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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. 

By Laureen J. Marinetti, PhD, F-ABFT

BTMPS (Bis[2,2,6,6-tetramethyl-4-piperidyl] sebacate), brand name Tinuvin®770, is commonly used in the manufacture of plastics as a UV-stabilizing additive to prevent degradation from sunlight and weather exposure. BTMPS was first identified in the U.S. illicit drug market in mid-2024 and spread rapidly across the country. The first identifications were by community drug checking organizations which identified BTMPS using Fourier Transform Infrared spectroscopy (FTIR). BTMPS is not the only impurity that may be found in the drug supply about which little is known, and not even the only light stabilizer normally used in manufacturing. For example, 2,2,6,6-tetramethyl-4-piperidinol has also been detected, but not in the quantities observed for BTMPS.

BTMPS is often found in samples alongside fentanyl, synthetic opioids, and stimulants, and sometimes at a greater concentration than the illicit drug. BTMPS’s appearance coincided with disruptions in the usual drug supply chain and reports of unusual odors and tastes in samples. BTMPS does not produce a “high” or any known psychoactive effects in humans. It may be used as a bulking agent to increase volume for profit or potentially to stabilize other chemical precursors.

Chemical Structure of BTMPS drawn by Kevin G. Shanks (2026)

BTMPS is not approved or studied for human use. Animal studies suggest potential cardiotoxicity, ocular damage, neurotoxicity, and sudden death. The safety data sheet for BTMPS states that human exposure can result in eye damage and skin irritation. BTMPS is a potent calcium channel blocker and nicotine receptor antagonist, which may enhance the toxicity of cooccurring substances.

Axis has confirmed one positive case with BTMPS in a blood sample. The case was an oxycodone overdose with a very high concentration of oxycodone and no illicit drugs detected. It is possible that the BTMPS was a contaminant on the oxycodone pills from the plastic medication bottle, and because so many of them were ingested at one time, the BTMPS accumulated to a detectable concentration. In the Washington drug detection data, it was found that in the following potential licit drug samples, BTMPS was detected. In 296 prescription opioid samples, 3.4% were positive for BTMPS, and in 163 samples sold as M30s (prescription oxycodone) or Percocet, 3.7% were positive for BTMPS.

BTMPS likely ended up in the illicit drug supply because it is cheap, readily available, and possibly introduced through contaminated precursor chemicals or manufacturing streams. It provides no known benefit to users and may increase health risks due to its toxicological profile. Axis monitors BTMPS 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).  

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

References

• UV Stabilizer BTMPS in the Illicit Fentanyl Supply in 9 US Locations, Letter, Journal of the American Medical Association, February 5, 2025.
• Where do we see BTMPS?, Addictions, Drug and Alcohol Institute, University of Washington, https://adai.washington.edu/WAdata/DrugChecking/BTMPS.html, 2025.

By Kevin Shanks, D-ABFT-FT

Stimulants come and go. New ones arrive on the illicit drug market all the time. One of the newest stimulants to be identified is MDPHP, also known as 3′,4′-Methylenedioxy-α-pyrrolidinohexiophenone. It is a substituted cathinone, a class of compounds related to cathinone, a naturally occurring stimulant alkaloid found in the plant Catha edulus (khat). MDPHP belongs to the pyrrolidinophenone subclass and is structurally related to older stimulant compounds, alpha-PVP and MDPV. MDPHP first appeared on world drug markets around 2014-2015, but has recently seen an increase in prevalence. While not explicitly listed as a controlled substance in the United States, it may be considered a positional isomer of the already controlled MDPV and alpha-PVP, and therefore be considered illegal to manufacture, possess, distribute, and consume.  

Chemical Structure of MDPHP drawn by Kevin G. Shanks (2026)

Pharmacologically, the substituted cathinones class primarily acts on monoamine transporters in the body and inhibits the reuptake of dopamine, norepinephrine, and/or serotonin and may act as releasers of any of the three neurotransmitters. MDPHP acts primarily as a dopamine and norepinephrine reuptake inhibitor. The end result of this action is an increased concentration of neurotransmitters in the nerve cell synapse, which leads to stimulant physiological effects on the body. People who use stimulants are typically seeking the desired effects such as euphoria, increased energy, sociability, and alertness. But adverse effects include anxiety, agitation, paranoia, hallucinations, and aggression. When taken in overdose, acute toxicity is demonstrated via hypertension, hyperthermia, tachycardia, severe agitation, hallucinations, seizure, kidney failure, rhabdomyolysis, and death. Chronic use can manifest in cognitive impairment, sleepiness/tiredness, psychosis, physical and psychological dependence and addiction. 

MDPHP has been implicated in fatalities in peer-reviewed published literature. In one case published by Di Candia et al., a 48 year old male with back and leg pain was found semi-unconscious on a public street. Emergency personnel were called and they documented history to include an HIV+ status and amnesia. After arrival at the hospital, his breathing and heart rate increased and he became unconscious before respiratory and cardiac activity stopped and could not be regained. At autopsy, various bone fractures, cerebral and pulmonary congestion and edema, and atrial and ventricular hemorrhages were documented. Toxicological analysis of postmortem femoral blood was positive for MDPHP (399 ng/mL). 

In a second case published by Croce et al. a 30 year old male with a history of drug use and addiction was found deceased in his bedroom. He was last seen alive 24 hours prior to discovery. At autopsy, pleural visceral congestion, pulmonary edema, and moderate hepatic steatosis were observed. Toxicological analysis was completed on postmortem central blood and peripheral blood, among other specimens drawn at autopsy. MDPHP was positive in the central blood (1,639.99 ng/mL) and in the peripheral blood (1,601.90 ng/mL).  

In a third case published by Casati et al. a 58 year old male was found floating in the water. He was last seen alive 7 days prior. Documented medical history included HIV+ status and he regularly used MDPV. At autopsy, rigor was present. Both hands were macerated and the heart was enlarged with mild ventricular hypertrophy. Cerebral and pulmonary congestion were also observed. Toxicological analysis was positive for MDPHP in femoral blood (350 ng/mL) and central blood (110 ng/mL). Other substances present included MDPV, MDPPP, MDPBP, citalopram, clonazepam, and 7-aminoclonazepam. 

As a new stimulant, it is prudent to be aware of MDPHP and its availability on the illicit drug market. Axis monitors MDPHP 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).  

If you have questions about MDPHP and how it 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 

• Di Candia, D., Boracchi, M., Ciprandi, B. et al. (2022) A unique case of death by MDPHP with no other co-ingestion: a forensic toxicology case. International Journal of Legal Medicine.  DOI: https://doi.org/10.1007/s00414-022-02799-w 
• Croce, E.B., Dimitrova, A., Grazia Di Mili, M. et al. (2025) Postmortem distribution of MDPHP in a fatal intoxication case. Journal of Analytical Toxicology.  DOI: https://doi.org/10.1093/jat/bkae092 
• Casati, S., Ravelli, A., Dei Cas, M. et al. (2025) Polydrug fatal intoxication involving MDPHP: Detection and in silico investigation of multiple 3,4-methylenedioxy-derived designer drugs and their metabolites. Journal of Analytical Toxicology.  DOI: https://doi.org/10.1093/jat/bkaf048 

By Stuart Kurtz, D-ABFT-FT

Drug Primer: Diphenidine 

1-(1,2-diphenylethyl)piperidine, commonly known as diphenidine, is part of the 1,2-diarylethylamine class. This class includes drugs such as phencyclidine (PCP), 3-methoxyphencyclidine (3-MeO-PCP), and ketamine. These compounds can interact with many different systems in the body depending on the groups attached to the core structure. These pharmacological interactions can include activation of opioid receptors, inhibition of monoamine transporters, and antagonism of glutamatergic N-methyl-D-aspartate (NMDA) receptors. NMDA receptor antagonism is part of the dissociative aspect of these compounds but how they affect other receptors is also a factor. 

Structures of several compounds related to PCP. Diphenidine is pictured in the bottom row in the middle. From Wallach, et. al., 2016. 

Diphenidine interacts with NMDA receptors, serotonin transporter inhibitors, dopamine receptors, and opioid receptors. There have been no human clinical trials for diphenidine so the effects in humans are not well known. Similarity to other substances, such as ketamine, can give some estimation of its effects. Limited toxicity data is available from documented cases of exposure that can also help determine what effects can be expected. Dissociative effects have been reported at lower doses with higher doses causing somatosensory phenomena and transient anterograde amnesia. Reported duration of these effects is about 3-6 hours. Reported adverse effects include hypertension, tachycardia, agitation, muscle rigidity, anxiety, confusion, disorientation, dissociation, and hallucinations. 

In one case report, a 30 year-old white male was found confused and agitated by his bed. A small baggie labeled as 1g diphenidine was on the floor nearby. Midazolam was administered by first responders at the scene and on route to the hospital with minimal effect on his mental state. Observed symptoms included increased heart rate (tachycardia), increased respiratory rate (tachypnea), and small (miotic) pupils. Examination at the hospital determined body temperature was slightly elevated at 100.4°F (38.0°C) and metabolic acidosis with a blood pH of 7.17. Normal blood pH is 7.35-7.45. Midazolam, diazepam, chlorpheniramine, haloperidol, and sodium bicarbonate were administered intravenously to sedate him and after 90 minutes, he regained consciousness and did not experience any amnesia. He reported to have taken diphenidine approximately 5 hours prior to being found by first responders. After 12 hours, he was discharged with stable heart rate, stable blood pressure, and normal body temperature. 

Diphenidine is not currently scheduled in the United States by the DEA. It is typically sold as a white or yellowish-white powder and consumed by snorting or oral ingestion. It’s marketed as a research chemical and does not have any medical or veterinary use. Because diphenidine exists in a legal gray area, there may be a traceable paper trail, such as records from online vendors and/or bank states documenting its purchase. Additionally, the packaging that it arrives in may be labeled with identifying information. 

Axis now screens and confirms for Diphenidine in the 70510 Comprehensive Panel, Blood and Analyte Assurance. For questions about diphenidine or other assistance with interpretation, please call us at 317-759-4869 option 3 or email us at [email protected]. 

• Wallach J, Kang H, Colestock T, Morris H, Bortolotto ZA, et al. (2016) Pharmacological Investigations of the Dissociative ‘Legal Highs’ Diphenidine, Methoxphenidine and Analogues. PLOS ONE 11(6): e0157021. https://doi.org/10.1371/journal.pone.0157021. 
• Wink CS, Michely JA, Jacobsen-Bauer A, Zapp J, Maurer HH. Diphenidine, a new psychoactive substance: metabolic fate elucidated with rat urine and human liver preparations and detectability in urine using GC-MS, LC-MSn , and LC-HR-MSn. Drug Test Anal. 2016 Oct;8(10):1005-1014. doi: 10.1002/dta.1946. Epub 2016 Jan 26. PMID: 26811026. 
• Gerace E, Bovetto E, Corcia DD, Vincenti M, Salomone A. A Case of Nonfatal Intoxication Associated with the Recreational use of Diphenidine. J Forensic Sci. 2017 Jul;62(4):1107-1111. doi: 10.1111/1556-4029.13355. Epub 2017 Jun 9. PMID: 28597920.