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Golden Thinker ® – Encyclopedia of Substances – Sunifiram

Sunifiram
What is Sunifiram?

Sunifiram (DM-235) is a synthetic molecule derived from piracetam. It’s often associated with the racetam family. However, due to some biochemical changes in its backbone structure, it’s not technically within this class of drugs.

Many drugs can be similar in structure, but their effects and potency can be very different. While similar to piracetam, sunifiram is thought to be 1000 times more potent.

This raises some issues regarding the safety of the drug, especially since all of our knowledge about the compound comes from animal models. However, sunifiram has been widely sold as a nootropic agent, with many users reporting positive effects.

It’s important to remember that without proper human clinical testing, we cannot be certain about the long-term safety of supplement. All indications from animal studies report no toxic effects at high doses, but these findings do need to be supported by regulated clinical trials for us to be certain about the compound’s safety.

Sunifiram was first developed with the aim of treating cognitive decline in Alzheimer’s disease. Preliminary animal studies have reported some profoundly interesting effects which suggest sunifiram may offer some potent nootropic benefits. Evidence from current user reports suggests that sunifiram supplementation can give impressive outcomes, including:

  • Improved learning
  • Enhanced memory
  • Increased focus and mental clarity
  • Elevated mood and energy
  • Visual and perceptual enhancement
Potential Brain Benefits and Mode of Action

While the preliminary studies from rodent models make the effects of sunifiram look exciting, it’s important to remember that all of the scientific evidence below comes from animal studies.

May Increase Learning Ability

Many users of sunifiram report an increased ability to study, learn and retain information. This is one of the reasons the compound has been labelled as a ‘smart drug’.

Although there have been no human studies, there are some data to support these testimonials from animal models.

In one animal study, researchers showed that mice were quicker to learn to avoid stressful stimuli after small doses of sunifiram. Another study using rats reported that sunifiram administration significantly increased the rate at which the animals learned to recognise social partners.

There have been some contradictory reports from other studies which have not replicated these findings. The key issue is that studies often use different doses of the compound which may underlie such disparate behavioural consequences.

Mode of action: Several preliminary animal studies have shown that sunifiram can stimulate the production the neurotransmitter acetylcholine, often referred to as the ‘learning’ neurotransmitter. One study showed that sunifiram was able to counteract the effects of a known acetylcholine inhibitor, suggesting that one of the main effects of the compound may be modulating levels of acetylcholine. The increase in acetylcholine could underlie some of the enhancements to learning we have observed in early research and hear reported by users.

May Improve Memory

No human studies into human populations have investigate the effects of sunifiram on memory. However, many users claim that the compound greatly increases their ability to remember and recall information with ease. There are some preliminary animal studies which report data to support these claims.

Two rodent studies have found that sunifiram was able to attenuate experimentally induced memory impairments and restore memory function. Another animal study also reported an interaction between sunifiram and a synaptic strengthening process called long-term potentiation (LTP).

LTP is a well characterised mechanism by with the individual synapses between neurons are strengthened. It is one of the key pillars of synaptic plasticity, and plays an important role in memory acquisition, encoding and consolidation.

It’s important to note that all of these studies have been based on what are known as ‘reversal’ or ‘rescue’ models. That means that all animals in the study have been subject to some experimental manipulation which impaired their memory prior to sunifiram administration. Sunifiram was able to reverse these memory deficits in all of these cases. However, we don’t currently have any data on sunifirams effect on healthy animals without any prior memory impairment.

Since sunifiram was originally designed to treat cognitive impaired associated with Alzhiemer’s disease, the drug may specifically target disease-related processes. It will be important to ensure there aren’t any negative effects in healthy individuals.

Mode of action: Binds major glutamatergic receptor, AMPA receptors, which underpin excitatory activity in the brain. AMPA receptors activation has been widely demonstrated to increase synaptic plasticity. AMPA receptor modulation has also been shown to be involved in a number of memory related processes such as consolidation and storage. Sunifiram has also been shown to promote the release of glutamate in both cultured cells and animals. This can increase activity of another key component of the glutamatergic system, NMDA receptors. NMDA receptor activity can enhance synaptic plasticity and a process called ‘long-term potentiation’ which strengthens synapses (and, in turn, memory storage and recall).

May Boost Energy

One of the most widely discussed effects of sunifiram is its ability to increase mental energy, focus and concentration. Many users report the drug helps them to obtain mental clarity and improves their ability to work on difficult tasks for long periods of time.

There has only been one study in animals which indicates sunifiram may have some effect on our wakefulness. In this study, researchers showed that sunifiram could partially counter-act the sleep-inducing effects of another drug (pentobarbital). They found that while mice still experienced drug-induced sleep, those who had been given sunifiram showed a reduction in the number of hours slept.

Mode of action: Our brain is the biggest largest consumer of oxygen and glucose of all bodily organs. Glucose acts as the main cellular fuel for neurons and it is delivered by the complex neurovascular system via red-blood cells. One early study suggested that sunifiram may optimise the transport of energy to neurons, and enhance the way neurons can use this energy. These researchers found that sunifiram was able to negate the effects of a drug called pentobarbital, which inhibits glucose transportation. An important dose-dependent finding was reported by this study: only low doses produce this increase in glucose uptake by neurons, higher doses actually decreased the uptake. At the appropriate dose, sunifiram may optimise how glucose is transported to and taken up by our cells. Subsequently, this may underlie the reported effect of improved mental energy, clarity and focus by optimising neuronal function and energy levels.

How to Use

Sunifiram is a particularly potent and experimental drug. At the moment, we have no clinical human data regarding the safety and efficacy of the drug. Experimental models in animals also report no overt side effects. While many users of sunifiram report positive experiences and no adverse side effects, others have reported some of the following symptoms:

  • Nausea
  • Headaches
  • Anxiety
  • Restlessness
  • Sweating
  • Insomnia and sleep quality issues
  • Forgetfulness
  • Mental Fatigue

We recommend caution when trialling this type of experimental substance. It may also be sensible to try other members of the racetam family of drugs first, to see if these more well-research compounds can provide you with the desired benefits. Other members of the racetam family are aniracetam, oxiracetam, coluracetam, pramiracetam and phenylpiracetam.

Sunifiram can be taken orally. Many users also recommend taking the substance sub-lingually (under the tongue) for maximum absorption.

Some users who have taken sunifiram at high doses or extended period of time report that they have build-up a ‘tolerance’ to sunifiram. There is no medical evidence to confirm these reports. However, this indicates that the drug shouldn’t be taken daily and should be consumed at low dosages.

Due to a lack of clinical trial data, we don’t have any information of any drug interactions sunifiram may have. It’s important to inform your doctor of any supplements you’re taking in order to further minimise the risk of adverse effects with experimental drugs.

Recommended Dose: 5-10mg

To date, there are no clinical trials which have identified an appropriate dose or safe upper limit for sunifiram supplementation. However, sunifiram has been established as a highly potent compound, meaning that very small doses are required to see effects compared to other nootropic substances.

It’s difficult to recommend a dose without the existence of clinical evidence. However, many users report that a dosage of 5-10mg daily to be both safe and effective. Some users consume 5-10mg three times daily without any adverse effects.

Since sunifiram is available in pill form, many users suggest taking the supplement sublingually (under the tongue) for maximum absorption.

This dose is somewhat in line with the dose we see used effectively in animal studies (1mg/kg). This gives a rough dose of 0.06-0.16mg/kg in humans, and would equate to around 5.4-11mg for a 150lb person.

As mentioned above, some users report a gaining a tolerance to the effects of sunifiram. In light of this, it may be wise to take this drug infrequently rather than daily.

If you’re thinking of trying sunifiram, we recommend caution with dosing. It’s wise to start with the lowest effective dose possible, since there is currently no human data regarding safe dosing.

Classification: Cognition, Memory, Energy

Early evidence and user reports suggest that sunifiram has positive and powerful effects on memory, learning and mental focus. Therefore, we’ve classified the compound as a cognition, memory and energy booster.

References
  1. Fulvio Gualtieri (2016) Unifi nootropics from the lab to the web: a story of academic (and industrial) shortcomings, Journal of Enzyme Inhibition and Medicinal Chemistry, 31:2, 187-194, DOI: 10.3109/14756366.2015.1021252
  2. Lee, Y. S., & Silva, A. J. (2009). The molecular and cellular biology of enhanced cognition. Nature reviews. Neuroscience, 10(2), 126–140. https://doi.org/10.1038/nrn2572
  3. Elisabetta Martini, Alberto Salvicchi, Carla Ghelardini, Dina Manetti, Silvia Dei, Luca Guandalini, Cecilia Martelli, Michele Melchiorre, Cristina Cellai, Serena Scapecchi, Elisabetta Teodori, Maria Novella Romanelli. (2009) Design, synthesis and nootropic activity of new analogues of sunifiram and sapunifiram, two potent cognition-enhancers. Bioorganic & Medicinal Chemistry.Volume 17, Issue 21. Pages 7606-7614, ISSN 0968-0896 https://doi.org/10.1016/j.bmc.2009.08.055.
  4. Ghelardini, .C., Galeotti, .N., Gualtieri, .F. et al. DM235 (sunifiram): a novel nootropic with potential as a cognitive enhancer. Naunyn-Schmiedeberg’s Arch Pharmacol 365, 419–426 (2002). https://doi.org/10.1007/s00210-002-0577-3
  5. Dina Manetti, Carla Ghelardini,, Alessandro Bartolini, Silvia Dei, Nicoletta Galeotti, Fulvio Gualtieri, Maria Novella Romanelli,Elisabetta Teodori. Molecular Simplification of 1,4-Diazabicyclo[4.3.0]nonan-9-ones Gives Piperazine Derivatives That Maintain High Nootropic Activity. Journal of Medicinal Chemistry 2000 43 (23), 4499-4507 DOI: 10.1021/jm000972h
  6. Moriguchi, S., Tanaka, T., Narahashi, T. and Fukunaga, K. (2013), Novel nootropic drug sunifiram enhances hippocampal synaptic efficacy via glycine‐binding site of N‐methyl‐D‐aspartate receptor. Hippocampus, 23: 942-951. doi:10.1002/hipo.22150
  7. Romanelli, M. N., Galeotti, N., Ghelardini, C., Manetti, D., Martini, E., & Gualtieri, F. (2006). Pharmacological characterization of DM232 (unifiram) and DM235 (sunifiram), new potent cognition enhancers. CNS drug reviews, 12(1), 39–52. https://doi.org/10.1111/j.1527-3458.2006.00039.x
  8. Shigeki Moriguchi, Tomoya Tanaka, Hideaki Tagashira, Toshio Narahashi, Kohji Fukunaga. (2013). Novel nootropic drug sunifiram improves cognitive deficits via CaM kinase II and protein kinase C activation in olfactory bulbectomized mice, Behavioural Brain Research, Volume 242, Pages 150-157, ISSN 0166-4328, https://doi.org/10.1016/j.bbr.2012.12.054.
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