symptoms, or addiction potential, unlike typical psychostimulants. This is supported by both human and animal research.

The precise molecular mechanism through which bromantane enhances dopamine synthesis directly remains unknown. However, it is established that bromantane activates certain intracellular signaling pathways, including cAMP-, Ca2+-, and phospholipid-dependent protein kinases such as protein kinase A and protein kinase C. These activated kinases, in turn, trigger increased transcription of TH and AAAD.

Researchers have found that amantadine and memantine, which belong to the same structural family as bromantane, bind to and activate the σ1 receptor. This receptor is implicated in the central dopaminergic effects of amantadine at therapeutically relevant concentrations, suggesting that a similar mechanism could underlie the action of bromantane. However, it’s worth noting that bromantane’s effects are distinctly different from those of amantadine and memantine.

Monoamine Reuptake Inhibition:

Bromantane was initially thought to act as a reuptake inhibitor for serotonin and dopamine. While it can inhibit serotonin, dopamine, and, to a lesser extent, norepinephrine reuptake in rat brain tissue in vitro, the concentrations required for this inhibition are exceptionally high (50–500 μM) and likely not clinically relevant. For example, one study found an IC50 for dopamine transport of 3.56 μM, compared to 28.66 nM for mesocarb, and neither drug affected serotonin transport at tested concentrations. This suggests that bromantane may not significantly function as a monoamine reuptake inhibitor but rather achieves its effects through dopamine synthesis enhancement.

Other Actions:

Bromantane has been found to increase the expression of neurotrophins such as brain-derived neurotrophic factor and nerve growth factor in specific rat brain regions.

At very high doses in animals, bromantane has exhibited anticholinergic effects, including both antimuscarinic and antinicotinic actions. However, these effects are not relevant at clinical dosages and are associated with toxicity in animals.

Pharmacokinetics:

In clinical practice, bromantane is administered at daily doses ranging from 50 mg to 100 mg for the treatment of asthenia.

The primary metabolite of bromantane is 6β-hydroxybromantane.

Chemistry

Bromantane belongs to the adamantane family of compounds and is also referred to as adamantylbromphenylamine, a name derived from its chemical structure.

History

During the 1960s, amantadine, an adamantane derivative known as 1-amino adamantane, was initially developed as an antiviral drug for combating influenza. Following its discovery, other adamantane antiviral compounds like rimantadine (1-(1-aminoethyl)adamantane) and adapromine (1-(1-aminopropyl)adamantane) emerged as well. Interestingly, it was serendipitously found in 1969 that amantadine had central dopaminergic psychostimulant-like effects. Subsequent investigations revealed that both rimantadine and adapromine also shared these psychostimulant properties. As a result, amantadine was repurposed for the treatment of Parkinson’s disease due to its capability to elevate dopamine levels in the brain. Furthermore, it has been employed to alleviate fatigue in individuals with multiple sclerosis.
Armed with the knowledge of the dopaminergic psychostimulant effects associated with adamantane derivatives, researchers at the Zakusov State Institute of Pharmacology, part of the USSR Academy of Medical Sciences (now known as the Russian Academy of Medical Sciences) in Moscow, developed bromantane in the 1980s. This compound, formally known as 2-(4-bromophenylamino)adamantane, was created with the aim of serving as a “psycho-activating and adaptogenic” drug to help individuals cope with challenging conditions such as hypoxia, high environmental temperatures, physical exhaustion, emotional stress, and more. Notably, bromantane exhibited more pronounced and prolonged psychostimulant effects compared to other adamantanes. It found use, particularly among soldiers in the Soviet and Russian armed forces, to expedite recovery after intense physical exertion.
Following the dissolution of the Soviet Union in 1991, bromantane continued to undergo research and characterization but was primarily utilized in sports medicine to enhance athletic performance. However, its presence as a doping agent was detected during the 1996 Summer Olympics when several Russian athletes tested positive for its use. Consequently, bromantane was classified as a banned substance by the World Anti-Doping Agency in 1997 due to its stimulant properties and potential masking effects.
Fast forward to 2005, bromantane experienced a resurgence in its purpose when it was repurposed as a treatment for neurasthenia, a condition characterized by chronic fatigue and debilitation. Through extensive, including large-scale clinical trials that demonstrated its efficacy and safety in managing neurasthenia, bromantane gained approval for this indication in Russia under the brand name Ladasten around the year 2009.

FAQ

  • What is Bromantane?
  • Bromantane is a chemical compound belonging to the adamantane family. It has been used for various purposes, including as an antiviral drug, psychostimulant, and adaptogen.
  • How was Bromantane Discovered?
  • Bromantane was developed in the 1980s at the Zakusov State Institute of Pharmacology in Moscow, Russia. It was initially created to have psycho-activating and adaptogen properties, particularly for individuals facing challenging conditions.
  • What Are the Effects of Bromantane?
  • Bromantane is described as a mild psychostimulant and anxiolytic. It may also possess antiasthenic properties, improving physical and mental performance.
  • Is Bromantane Used for Medical Purposes?
  • Yes, Bromantane has been used medically to treat neurasthenia, a condition characterized by chronic fatigue and debilitation. It has undergone extensive clinical trials and has been approved for this indication in Russia.
  • Are There Any Side Effects of Bromantane?
  • Bromantane is generally well-tolerated, and side effects are minimal, particularly at therapeutic doses. However, like any medication, individual responses may vary.
  • Is Bromantane Legal?
  • The legal status of Bromantane varies by country. In Russia, it is approved for medical use, but in some regions, it may be regulated or considered a controlled substance.
  • Is Bromantane Considered a Performance-Enhancing Drug?
  • Bromantane has been associated with enhanced physical and mental performance and was previously used by athletes to shorten recovery times after strenuous activity. It was banned by the World Anti-Doping Agency (WADA) due to its stimulant properties and potential masking effects.
  • How Does Bromantane Work?
  • The exact mechanism of action of Bromantane is not fully understood. It is believed to indirectly enhance dopamine synthesis in the brain through genomic mechanisms, resulting in increased dopaminergic neurotransmission.
  • Can I Use Bromantane for Fatigue or Stress?
  • Bromantane has been used to alleviate fatigue, especially in cases of neurasthenia. However, it is important to consult with a healthcare professional before using it for such purposes.
  • Is Bromantane Available Over-the-Counter?
  • The availability of Bromantane varies by country and region. In some places, it may be available over-the-counter, while in others, it may require a prescription or be prohibited.
  • Are There Any Precautions When Using Bromantane?
  • It is crucial to follow dosing guidelines and consult with a healthcare provider before using Bromantane, especially if you have underlying medical conditions or are taking other medications.
  • Is Bromantane Safe for Long-Term Use?
  • Long-term safety data for Bromantane are limited. It is advisable to use it as directed by a healthcare professional and monitor for any adverse effects with prolonged use.

References

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