BLOG & STORIES

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.

By Kevin Shanks, D-ABFT-FT

It has been a little over 4 years since Axis mentioned synthetic cannabinoids on this blog. So, briefly, synthetic cannabinoids are man-made compounds that bind to cannabinoid receptors 1 (CB1) and 2 (CB2) in the body and mediate effects of the endocannabinoid receptor system.  While delta-9-tetrahydrocannabinol (THC), the main psychoactive cannabinoid found in cannabis, is a partial agonist of the cannabinoid receptors, most synthetic cannabinoids are full agonists at the same receptors. Synthetic cannabinoids are comprised of many structural variants, which change over time as compounds are controlled by Federal and state governments. Synthetic cannabinoids have been implicated in several outbreaks of illnesses and hospitalizations in the USA as well as associated with cause of death in postmortem toxicology. 

Chemical Structure of 5F-ADB  Drawn by Kevin G. Shanks (2025)

Methyl-2-[1-(5-fluoropentyl)-1H-indazole-3-carboxamido]-3,3-dimethylbutanoate, also known as 5F-ADB or 5F-MDMB-PINACA, is a potent synthetic cannabinoid compound that first emerged in  Japan in late 2014 when it was identified on plant material products. Synthetic cannabinoids are commonly sprayed on plant material or soaked into small pieces of paper. 5F-ADB’s molecular formula is C20H28FN3O3 and its molecular weight is 377.4 g/mol. 5F-ADB is of the indazole-3-carboxamide family of compounds and consists of an indazole core structure, a fluorinated pentyl chain, and a carboxamide linking group. Common adverse effects after consumption of the substance include psychomotor agitation, tachycardia, confusion, anxiety, and loss of consciousness, psychosis, and fatality. 

5F-ADB Detections by US DEA Reported in NFLIS Annual Drug Reports (2015-2022)

The drug was first reported by the United States Drug Enforcement Administration (DEA) in 2014 and emerged in toxicology testing in 2015. It was made a Schedule I controlled substance in the USA in 2017. After emergence, 5F-ADB hit peak prevalence in 2018 and then rapidly disappeared from the illicit drug market with just a handful of reports by the DEA by 2022. During 2021-2022, Axis Forensic Toxicology had zero detections of 5F-ADB in postmortem toxicology testing. Because of the combined DEA and Axis data, the lab decided to remove it from the scope of synthetic cannabinoid testing in 2022. 

Until recently, the compound was considered to be non-existent on the street, but new reports suggest 5F-ADB has made a comeback as one of the top synthetic cannabinoids of choice in the USA. Published reports from NPS Discovery and the Center for Forensic Science Research and Education (CFSRE) in 2025 detail 5F-ADB’s comeback as either the first or second most identified synthetic cannabinoid in cases sent to them. Axis Forensic Toxicology has also spoken to pathologists who have had positive casework for 5F-ADB, over the last few months, especially in the prison population. Because of these recent events, the lab has added 5F-ADB back into the screening scope of analysis in the comprehensive panel (order code 70510). 5F-ADB is rapidly metabolized/degraded to its 3,3-dimethylbutanoic acid metabolite by enzymes in the blood and therefore must be analyzed by monitoring the metabolic product. The reporting limit for 5F-ADB 3,3-dimethylbutanoic acid on the screening test is 2 ng/mL. The result is reported as qualitative. Instrumentation used for analysis is liquid chromatography with quadrupole time of flight mass spectrometry (LC-qToF-MS). Upon publication of this blog post, Axis has had recent detections of 5F-ADB via its metabolite in 5 different states – Florida, Indiana, Missouri, Ohio, and South Dakota. 

It is important to remember that while most novel psychoactive substances emerge and then disappear rapidly from the illicit market, some persist for months and years. And in the case of 5F-ADB, it emerged, peaked, rapidly disappeared, and now has made a resurgence years later. As a toxicology laboratory, it is prudent to monitor the ever-changing scope of the drug market and adapt testing panels accordingly. The current scope of testing offered by Axis Forensic Toxicology can be found in the online test catalog at https://axisfortox.com. As always, if you have questions about 5F-ADB or any other synthetic cannabinoid substances and how they may play a role in your medical-legal investigation, please reach out to our subject matter experts by email ([email protected]) or phone (317-759-4869, Option 3).  

References 

• Synthetic Cannabinoids. Disposition of Toxic Drugs and Chemicals in Man. Twelfth Edition. Randall C. Baselt. Biomedical Publications. Pages 1979-1986. (2020).  
• Tetrahydrocannabinol. Disposition of Toxic Drugs and Chemicals in Man. Twelfth Edition. Randall C. Baselt. Biomedical Publications. Pages 2041-2045. (2020).  
• Synthetic Cannabinoid Receptor Agonists. Novel Psychoactive Substances: Classification, Pharmacology, and Toxicology. Paul Dargan and David Wood. Academic Press (Elsevier). 317-338. (2013). 
• NPS Discovery and CFSRE Trend Reports, Q1-Q3, 2025.  
• Axis Forensic Toxicology. Laboratory Data. Indianapolis, IN. (accessed October 2025). 

By Stuart Kurtz, D-ABFT-FT

Axis Forensic Toxicology has previously written on kratom and cases involving kratom fatalities. As a quick recap, Mitragyna speciosa, is a tree or shrub that grows in southeast Asia. It’s part of the Rubiaceae family which includes coffee plants. It can be consumed by chewing leaves, brewing a beverage, or pulverized and smoked or put in a capsule. Fatalities have been reported from kratom use with mitragynine as the primary alkaloid responsible for toxic effects. 

7-OH mitragynine is naturally occurring in the kratom plant at about 2% of the alkaloid content and is 10 times more potent than mitragynine. Reported side effects include agitation, nausea, vomiting, confusion, seizures, and fast heart rate. Due to activity at the mu opioid receptor, the receptor primarily associated with opioids such as fentanyl and morphine, severe cases can present similar to opioid overdoses. 7-OH mitragynine is further metabolized into mitragynine pseudoindoxyl which is 100 times more potent than mitragynine. Mitragynine pseudoindoxyl is also found in the kratom plant in low concentrations. Labs that test for mitragynine may not currently be testing for 7-OH mitragynine. Historically, the concern with kratom related toxicity has been centered on testing for mitragynine since that was the primary alkaloid in kratom products. However, new products may contain higher amounts of 7-OH mitragynine and/or mitragynine pseudoindoxyl and low or no amount of mitragynine which investigators and labs should be aware of moving forward with these cases. 

Image from United States Food and Drug Administration showing 7-OH mitragynine extract (left), powder (middle), and gummies (right). 

7-OH mitragynine products are manufactured by converting mitragynine in the kratom plant to 7-OH mitragynine. Available products containing primarily 7-OH mitragynine include concentrates, edibles, extracts, beverages, and tablets for chewing or swallowing. Testing of these products shows that they are primarily 7-OH mitragynine with a variable amount of unconverted mitragynine and other products that could be related to the synthesis process. These can often be found in stores that also sell kratom products and lead to confusion as to what the buyer is actually getting. Given the increase in potency of 7-OH mitragynine compared to mitragynine, the primary alkaloid in kratom, a naïve user may experience a toxic event if they are expecting the product to behave like kratom. 

Image from United Nations Office on Drugs and Crime Laboratory and Scientific Services Portal showing 7-OH mitragynine tablets and testing results of the contents. 

Interpretation can be tricky when it comes to mitragynine presence. It can be associated with kratom use or synthesis of mitragynine to produce the more potent 7-OH mitragynine instead of, or in addition to, mitragynine. A good indicator will be what products are found at the scene and if they are consistent in how they are labeled between products. A product labeled as kratom or mitragynine may actually be a 7-OH mitragynine product especially since the FDA is currently in the process of scheduling mitragynine only, which may lead to more products containing 7-OH mitragynine to avoid legal issues. Therefore, testing for both mitragynine and 7-OH mitragynine will be useful. Axis recommends that you check the testing scope with your lab to see if they test for one, both, or neither of these compounds. Axis currently screens with LC-QToF-MS for mitragynine and 7-OH mitragynine in our 70510 Comprehensive Panel with Analyte Assurance. Confirmation of mitragynine is quantitative using LC-MS/MS and 7-OH mitragynine is qualitative using LC-QToF-MS. 

If you have any questions regarding this or other topics, please reach out to us via email [email protected] or call at 317-759-4869 option 3. 

Krotulski, AJ; Denn, MT; Brower, JO; Papsun, DM; Logan, BK. (2025), Evaluation of Commercially Available Smoke Shop Products Marketed as “7-Hydroxy Mitragynine” & Related Alkaloids, Center for Forensic Science Research and Education, United States. 

Anderer S. What to Know About 7-OH, the New Vape Shop Hazard. JAMA. 2025;334(12):1045–1046. doi:10.1001/jama.2025.13592 

Smith, K.E., Boyer, E.W., Grundmann, O., McCurdy, C.R. and Sharma, A. (2025), The rise of novel, semi-synthetic 7-hydroxymitragynine products. Addiction, 120: 387-388. https://doi.org/10.1111/add.16728 

Pullman MK, Kanumuri SRR, Leon JF, Cutler SJ, McCurdy CR, Sharma A. Cardio-pulmonary arrest in a patient revived with naloxone following reported use of 7-hydroxymitragynine. Clin Toxicol (Phila). 2025 Sep 30:1-2. doi: 10.1080/15563650.2025.2565428. Epub ahead of print. PMID: 41025553. 

By Kevin Shanks, M.S., D-ABFT-FT

We have previously discussed both fentanyl and 4-ANPP in this blog (1-2), but briefly, fentanyl is a mu opioid receptor agonist that is used as both a pharmaceutical medication and as an illicit drug found on the street typically as a powder or tablet. Fentanyl itself is metabolized primarily by the CYP3A4 enzyme in the human body. It can be dealkylated, hydroxylated, methylated, and hydrolyzed (3-4). At Axis, we monitor for the presence of the unchanged drug, fentanyl, alongside its primary metabolite, norfentanyl, in blood and urine. Several years ago, we added a second fentanyl-related substance to the scope of testing – 4-ANPP. 

Chemical structure of 4-ANPP 
Drawn by Kevin G. Shanks (2022)

So, what is 4-ANPP? The substance is known chemically as N-phenyl-1-(2-phenylethyl)-4-piperidinamine, but is also referred to as despropionyl fentanyl. It is formed via amide hydrolysis of the parent substance. It is considered to be a minor inactive metabolite of fentanyl – meaning it does not produce a pharmacological effect on the body (5-6). But it is also a precursor or starting material used in the synthesis of illicitly manufactured fentanyl and various related fentanyl derivatives or analogs. As an example, 4-ANPP can be reacted with propionyl anhydride to form fentanyl or acetic anhydride to form acetylfentanyl. 4-ANPP is not used in the synthesis of pharmaceutical-grade fentanyl. 

Why is all of this important? The presence of illicitly manufactured fentanyl in the street drug supply in the USA has rapidly increased over the past 10-12 years (7). And with that increased presence comes a large increase in overdose deaths due to the substance. Recent CDC data shows that over 100,000 people died yearly from drug overdoses in the USA in 2022-2024, with the major driving factor being the prevalence of illicit fentanyl in the street drug supply (8). 

Ultimately, the presence of 4-ANPP in a biological specimen such as blood or urine is merely a marker for fentanyl use or exposure. The product used may have been either pharmaceutical fentanyl or illicitly manufactured fentanyl. The origin of the fentanyl – pharmaceutical vs. street – cannot be determined by the toxicology results alone. In order to ascertain if 4-ANPP is present in the body from metabolism or if it was ingested by using an impure illicit street product, testing must be conducted on evidence from the scene which may include unidentified powders or tablets. If 4-ANPP is detected in the non-biological evidence, then it may be determined that the fentanyl exposure is from a non-pharmaceutical origin.  

Axis Forensic Toxicology tests for the presence of 4-ANPP in our Comprehensive Drug Panel with Analyte Assurance™, Blood (order code 70510), which is completed by liquid chromatography with quadrupole time of flight mass spectrometry (LC-QToF-MS) and liquid chromatography with tandem mass spectrometry (LC-MS/MS). The reporting limit is 100 pg/mL and the substance is reported as qualitatively positive or negative – it is not reported quantitatively. 

If you have any questions regarding the presence or absence of 4-ANPP or its role in your toxicology casework, please reach out to Axis’ subject matter experts at [email protected]. 

References

1. Drug Primer: Fentanyl (2021). Axis Forensic Toxicology Blog. Drug Primer: Fentanyl – Axis Forensic Toxicology (axisfortox.com). 
2. Drug Primer: 4-ANPP (2022). Axis Forensic Toxicology Blog. Drug Primer: 4-ANPP – Axis Forensic Toxicology (axisfortox.com). 
3. Fentanyl. Disposition of Toxic Drugs and Chemicals in Man. Twelfth Edition. Randall C. Baselt. Biomedical Publications. Pages 844-847. (2020).  
4. Opioids. Principles of Forensic Toxicology. Fourth Edition. Barry Levine. AACC, Inc. Pages 271-291 (2017). 
5. Labroo, R.B., Paine, M.F., Thummel, K.E., Kharasch, E.D. (1997) Fentanyl Metabolism by Human Hepatic and Intestinal Cytochrome P450 3A4: Implications for Interindividual Variability in Disposition, Efficacy, and Drug Interactions. Drug Metabolism and Disposition, 25: 9. 1072-1080. 
6. Wilde, M., Pichini, S., Pacifici, R., Tagliabracci, A. et al. (2019) Metabolic Pathways and Potencies of New Fentanyl Analogs. Frontiers in Pharmacology, 10: 238. 1-16. 
7. 2022 Annual Drug Report. National Forensic Laboratory Information System (NFLIS). Drug Enforcement Administration. Springfield, VA. 
8. Provisional Drug Overdose Death Counts. National Vital Statistics System. Center for Disease Control. Vital Statistics Rapid Release – Provisional Drug Overdose Data. (Accessed 07/31/2025).