Pregabalin

Pregabalin
The skeletal formula of pregabalin
Chemical Nomenclature
Common names	Lyrica, Nervalin, Pregabalin
Systematic name	(S)-3-(aminomethyl)-5-methylhexanoic acid
Routes of Administration
Oral Dosage WARNING: Always start with lower doses due to differences between individual body weight, tolerance, metabolism, and personal sensitivity. See responsible use section. DISCLAIMER: PW's dosage information is a summary of data gathered from users and resources. It is NOT a recommendation and should be verified with other sources for accuracy. Bioavailability 90% Threshold 75-150 mg Light 150 - 300 mg Common 300 - 600 mg Strong 600 - 900 mg Heavy > 900 mg Duration Total 4 - 6 hours Onset 60 - 90 minutes

Summary sheet: Pregabalin

Pregabalin, marketed as Lyrica by Pfizer, is a central nervous system depressant drug. It is used to treat neuropathic pain, anxiety, restless leg syndrome, and as an adjunct drug in the treatment of seizures.

The pharmacological action of pregabalin is mediated by binding to the α2δ-1 site of voltage-gated calcium channels. This site has also been referred to as the gabapentin receptor, as it is the target of the related drug gabapentin (also developed by Pfizer). Advantages to pregabalin over gabapentin include higher bioavailability and potency.

Chemistry

This chemistry section is incomplete. You can help by adding to it.

Pregabalin contains a carboxylated chain of hexane called hexanoic acid. This chain of carbons is substituted with an aminomethyl group in (S) conformation at C3.

Pharmacology

Although pregabalin is a chemical derivative of GABA, it displays no activity at any GABA receptors, including GABA-A, GABA-B and the benzodiazepine site. Pregabalin, despite its GABA backbone, does not appear to alter GABA levels in the brain, so its pharmacological activity is presumed to be unrelated to GABA. Instead, it is its binding to the α2δ-1 site of voltage-gated calcium channels that appears to be the source of its subjective effects. By binding to this site, pregabalin reduces the release of several excitatory neurotransmitters, including glutamate, Substance P, acetylcholine and norepinephrine. Pregabalin and gabapentin form a new class of drugs with high affinity for the α2δ-1 or gabapentin site and reduce brain overexcitability by decreasing excitatory neurotransmission.

One study has also shown that pregabalin promotes deep sleep, thus enhancing sleep quality. This may be important because reductions in slow-wave sleep have been associated with anxiety and fibromyalgia.

In addition, an independent action of the gabapentin site on the neurogenesis of excitatory synapses has been discovered. The endogenous neurochemical thrombospondin also binds to this site and is important for the generation of new excitatory synapses. Gabapentin and pregabalin, having a high affinity for this site, block this action and result in lower levels of excitatory synapses in animal models. This may form part of the therapeutic action of these drugs, as they treat conditions associated with overexcitability of the brain (anxiety, epilepsy, neuropathic pain).

Subjective effects

The effects listed below are based upon the subjective effects index and personal experiences of PsychonautWiki contributors. The listed effects will rarely (if ever) occur all at once, but heavier dosages will increase the chances and are more likely to induce a full range of effects.

Physical effects

The physical effects of pregabalin can be broken down into several components which progressively intensify proportional to dosage.

These are described below and generally include:

• Sedation - Pregabalin produces mild sedation and improves sleep onset latency modestly, while sleep quality is also improved. However, it is not an overly sedating drug when taken in the daytime.
• Pain relief - Pregabalin is effective against certain types of chronic pain, but not against acute pain.
• Muscle spasms - Somewhat paradoxically, since pregabalin is used as an adjunct treatment for epilepsy, pregabalin, especially in higher doses, can produce muscle spasms. Anecdotally, seizures have been reported in overdose.
• Respiratory depression
• Dizziness
• Motor control loss
• Seizure suppression

Visual effects

The visual effects of pregabalin only occur at higher doses and are subtly psychedelic. These generally include:

• Internal hallucinations - At high dosages, one may experience dream-like states and hypnagogia.
• Visual acuity enhancement
• Colour enhancement

Cognitive effects

The cognitive effects of pregabalin can be broken down into several components which progressively intensify proportional to dosage. Pregabalin's headspace is comparable to a more clear-headed alcohol or benzodiazepine intoxication, although it can take a more dissociative turn at very high dosages.

The most prominent of these cognitive effects generally include:

• Empathy, love and sociability enhancement - At moderate to high doses, pregabalin presents strong entactogenic/empathogenic effects which, although weaker than MDMA, are still prominent and tend to dominate the headspace.

• Amnesia - Compared to benzodiazepines, pregabalin is only mildly amnesiac if not combined with other depressants. With chronic usage or high dosages, one should expect more "tip of the tongue" moments and impaired short-term memory (e.g., walking into a room and forgetting what you were supposed to do there). Total blackouts do not seem to occur except in combination with other drugs.
• Motivation enhancement - Like kratom, pregabalin can be mildly sedative yet increase motivation in a stimulant-like fashion.
• Anxiety suppression
• Euphoria
• Thought deceleration
• Disinhibition
• Information processing suppression

Auditory effects

• Enhancements

Toxicity and harm potential

Pregabalin not co-ingested with other substances has a low acute toxicity.

Lethal dosage

Both rat and mouse oral acute LD50 has been established to be greater than 5000mg/kg. Rat IV LD50 was also established to be greater than 300mg/kg.

In terms of humans, there exists a case report of a man who ingested 8,400mg pregabalin and eventually fell into a coma, but was managed with supportive care alone until he regained consciousness. For comparison, the maximum recommended therapeutic dose of pregabalin is 300mg twice per day. Another case report details a man's suicide attempt with the co-ingestion of an estimated 11.5 grams of pregabalin and 32 grams of lamotrigine, another anti-epileptic agent which, by blocking sodium channels, lowers glutamate levels similar to pregabalin. He presented with a lowered level of consciousness and an aggressive demeanor when not sedated. Eventually, he suffered respiratory problems that required intubation and ventilation. After 28 days in the hospital (19 of which where in the intensive care unit) the man was discharged from the hospital. The man suffered seizures which were attributed to his underlying epilepsy. Pfizer's official package insert for Lyrica states that the highest accidental ingestion of pregabalin during clinical trials was 8 g, with no significant consequences.

As seen in these case reports, pregabalin appears to have a large therapeutic window and is relatively benign in overdose compared to other depressants. Combinations with other central nervous system depressants, however, will increase its effects (including respiratory depression and amnesia).

Finally, anecdotal reports of muscle spasms and seizure activity following pregabalin overdoses must be mentioned, although they are not attested in the medical literature. In the literature, seizure activity associated with pregabalin overdoses has been attributed to underlying epilepsy (as that is one of pregabalin's medical indications). However, anecdotal reports insist that high doses can lower the seizure threshold, paradoxically, since low doses are used to raise it.

Tolerance and addiction potential

Pregabalin was initially thought to be non-addictive with a low abuse potential and low tolerance development. However, recreational use of the drug has caused a re-evaluation of this assessment. The euphoric effects of the drug and the development of tolerance can lead to the use of dosages far above the therapeutic range. Pregabalin is indubitably both recreational and addictive.

The withdrawal effects of abrupt cessation of chronic usage include anxiety, insomnia, sweating, muscle spasms, gastrointestinal problems, hot and cold flashes, nausea, and a flu-like feeling. There exist reports of patients with history of opioid and/or benzodiazepine abuse who considered pregabalin withdrawal to be worse than benzodiazepine or heroin withdrawal.

Interactions

Pregabalin's serotonergic effects enable it to interact, potentially fatally, with other serotonergics such as antidepressants (like monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, noradrenergic and specific serotonergic antidepressants, serotonin antagonists and reuptake inhibitors, etc.). It may also interact fatally with certain analgesics (such as pethidine (meperidine), tapentadol, oxycodone, dextromethorphan and fentanyl), certain anxiolytics (such as the SSRIs and buspirone), certain antibiotics (namely, linezolid and isoniazid), certain herbs (e.g. St. John's wort, syrian rue, passiflora, etc.), certain recreational drugs (e.g. MDMA), phentermine, lithium, methylene blue and numerous other therapeutic agents.

Legal issues

Pregabalin is regulated as a prescription drug in most countries.

• US: Pregabalin is in Schedule V, the lowest drug schedule. For comparison, benzodiazepines are in Schedule IV.
• Norway: Pregabalin is in prescription schedule C, the lowest schedule, although it has been suggested that it be moved to schedule B alongside benzodiazepines.

Experience reports

Anecdotal reports which describe this compound within our experience index include:

See also

• Responsible use
• Psychoactive substance index
• Gabapentin
• 4-methylpregabalin
• Benzodiazepines