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.