Pagoclone is a pharmaceutical substance that was under development for stuttering until the 2010s and was previously investigated for panic, anxiety, and premature ejaculation. It does not have a benzodiazepine structure, but it operates at the benzodiazepine site.
Although it had some efficacy in panic and stuttering, it was not sufficient to maintain investment, so the drug has never been commercialized.
It has occasionally been sold online, but its use outside of clinical research settings is minimal.
Pagoclone = RP 59037 (the racemate)
Molecular formula: C23H22ClN3O2
Molecular weight: 407.898 g/mol
The dosing in medical trials was 0.3 to 0.6 mg/d (oral). The dose was split across two or three administrations per day.
Larger doses upwards of 5 mg have sometimes been used outside of those settings. Those amounts may come with more nonmedical/recreational properties, as seen in an abuse potential study that used 4.8 mg (de Wit, 2006).
When given orally, it seems to last for around 4 to 6 hours.
It was primarily studied for stuttering and anxiety/panic. In both cases it was found to be effective (Maguire, 2010; Sandford, 2001) but larger trials didn’t demonstrate enough efficacy to justify further development. Pagoclone also did not have adequate efficacy for premature ejaculation and no results were ever published for its use in that condition.
An 8-week controlled trial of pagoclone for stuttering in 132 participants found it significantly improved symptoms while producing minor side effects (Magquire, 2010). Similarly positive results were seen in the 119 individuals who elected to continue treatment in a yearlong open-label extension period. When a larger group of people was studied, the results were not as significant, leading to an abandonment of research even though pagoclone may indeed have some efficacy in the condition.
A trial of 16 patients with panic disorder with agoraphobia was somewhat positive (Sandford, 2001). Pagoclone at 0.1 mg three times per day significantly reduced the frequency of panic attacks, though without any consistent impact on other measures of anxiety or condition severity. The impact, while statistically significant, only involved a reduction in panic attacks by 2.2 per two-week period vs. 1.5 with placebo.
Some of the interest in the substance has come from its potential use as an anxiolysis-selective GABAergic or as an alcohol alternative in social settings. A few reports of people using 5-30 mg can be found online, but there are too few reports to characterize the effects of those doses. It can only be said that pagoclone appears useful for anxiety and sleep for some people. It doesn’t seem to have much euphoric potential.
Very strong sedative effects don’t appear to exist even at high doses around 5 mg. Diazepam and other benzodiazepines may be more effective in that regard.
An abuse potential study found 4.8 mg of pagoclone significantly increased some measures of drug-liking and “good effects,” while 1.2 mg did not (de Wit, 2006).
Pagoclone is a member of the cyclopyrrolone class of nonbenzodiazepines, which also includes the sleep medication zopiclone.
Its structure consists of a core isoindolin-1-one ring-system with a secondary 7-chloro-1,8-naphthyridin-2-yl ring-system bound at its 2 position and a 5-methyl-2-oxohexyl side-chain bound at its 3 position.
It is the active (+)-enantiomer of the racemate RP 59037.
It is a benzodiazepine site agonist. Like the nonbenzodiazepine Z-drugs (e.g. zopiclone and zolpidem), it is more selective than benzodiazepines, meaning it preferentially affects GABAA receptors with specific compositions.
Pagoclone has a high affinity for GABAA receptors with an α1, α2, α3, or α5 subunit (Atack, 2006). It’s essentially a full agonist at α3 receptor subtypes, while it’s a partial agonist at the rest. The EC50 values for those receptor types range from 3.1 to 6.6 nM.
Physical dependence may not develop as quickly, though the evidence for this only comes from a couple animal studies in which the racemate RP 59037 didn’t produce hypersensitivity to a benzodiazepine site inverse agonist after heavy dosing for three days (Stutzmann, 1991; Piot, 1992).
In humans, a PET study supported its status as a partial benzodiazepine site agonist. It reduced the uptake of the benzodiazepine antagonist flumazenil and occupied more receptors than lorazepam while producing less of a response (Lingford-Hughes, 2005).
5′-hydroxy-pagoclone, an active metabolite, may be responsible for more activity than pagoclone itself. It’s present at even higher concentrations in the plasma and brain of rats following pagoclone administration (Atack, 2006) and it’s more potent as a GABAA benzodiazepine site agonist. The metabolite is also a full agonist at receptors with the α1 subunit, unlike pagoclone.
Low doses (0.6 mg/d for five days) combined with ethanol produced no clear synergism (Haig, 2003).
Human and animal studies have shown pagoclone is extensively metabolized to the active substance 5′-hydroxy-pagoclone (Dalvie, 2009; Atack, 2006).
Pagoclone was discovered by Rhone-Poulenc, a French pharmaceutical company that would come to be known as Aventis following a merger with Hoechst Marion Roussel. A 1994 patent (5498716) from Rhone-Poulenc described it as exhibiting “remarkably anxiolytic, hypnotic, anticonvulsant, antiepileptic, and muscle relaxant properties.”
Rhone-Poulenc licensed it to Interneuron Pharmaceuticals, an American pharmaceutical company that later changed its name to Indevus.
Interneuron (Indevus) licensed the substance to Warner-Lambert, which was acquired by Pfizer a few months later. Pfizer received exclusive worldwide rights to pagoclone for the treatment of panic and generalized anxiety disorders. In exchange, Interneuron received an upfront payment of $13.75 million and was entitled to receive up to $60 million in additional payments based on clinical and regulatory milestones, as well as royalties from net sales.
Under this deal, Pfizer would conduct and fund all further clinical development, regulatory review, manufacturing, and marketing for the substance.
Pagoclone is one of Interneuron’s most valuable assets, and we are enthusiastic that our partner, Pfizer, has initiated the clinical program on this important product…We continue to be very impressed with Pfizer ‘s extensive capabilities in taking pagoclone forward in a comprehensive and timely manner, reflecting the recognition by both companies that pagoclone has the potential to make a significant impact upon the market to treat panic disorder and other anxiety disorders. – Dr. Glenn Cooper, president and CEO, Interneuron Pharmaceuticals
Indevus received the exclusive worldwide rights to pagoclone back from Pfizer, which decided not to pursue development of the drug for anxiety and panic conditions. This came after insufficient efficacy was demonstrated in those conditions. Because Aventis had some rights to the drug, Indevus and Aventis would decide together about pagoclone’s future following additional analysis of trial data.
While we are disappointed that Pfizer has elected not to pursue this project, we believe that further development of pagoclone for anxiety disorders may be merited, – Dr. Glenn Cooper, Indevus
Indevus announced it had begun new corporate partnership discussions and it would decide on the clinical development of the drug for anxiety/panic based on analyses of six clinical trials and based on ongoing consultation with Aventis.
Due to its contractual rights to the drug, Aventis had a period of 90 days from the termination of the Pfizer deal to decide if it would develop the drug. It decided not to.
Indevus received a US patent covering the use of pagoclone for the treatment of stuttering.
An article in the Boston Globe said pagoclone “shows promise” for stutterers. Brooke Wagner, an Indevus spokesperson, said a larger trial with 600 to 1,000 patients was needed to confirm its effects.
ABC News reported that pagoclone, unlike other stuttering medications, produces just a few mild side effects and researchers believe it works by lowering dopamine levels in the brain.
Some perspectives on the use of pagoclone or other medications for stuttering were featured:
Medical therapy is not likely to be a first-line treatment for stuttering. – Richard Merson, a speech and language pathologist at William Beaumont Hospital in Royal Oak, Michigan
Merson said it will likely only be used in the tiny minority of patients who are not helped by speech therapy.
As a stutterer, I see the value in medication but also the importance of good speech therapy, – Ross Barrett, a speech therapist at East Virginia School of Medicine
Indevus announced it was moving towards regulatory approval for persistent developmental stuttering (PDS) and that it would initiate a Phase 3 trial in the first half of 2007. The company intended to explore pediatric uses as well and it would start a small pharmacokinetic population in children so that it could pick doses for a Phase 2 or 3 study in 2007.
The Company met with the FDA to discuss the results of our Phase II trial in adults with PDS and to explore ideas for the design and conduct of future trials…Although the FDA had never considered a drug for stuttering, FDA officials were, in my opinion, extremely well-prepared and were able to give us specific and useful guidance that has allowed us to map out a clear path toward an NDA submission.
Specifically, the FDA advised the Company to: 1) pursue pediatric studies in parallel with adult studies so that if pagoclone is effective and safe in both populations, the NDA could be approvable for the broadest possible stuttering population; 2) conduct the next adult and pediatric placebo-controlled trials as fixed dose-response studies to determine the minimally-effective dose; 3) pursue Phase III trials under special protocol assessments (SPAs) to allow the FDA to formally sign off on trial designs.
Importantly, the FDA tentatively agreed, pending the SPA review process, to the Company’s proposal on primary and secondary study endpoints and study duration. – Dr. Glenn Cooper, CEO, Indevus
It also announced it would not continue a Phase 2 trial for premature ejaculation due to insufficient efficacy.
Interest in the drug grew after a promising Phase 2 trial. Indevus signed a development, licensing, and commercialization agreement with Teva Pharmaceuticals, which received the exclusive, worldwide rights to pagoclone.
Indevus would conduct the Phase 2B study and be reimbursed by Teva. The new placebo-controlled trial would involve 300 patients and a six-month evaluation period. Enrollment was set to begin by Q1 2009.
Though it was the first drug tested through the FDA process specifically for stuttering, Dr. Gerald Maguire, one of the main pagoclone researchers, revealed the latest data was not impressive. During the US National Stuttering Association conference in Ohio, Dr. Maguire informally discussed the Phase 2B study results and said the pre-specified criteria for success were not met. Significant and lasting gains in fluency were not seen.
Dr. Gerald Maguire said pagoclone would not be approved by the FDA for stuttering anytime soon. He thinks the antipsychotic asenapine “is going to be better.”
Endo Pharmaceuticals decided not to continue its research program focused on pagoclone for stuttering.
Some anecdotal reports of success with pagoclone for stuttering were seen in the stuttering community online and it was also sold via research chemical websites, though it’s rarely been used outside of trial settings.
As of 2018
It has never been commercialized and is an uncommon drug.
Legality (as of June 2018)
United States: Unscheduled
Australia: Not specifically controlled
UK: It is not specifically scheduled, but it does fall under the Psychoactive Substances Act.
At the low medical doses of 0.3 to 0.6 mg/d, the side effects are minimal and not very concerning. It can cause drowsiness, headache, and impairment in some individuals, but that’s about the extent of the concern based on the available data.
Even at higher doses, such as the 4.8 mg used in the abuse potential study, the primary issue is impairment. A direct toxic effect capable of causing death is unlikely to be reached at any of the doses described in this overview. There may be a lethal dose, but pagoclone does not have a low therapeutic index and seems to be a mostly nontoxic drug at the doses evaluated so far.
Physical dependence may build slower than with benzodiazepines, but it probably does build over a sufficient length of time, leading to tolerance and perhaps withdrawal symptoms like anxiety and insomnia.
Pagoclone can acutely cause sedation and impairment in learning, memory, and alertness.
Risky Combinations (list may not be exhaustive)
Other depressants including alcohol (ethanol), benzodiazepines, and opioids.