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By Kevin G. Shanks, D-ABFT-FT

We’ve covered many stimulants on this blog in the past. Most recently, we discussed newer substituted cathinones, MDPHP and Alpha-PHP/PiHP.  

As a brief summary, substituted cathinones are a class of compounds that are related to cathinone, a naturally occurring stimulant alkaloid found in the plant Catha edulus (khat). These stimulants first appeared in the USA in the early 2010s and continue to be detected year after year in seized drug evidence and forensic toxicology specimens. MDPHP and alpha-PHP/PiHP (Figure 1) belong to the pyrrolidinophenone subclass of substituted cathinones and are structurally related to older compounds MDPV and alpha-PVP. 

Figure 1. Chemical Structure of Alpha-PHP  Drawn by Kevin G. Shanks (2026)

Over the last year, two new compounds (alpha-PHPP and alpha-PiHPP) in the pyrrolidinophenone subclass and one in a related subclass (alpha-PipHP) emerged on the illicit drug market in the USA. As is normal, these compounds have very complex names with some of them also going by alternative names or acronyms. Alpha-PHPP is also known as alpha-pyrrolidinoheptiophenone or PV8. Alpha-PiHPP is also known as alpha-pyrrolidinoisoheptanophenone or iso-PV8 (Figure 2). Alpha-PipHP is also known as alpha-piperidonhexanophenone. 

Figure 2. Chemical Structure of Iso-PV8 Drawn by Kevin G. Shanks (2026)

The pyrrolidinophenone compounds differ from other cathinones by incorporating a pyrrolidine ring and often a longer alkyl side chain, while alpha-PipHP is structurally related to older cathinones, alpha-PHP and alpha-PiHP. Though the published pharmacology literature remains sparse, rather than functioning primarily as monoamine releasing agents, compounds with similar chemical structures as these three stimulants typically act as potent inhibitors of dopamine and norepinephrine transporters. This makes them function in a similar fashion to cocaine but with greater potency and longer durations of action. This pharmacological action of transporter inhibition leads to elevated extracellular dopamine in the neuronal synapse and contributes to increased locomotor activity, euphoria, reinforcement, and abuse liability. Increased norepinephrine in the synapse contributes to sympathetic activation, including tachycardia, hypertension, hyperthermia, and heightened alertness. The severity of toxicity varies widely depending on factors such as dose, route of administration, co-administration of other substances, health or disease state of the user, and the use history of the individual. Expected metabolism and excretion of these compounds includes reduction, hydroxylation, oxidation, and conjugation with glucuronic acid or sulfate. 

There have been a couple of reports over the last decade of the detection of PV8 in postmortem casework outside of the USA.  

In 2018, Pieprzyca et al. reported two fatal cases involving PV8 in Japan. In the first case, a 36 year old man was found dead in his apartment. The previous night he had consumed alcohol with friends. Blood was positive for ethanol (1.8 mg/L), clindamycin (1.95 mcg/mL), and PV8 (0.26 mcg/mL). In the second case, a 37 year old female arrived at the hospital with gastrointestinal bleeding, vomiting, diarrhea, hyponatremia, and hypokalemia. Postmortem blood was acetaminophen (1.49 mcg/mL), metamizole (0.32 mcg/mL), lidocaine (0.68 mcg/mL), dextromethorphan (0.28 mcg/mL), drotaverine (0.25 mcg/mL), and PV8 (0.07 mcg/mL). Both deaths were concluded to be fatal intoxications with PV8. 

In 2021, Mochizuki et al. described a fatal case of poisoning with PV8, alongside other stimulants 4-FMC, 4-MeO-alpha-PVP, and 4-F-alpha-PVP. The male decedent was found without clothes in his room and with his head embedded in the wall. A syringe and vials of liquid were also found in the room. PV8 was quantified in postmortem heart blood (218±3 ng/mL) and in postmortem femoral blood (167±4 ng/mL). 4-FMC, 4-MeO-alpha-PVP, and 4-F-alpha-PVP were also quantified in both samples. The authors concluded the cause of death to be acute poisoning with the combination of substances detected. 

As these compounds are now on the illicit drug market, it is prudent to be aware of them. Axis monitors alpha-PipHP, Alpha-PHPP (PV8), and Alpha-PiHPP (iso-PV8) in the Novel Emerging Compounds (NEC) panel (order code 13710) and Comprehensive Panel, Blood with Analyte Assurance™ (order code 70510) using liquid chromatography with quadrupole time of flight mass spectrometry (LC-QToF-MS). Since the addition to the scope of testing in April 2026, the laboratory has detected alpha-PiHPP (iso-PV8) in 4 postmortem blood cases. Each of the cases originated in the state of Florida. Of the four cases, 2 decedents were female and 2 decedents were male. Other drugs detected alongside alpha-PiHPP (iso-PV8) included cocaine/metabolites (2), fentanyl/metabolite (2), and methamphetamine/amphetamine (2). Alpha-PipHP and Alpha-PHPP (PV8) have not been detected in the laboratory. 

If you have any questions or concerns about these new stimulants and how they may play a role in your medical-legal investigation, please reach out to subject matter experts by email ([email protected]) or phone (317-759-4869, Option 3). 

References 

• Shanks, K. (2026) Drug Primer: MDPHP. https://axisfortox.com/drug-primer-mdphp/ 
• Shanks, K. (2023) Poster Presentation: Detection of the Substituted Cathinone, Alpha-PiHP, in Postmortem Toxicology Cases. https://axisfortox.com/poster-presentation-detection-of-the-substituted-cathinone-alpha-pihp-in-postmortem-toxicology-cases/ 
• Shanks, K. (2023) A Closer Look at the Novel Emerging Compounds Panel: Alpha-PiHP and N,N-dimethylpentylone. https://axisfortox.com/a-closer-look-at-the-novel-emerging-compounds-panel-alpha-pihp-and-nn-dimethylpentylone/ 
• Pieprzyca, E., Skowronek, R., Korczynska, M., Kulikowska, J., and Chowaniec, M. (2018) Two fatal cases of poisoning involving new cathinone derivative PV8. Legal Medicine (Tokyo). https://doi.org/10.1016/j.legalmed.2018.05.002. 
• Mochizuki, A., Adachi, N., and Shojo, H. (2021) Detection of 4-FMC, 4-MeO-α-PVP, 4-F-α-PVP, and PV8 in blood in a forensic case using liquid chromatography-electrospray ionization linear ion trap mass spectrometry. Forensic Science International. https://doi.org/10.1016/j.forsciint.2021.110888. 

By Kevin G. Shanks, D-ABFT-FT

The term designer opioid generally refers to the class of synthetically derived opioid analogs that are intentionally modified by clandestine chemists to circumvent existing drug laws while maintaining opioid receptor activity. This concept has been ongoing over the years with the initial appearance of fentanyl analogs such as alpha-methylfentanyl and 3-methylfentanyl during the 1980s and the reemergence of them on illicit drug markets in the 2010s. Shortly thereafter, the fentanyl class of compounds was heavily controlled by the government, and clandestine labs moved on to the synthesis of the nitazene family of opioids, which gained prominence in the late 2010s to early 2020s. As the nitazenes have become regulated, the market looks to be shifting again, and the orphine class of opioids has the potential to be the next type of designer opioid to become prevalent. 

The orphine class of substances have an origin in academic and pharmaceutical research conducted during the 1960s and 1970s, particularly in laboratories associated with Paul Janssen, whose work also produced fentanyl and related fentanyl analogs. Many of these compounds were initially synthesized as potential analgesics, but they remained relatively obscure within scientific literature and patents. In the last few years, these compounds have been rediscovered and have found their way to the street as illicit drugs. 

The modern recognition of the orphine class began with the detection of brorphine on illicit drug markets in Europe in 2019 and in the United States in 2020. Brorphine is a benzmidazol-2-one derivative that contains a cyclized benzimidazole ring system. Other compounds in this class include cyclorphine (also known as N-propionitrile chlorphine), and 5,6-dichloro desmethylchlorpine (also known as S-17018), and 5,6-dichloro brorphine (also known as SR-14968). 

Chemical Structure of Brorphine Drawn by Kevin G. Shanks (2026)

The other structural group of orphine compounds are the spiropiperidine derivatives, which contain a spiro-linked piperidine ring fused with an imidazole or other related aromatic system. Compounds in this class include spirorphine, spirochlorphine, and spirobrorphine. 

The orphines may differ from the traditional morphine derivatives and the typical fentanyl analogs in chemical structure, but the pharmacological effect is similar, as they act as potent mu opioid receptor agonists. This activity produces analgesia, euphoria, sedation, central nervous system depression, and respiratory depression. In overdose, the breathing slows down, and may stop temporarily (apnea).  Apnea leads to hypoxia, or lack of oxygen distribution to the surrounding tissues including the brain. Hypoxia can lead to cardiac arrest and death. 

Chemical Structure of Cyclorphine  Drawn by Kevin G. Shanks (2026)

The orphine class of opioids is particularly concerning from a toxicological perspective as some of the analogs are considered to be high potency, with several of them being similar to fentanyl in pharmacological activity. Many of these compounds have very limited toxicological data as they never underwent routine animal or human clinical testing. Because of these factors and with the potential increased prevalence in drug materials on the street, forensic toxicology laboratories have begun expanding their analytical methods to identify these compounds in postmortem analyses. As always, the cycle of innovation by clandestine chemists and then governmental prohibition drives the continual appearance of new opioids on the drug market. Although only a limited number of analogs have been detected so far, their appearance illustrates how the drug market changes rapidly over the course of months and years. 

Axis Forensic Toxicology has been testing for brorphine since 2023 and recently added chlorphine, N-propionitrile chlorphine (cyclorphine), 5,6-dichloro brorphine, 5,6-dichloro desmethylchlorphine, spirobrorphine, and spirochlorphine to a newly developed Orphine Analog Panel (order code 13410), and Comprehensive Panel, Blood with Analyte Assurance™ (order code 70510) using liquid chromatography with quadrupole time of flight mass spectrometry (LC-QToF-MS). Reporting of these analytes is qualitative. Reporting limits are 10 ng/mL for 5,6-dichloro brorphine and 5,6-dichloro desmethylchlorphine and 1 ng/mL for chlorphine, N-propionitrile chlorphine, spirobrorphine, and spirorchlorphine. 

If you have any questions or concerns regarding the role of these orphine opioids or any other newly emerged substance in your investigation, please reach out to our Axis Forensic Toxicology subject matter experts at [email protected] or by phone (317-759-4869, Option 3). To stay current with the scope of testing for all services offered by Axis, please consult the online catalog.