Substance identification p-Methoxy-butyrylfentanyl (IUPAC name: N-(4-methoxyphenyl)-N-[1-(2-phenylethyl)piperidin-4- yl]butanamide) is a synthetic analog of the opioid analgesic fentanyl. In Europe, it was first reported in 2015 followed by the Untied States of America later on. Samples obtained from seizures and collections suggest that p-methoxy-butyrylfentanyl occurs in powder, tablet, and nasal spray form. WHO Review History p-Methoxy-butyrylfentanyl has not been previously pre-reviewed or critically reviewed. Chemistry There is no specific information available about the routes of synthesis employed for the p- methoxy-butyrylfentanyl products circulating on the drug market but straightforward methods for its preparation exist without requiring access to precursors that are controlled internationally. Routes of synthesis also exist that might require the use of a controlled precursor. Ease of convertibility into controlled substances p-Methoxy-butyrylfentanyl could be converted into various other fentanils but retaining the 4- methoxyphenyl group would also render them uncontrolled at this time. Similarity to known substances / Effects on the central nervous system Data from human studies are not available but the information available so far suggests that the effects induced by p-methoxy-butyrylfentanyl are also shared by other synthetic opioids such as fentanyl and heroin. General pharmacology Pharmacological studies have shown that p-methoxy-butyrylfentanyl is qualitatively similar to fentanyl and heroin. p-Methoxy-butyrylfentanyl binds to μ-opioid receptors (MOR) with high selectivity over the κ- and δ-opioid receptors and has been shown to act as a partial agonist at MOR in a [35S]GTPγS binding assay. Similar to both fentanyl and morphine, p-methoxy- butyrylfentanyl was also shown to induce locomotor activity and antinociceptive effects in mice. Antinociceptive effects were attenuated by pre-treatment with naltrexone. Toxicology Data on the toxicology of p-methoxy-butyrylfentanyl could not be identified. Adverse reactions in humans p-Methoxy-butyrylfentanyl has been detected in biological samples obtained from acute intoxication cases. Reported clinical features included reduced level of consciousness, respiratory depression, miosis, tachycardia, renal insufficiency, suspected aspiration, and apea. Naloxone treatments were required in some cases to reverse drug-induced respiratory depression. Dependence potential No studies available. Experience with fentanyl and other synthetic opioids suggest that the dependence potential might extend to p-methoxy-butyrylfentanyl but further studies are warranted to explore this. Abuse potential Whilst no formal studies exist, the limited available information indicates that p-methoxy- butyrylfentanyl is used by experimental users (psychonauts) including people who have a history of abusing other synthetic opioids and opiates. It seems likely that p-methoxy-butyrylfentanyl might be associated with abuse liability. Therapeutic applications / usefulness p-Methoxy-butyrylfentanyl is not known to have any therapeutic uses. Listing on WHO Model List of Essential Medicines p-Methoxy-butyrylfentanyl is not listed. Marketing authorizations p-Methoxy -butyrylfentanyl is not known to have any marketing authorizations. Industrial use p-Methoxy-butyrylfentanyl is not known to have any agricultural, industrial or cosmetic uses even though it is available for purchase as a ‘research chemical’. Non-medical use The mode of use may involve the combinational use (intentionally or unintentionally) of other drugs and users may be unaware of the exact dose or compound being ingested (by whatever route). Similar to other fentanils, p-methoxy-butyrylfentanyl may be administered as a solution (e.g. using nasal sprays), orally as a powder (including in capsules or tablets), or by insufflation of a powder; it can also be administered sublingually or intranasally via a spray; administered by injection (intramuscular or intravenous) or inhaled by vaporizing. Nature and magnitude of public health problems Use of p-methoxy-butyrylfentanyl appears to be limited to recreational substance users rather than the general population. Marginalized and vulnerable opioid users including those who inject such substances also use fentanyl analogs. However, users may not be aware of using them and the high potency associated with fentanyl analogs might result in increased risks of life- threatening overdoses. At the same time, fentanyl and its analogs pose a serious risk of accidental exposure to products with the potential for subsequent poisoning of the public, law enforcement and emergency personnel, as well as medical/laboratory personnel. Licit production, consumption, and international trade p-Methoxy-butyrylfentanyl is not known to have any agricultural, industrial or cosmetic uses even though it is available for purchase as a ‘research chemical’. Illicit manufacture and traffic So far the total number of reports describing the identification of p-methoxy-butyrylfentanyl is very limited. p-Methoxy-butyrylfentanyl can be purchased from Internet retailers. Current international controls and their impact p-Methoxy-butyrylfentanyl is not controlled under the 1961, 1971 or 1988 United Nations Conventions. Current and past national controls See Annex