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Hydrafinil (Fluorenol): A Modafinil Analogue with Questionable Safety

Hydrafinil (Fluorenol) is an unregulated research chemical originally synthesized by Cephalon Pharmaceuticals (now owned by Teva) as a eugeroic (wakefulness-promoting agent).  After its synthesis, fluorenol was one of several agents to be considered as a hypothetical successor to the popularized and FDA-approved drug, Provigil (Modafinil).  Comparative data from animal trials indicated that fluorenol exhibited ~39% greater eugeroic efficacy than modafinil over a short-term (4 hour) span.

However, for undisclosed reasons, Cephalon scrapped development of fluorenol as a potentially novel eugeroic.  Instead, they directed efforts and resources to investigate, develop, and market the drug armodafinil.  Armodafinil (sold under the brand name “Nuvigil”) would become known as the official pharmaceutical successor to Provigil, leaving many to wonder whether fluorenol may have been a superior development.

Some speculate fluorenol’s former usage as an insecticide in the late 1930s, proven toxicity to aquatic wildlife, and an expiring Cephalon patent may have been reason enough to discontinue its development.  As of 2015, fluorenol has regained popularity among nootropic enthusiasts and is now being sold as an unregulated substance online under the brand “Hydrafinil.”  Many self-experimenters are vouching for its efficacy, but others are skeptical of these claims and wary of its undocumented, potentially perilous side effect profile.

Hydrafinil (Fluorenol): Hypothesized Mechanism of Action

The mechanism of action associated with hydrafinil is relatively unclear.  Many speculate that it functions as a 5-HT6 receptor antagonist and negligible dopamine reuptake inhibitor (DRI).  Whether these speculations are accurate is debatable since it hasn’t been formally researched in humans.  In any regard, hydrafinil likely bolsters psychomotor vigilance and cognitive performance principally via upregulation of dopaminergic and noradrenergic transmission.

  • 5-HT6 antagonist: Manufacturers of hydrafinil hypothesize that it acts primarily as a 5-HT6 receptor antagonist. Assuming 5-HT6 receptor antagonism is an accurate portrayal of hydrafinil’s pharmacodynamics, it would enhance cognitive function.  In fact, several new schizophrenia medications in development (2015) to address the cognitive deficits associated with the disease target 5-HT6 receptors as antagonists.  Antagonism of the 5-HT6 receptor is known to increase glutamate and choline in various regions of the brain, as well as increase dopamine and norepinephrine specifically in the prefrontal cortex.
  • Dopamine reuptake inhibitor: Hydrafinil may function as a weak dopamine reuptake inhibitor, thereby increasing extracellular concentrations of dopamine. Increasing dopamine is known to enhance cognitive processes.  Since hydrafinil may exert modest or negligible dopamine reuptake inhibition, users are unlikely to experience significant dopaminergic pleasure associated with more potent dopamine reuptake inhibitors.
  • GABAergic modulation: If hydrafinil functions similarly to modafinil, it is necessary to consider that it may alter the transmission of GABA. Modafinil is thought to decrease GABA levels in specific regions of the brain such as the medial preoptic area and posterior hypothalamus.  These effects may improve vigilance and increase levels of histamines.
  • Glutamate increase: As was already mentioned, antagonism of 5-HT6 receptors increases concentrations of the excitatory neurotransmitter, glutamate. Suboptimal levels of glutamate impair learning and memory processes, whereas optimal glutamatergic function promotes learning and memory.  It is possible that cognitive-enhancing effects of hydrafinil may be a result of glutamatergic increases.
  • Histamine increase: Eugeroics like modafinil are known to increase levels of histamine in the hypothalamus. Histamine plays a critical role in regulating sleep/wake cycles and the circadian rhythm.  It is possible that hydrafinil may also increase histamine levels in the hypothalamus, perhaps provoking allergy-like reactions (e.g. itchy skin) in some users.
  • Neuroelectrical alterations: Substances like modafinil are known to affect neuroelectrical activity via suppression of slow brain waves (e.g. delta waves). These neuroelectrical alterations may be a byproduct of increased overall neurophysiologic stimulation.  In other words, sympathetic tone may have increased, as well as neurotransmission to facilitate wakefulness, which in turn, manifests as a reduction of the delta band on an EEG.
  • Norepinephrine increase: It is unknown as to whether hydrafinil affects the norepinephrine transporter (NET) or acts as a norepinephrine reuptake inhibitor. However, 5-HT6 receptor antagonism is known to increase norepinephrine levels in the prefrontal cortex.  Elevations in norepinephrine concentrations are known to enhance vigilance and cognition.
  • Orexin increase: Orexin is a neuropeptide that regulates wakefulness, and when levels are high, an individual feels alert and awake. Possibly one mechanism by which hydrafinil alters neurochemistry and enhances vigilance is via increasing levels of orexin.  Orexin may also increase levels of other stimulatory neurotransmitters such as dopamine and norepinephrine.
  • Serotonin modulation: Hydrafinil is believed to exhibit a greater affinity for 5-HT6 receptors than related compounds. This may facilitate increased serotonin to accumulate within the synapse, which may have implications for one’s mood.  Most speculate that the serotonergic effects associated with hydrafinil improve mood to a modest extent.

Hydrafinil (Fluorenol) Effects: What Users May Experience

It is unknown exactly what the effects of hydrafinil are in a majority of human users.  That said, it is believed to increase wakefulness and vigilance.  Anecdotal reports indicate that it may be less stimulating than modafinil, but superior in regards to promoting wakefulness.  Furthermore, it may improve mood to a slight extent as a result of serotonergic effects.

  • Attention: It is viable to assume that hydrafinil may improve measures of attention. In other words, taking it could improve a users’ ability to sustain focus.  This attentional enhancement may be facilitated via prefrontal increases in dopamine and norepinephrine.
  • Cognitive enhancement: Many individuals take hydrafinil to enhance overall cognitive function. Whether it actually enhances cognition remains unknown and isn’t clear.  One would need to conduct a double-blind, randomized, placebo-controlled trial before concluding that it significantly enhances cognitive performance and/or ameliorates deficits.  That said, 5-HT6 receptor antagonism is understood to improve various measures of cognitive function.
  • Energy increase: Some individuals may experience a noticeable increase in energy level after taking hydrafinil. This energy boost may be less noticeable than experienced while taking modafinil and/or armodafinil.  Any substance that increases concentrations of dopamine and norepinephrine typically bolsters neurophysiologic energy.
  • Learning/memory: It may become easier to learn new information while taking hydrafinil simply due to the fact that dopamine and norepinephrine are upregulated. However, it is possible that hydrafinil-induced glutamate increases also improve ability to learn and memorization.
  • Motivation: Studies investigating modafinil suggest that it increases dopaminergic receptors (D1R) associated with motivational behavior. It is possible that hydrafinil elicits a similar effect, perhaps to a lesser extent.  For this reason, some users may report a spike in motivation after taking hydrafinil.
  • Subtle mood boost: Anecdotal reports suggest that hydrafinil may improve mood to a modest extent. This mood boost may be due to increased synaptic build-up of serotonin.  When serotonin levels increase in combination with prefrontal dopamine/norepinephrine, this may ameliorate depressive symptoms.
  • Wakefulness: In animal studies, eugeroic efficacy was deemed 39% greater among mice that had received hydrafinil (fluorenol) compared to those that received modafinil. In other words, hydrafinil was considered more effective for inducing/maintaining wakefulness than modafinil.  Whether this increased wakefulness efficacy is evident among humans isn’t known.

Possible Advantages of Hydrafinil (Fluorenol)

When compared to other eugeroics, hydrafinil may have some advantages.  Since it hasn’t been well-researched in humans, whether the hypothetical advantages are accurate remains unknown.  Examples of some potential advantages include: low cost, reduced stimulation, superior eugeroic efficacy, and its unregulated status.

  • Cost: Vendors of hydrafinil sell it at around $25 for 2 grams, some are even cheaper. Assuming you purchased hydrafinil for this amount, and administered 100 mg doses, it would cost around $1.25 per dose.  This cost is considered less than purchasing modafinil from a reputable online vendor.
  • Less stimulating: Not everyone wants the same level of stimulation that can be attained from usage of modafinil or armodafinil. Anecdotal reports and manufacturers speculate that hydrafinil is likely less stimulating than other eugeroics.  This means it may be less likely to provoke anxiety, jitters, and/or a crash.  And even though modafinil isn’t considered addictive, hydrafinil may be less addictive as a result of reduced psychostimulation.
  • Mood enhancement: Some believe that hydrafinil may improve mood to a greater extent than modafinil. Many individuals have had success utilizing modafinil for depression and/or as an antidepressant augmentation strategy.  Since hydrafinil may be more serotonergic than other eugeroics, its propensity to improve mood may be greater than related substances.
  • Subtler effect: The overall effect of hydrafinil is thought to be subtler and “cleaner” than other eugeroics. Whether it is actually less subtle is up for debate, but many anecdotal reports make this assertion.  Some may not want as noticeable of an effect as derived from modafinil, and may wish to take something less potent.
  • Superior wakefulness: Hydrafinil’s ability to enhance wakefulness may be superior than other eugeroics such as modafinil. Although it may be less stimulating, it may actually sustain wakefulness for a longer duration and/or in more users than modafinil.  This speculation is purely based off of research in mice.
  • Unregulated: The fact that hydrafinil is unregulated may be perceived as an advantage in that it is available to anyone that wants it. In other words, those who wish to experiment with it aren’t held back by the government.  As a result, hydrafinil can be purchased by anyone and used under their own discretion.

Possible disadvantages of Hyrafinil (Fluorenol)

Compared to other eugeroics, there are some obvious potential disadvantages associated with hydrafinil.  Perhaps the biggest disadvantage is that we don’t truly know whether its safe, associated with adverse effects, and/or deleterious long-term effects.  Anyone contemplating hydrafinil usage should be cognizant of all possible disadvantages.

  • Adverse effects: Users of hydrafinil may report adverse effects and won’t know how to cope with them. Though it’s necessary to seek a medical professional to treat any adverse reaction experienced while taking hydrafinil, the medical professional may be unaware of how hydrafinil (in particular) caused the reaction, possibly making the reaction difficult to treat.
  • Contraindications: The drugs that interact with hydrafinil aren’t understood because it hasn’t been extensively studied in humans. This means we don’t really know the isoenzymes responsible for its metabolism and will have a difficult time pinpointing possible inhibitors of CYP450 isoenzymes that metabolize hydrafinil.  Additionally, we don’t know the full extent of neurochemical changes induced by hydrafinil to rule out conditions like serotonin syndrome when taken with a serotonergic agent.
  • Ineffective: It could be that hydrafinil is completely useless in humans as a eugeroic as well as for other purposes. There is no clinical data to suggest its efficacy in humans and limited data to suggest its efficacy in animal models.  Upon initial glance, one may speculate that since it is similar to modafinil, that it is automatically “effective” for a specific purpose.  It may end up being entirely ineffective.
  • Minimal stimulation: Some users may dislike the fact that hydrafinil is less stimulating than other agents such as modafinil and armodafinil. If you’re looking for higher-octane eugeroics stimulation, hydrafinil may be a letdown.  Many individuals are seeking something that increases arousal to a significant extent as wakefulness.
  • Risks: The full extent of risks associated with hydrafinil are unknown. However, any substance that hasn’t been researched in humans is risky to ingest.  While an unlikely possibility, it is possible that regular administration of hydrafinil over a long-term could be toxic and/or deleterious to general health, increasing risk of early mortality.
  • Unregulated status: Though many perceive “unregulated” substances as favorable in that there’s no need to consult a doctor and/or pay high fees for a prescription, this unregulated status is also dangerous. It’s dangerous in that anyone can buy hydrafinil online, administer it (at whatever dosage they please), and they don’t really have a clue of contraindications and/or what it’s really doing to their body/brain.  A teenager without a fully developed brain could impulsively order and decide to test hydrafinil, potentially yielding unwanted long-term neurological consequences.

Hydrafinil (Fluorenol) Risks: Questionable safety in humans

Despite the fact that users and/or manufacturers speculate that hydrafinil is likely “safe” for humans, this speculation isn’t justified.  Hydrafinil hasn’t been subject to extensive animal research, let alone human trials.  Until hydrafinil has met clinical endpoints for safety in large-scale, robust human trials, there’s absolutely zero way we can conclude, or even imply that hydrafinil is fit for human consumption.

Future published research may reveal that hydrafinil is a low-risk, safe substance when ingested by humans – perhaps even safer than existing FDA approved eugeroics.  However, until the actual human research is funded and conducted, we won’t know, and therefore have no evidence to warrant speculation of safe vs. unsafe.  On the flipside, it is necessary to consider that hydrafinil may determine that it’s highly carcinogenic, mutagenic, and neurotoxic – and ultimately to be avoided.

Until the data is collected, any hydrafinil user is taking a [potentially massive] gamble with their healthspan and future livelihood.  Furthermore, this gamble is an unnecessary one due to the fact that safer, proven (and potentially superior) eugeroics exist (e.g. modafinil and armodafinil).  Heck, there’s even more research available for adrafinil, a less favorable (comparatively) substance than modafinil and armodafinil.

  • Adverse reactions: Nearly every pharmaceutical drug has potential to cause adverse reactions that can occur in a small subset of users. Since hydrafinil isn’t well-researched, should anyone experience an adverse reaction while taking it, it’ll be tough to determine whether it was likely caused by hydrafinil or another factor. For example, if someone (hypothetically) experienced a heart attack while taking hydrafinil, we could conclude that it was from the hydrafinil.  However, this conclusion may be unwarranted since a completely different factor could’ve caused the heart attack.  Although we can speculate that adverse reactions associated with hydrafinil may be similar to related drugs (e.g. modafinil), the accuracy of these speculations remains unknown.
  • Agranulocytosis: Certain drugs may induce a deficiency of granulocytes within the bloodstream, increasing an individual’s susceptibility to infection. While hydrafinil may not cause agranulocytosis, we cannot confirm nor deny this as a potential adverse reaction until more research is conducted.
  • Carcinogenic: Nearly every approved pharmaceutical drug is extensively tested in animal models and undergoes long-term human clinical trials prior to approval. Once approved, the drugs are continuously evaluated for safety and efficacy.  Though modafinil has been on the market for a long-term and isn’t considered carcinogenic, hydrafinil is a different chemical that could prove carcinogenic to humans.
  • Contraindications: The pharmacokinetics of hydrafinil aren’t well understood in animals, let alone humans. If you’re taking another supplement and/or medication along with hydrafinil, you may be putting yourself at even greater risk of an adverse reactions.  Though many users believe hydrafinil doesn’t tax CYP450 isoenzymes, this cannot be confirmed.  Furthermore, there’s always the possibility of a neurochemical interaction (e.g. excessive amounts of particular neurotransmitters).
  • Hepatotoxic: Manufacturers of hydrafinil allege that it is unlikely to induce hepatotoxicity (liver damage). They believe that it doesn’t undergo extensive hepatic CYP450 isoenzyme metabolism like other eugeroics.  As of current, however, they have no valid data to support these allegations.  If you happen to use hydrafinil, getting your liver function checked regularly may be a smart idea.
  • Mutagenic: It is possible that hydrafinil is mutagenic in that it could mutate your DNA, thereby increasing susceptibility to various forms of cancer. Not all mutations may lead to cancer, but it is necessary to consider that mutations may compromise functionality of your neurophysiology.
  • Neurotoxic: Another possibility to consider is that hydrafinil is neurotoxic in that it actually kills brain cells and compromises brain function. Though many hypothesize that neurotoxicity associated with hydrafinil is an unlikely outcome, it is still a possibility.  Until we’ve gathered legitimate data from hydrafinil trials, consider that neurotoxicity is a possible adverse effect.
  • Skin conditions: A rare adverse reaction that occurs in a small percentage of modafinil and armodafinil users is a serious medical condition called Stevens-Johnson Syndrome (SJS). This condition is considered a medical emergency in that it can be fatal.  It is characterized by flu-like symptoms, a red/purple rash, blisters, and/or swelling.

Why you should refrain from using hydrafinil…

If you haven’t yet used hydrafinil, I’d recommend steering clear from the substance until more legitimate (preferably human) research is conducted regarding its safety.  Although you have the freedom to make your own decisions and alter your personal neurophysiology however you see fit (provided it’s legal), experimenting with a substance like hydrafinil, even over a short-term, is risky.  You may end up experiencing an adverse effect that was never reported on forums and could end up in the emergency room.

It could damage your brain, nervous system, or increase likelihood of early mortality. Additionally, it is not as if hydrafinil is free-of-charge – people are paying money to take an unproven research chemical.  In other words, it may have no therapeutic effect, and any beneficial effect claimed from hydrafinil ingestion could merely be a placebo effect.

Unless you’re in dire straits to find a eugeroic drug to treat a severe case of narcolepsy for which no other drug worked (which is likely impossible), using hydrafinil is a poor choice.  There are plenty of safe, proven, and time-tested drugs available (e.g. modafinil and armodafinil) that will sustain wakefulness, enhance cognition, and deliver the effect that is sought by nootropic enthusiasts.  Considering the fact that many “safe” approved pharmaceuticals are associated with risks and problems, ingesting an untested exogenous chemical is far from a wise choice.

Have you tested hydrafinil as a eugeroic and/or cognitive enhancer?

If you have experience using hydrafinil, be sure to share a comment below.  Mention whether you found it effective as a cognitive enhancer (nootropic) and/or eugeroic (wakefulness-promoting agent).  To help others get a better understanding of your situation, share some additional details regarding your usage including: the source from where you purchased hydrafinil, dosage taken, duration of usage, and whether you co-administered it with other drugs/supplements.

For those that were taking hydrafinil along with other agents, can you be sure that the hydrafinil exhibited any significant effect?  It is important to realize that many individuals taking hydrafinil may report benefits, when in reality, these benefits (or the significant ones) could be chalked up to a placebo effect.  If you have experience taking other substances such as modafinil (Provigil), armodafinil (Nuvigil), and/or adrafinil (Olmifon) – mention how Hydrafinil subjectively compares.

What was your motivation behind taking an untested substance like hydrafinil?  Did you carefully consider the potential deleterious implications of your usage prior to ingestion?  If so, what (piece(s) of evidence) convinced you that hydrafinil was likely safe for a test run and/or trial?

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