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Vaccine-driven pharmacodynamic dissection and mitigation of fenethylline psychoactivity


Fenethylline, also known by the trade name Captagon, is a synthetic psychoactive stimulant that has recently been linked to a substance-use disorder and ‘pharmacoterrorism’ in the Middle East1,2,3,4. Although fenethylline shares a common phenethylamine core with other amphetamine-type stimulants, it also incorporates a covalently linked xanthine moiety into its parent structure5,6. These independently active pharmacophores are liberated during metabolism, resulting in the release of a structurally diverse chemical mixture into the central nervous system7,8,9. Although the psychoactive properties of fenethylline have been reported to differ from those of other synthetic stimulants, the in vivo chemical complexity it manifests upon ingestion has impeded efforts to unambiguously identify the specific species responsible for these effects10,11. Here we develop a ‘dissection through vaccination’ approach, called DISSECTIV, to mitigate the psychoactive effects of fenethylline and show that its rapid-onset and distinct psychoactive properties are facilitated by functional synergy between theophylline and amphetamine. Our results demonstrate that incremental vaccination against a single chemical species within a multi-component mixture can be used to uncover emergent properties arising from polypharmacological activity. We anticipate that DISSECTIV will be used to expose unidentified active chemical species and resolve pharmacodynamic interactions within other chemically complex systems, such as those found in counterfeit or illegal drug preparations, post-metabolic tissue samples and natural product extracts.

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Figure 1: Vaccination with FEN–KLH hapten generates antibodies against fenethylline and its active metabolites.
Figure 2: Vaccination with FEN–KLH blunts the behavioural effects of fenethylline.
Figure 3: Vaccination with THEO–KLH and 1-A1–KLH haptens reveals dominant activity for amphetamine.
Figure 4: Synergistic stimulant effects of theophylline and fenethylline support activity of fenethylline.

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  1. Katselou, M. et al. Fenethylline (Captagon) abuse—local problems from an old drug become universal. Basic Clin. Pharmacol. Toxicol. 119, 133–140 (2016)

    Article  CAS  Google Scholar 

  2. Al-Hemiary, N. J., Al-Diwan, J. K., Hasson, A. L. & Rawson, R. A. Drug and alcohol use in Iraq: findings of the inaugural Iraqi Community Epidemiological Workgroup. Subst. Use Misuse 49, 1759–1763 (2014)

    Article  Google Scholar 

  3. Van Hout, M. C. & Wells, J. Is Captagon (fenethylline) helping to fuel the Syrian conflict? Addiction 111, 748–749 (2016)

    Article  Google Scholar 

  4. Fond, G. & Howes, O. Pharmacoterrorism: the potential role of psychoactive drugs in the Paris and Tunisian attacks. Psychopharmacology (Berl.) 233, 933–935 (2016)

    Article  CAS  Google Scholar 

  5. Klingler, K. H. Theophylline derivatives. US patent 3245994 (1966)

  6. Kristen, G., Schaefer, A. & von Schlichtegroll, A. Fenetylline: therapeutic use, misuse and/or abuse. Drug Alcohol Depend. 17, 259–271 (1986)

    Article  CAS  Google Scholar 

  7. Ellison, T., Levy, L., Bolger, J. W. & Okun, R. The metabolic fate of 3H-fenetylline in man. Eur. J. Pharmacol. 13, 123–128 (1970)

    Article  CAS  Google Scholar 

  8. Yoshimura, H., Yoshimitsu, T., Yamada, H., Koga, N. & Oguri, K. Metabolic fate of fenetylline in rat and man. Xenobiotica 18, 929–940 (1988)

    Article  CAS  Google Scholar 

  9. Kraemer, T. & Maurer, H. H. Toxicokinetics of amphetamines: metabolism and toxicokinetic data of designer drugs, amphetamine, methamphetamine, and their N-alkyl derivatives. Ther. Drug Monit. 24, 277–289 (2002)

    Article  CAS  Google Scholar 

  10. Nickel, B., Niebch, G., Peter, G., von Schlichtegroll, A. & Tibes, U. Fenetylline: new results on pharmacology, metabolism and kinetics. Drug Alcohol Depend. 17, 235–257 (1986)

    Article  CAS  Google Scholar 

  11. Dimpfel, W., Spüler, M., Nickel, B. & Tibes, U. ‘Fingerprints’ of central stimulatory drug effects by means of quantitative radioelectroencephalography in the rat (tele-stereo-EEG). Neuropsychobiology 15, 101–108 (1986)

    Article  CAS  Google Scholar 

  12. Nelson, M. E., Bryant, S. M. & Aks, S. E. Emerging drugs of abuse. Emerg. Med. Clin. North Am. 32, 1–28 (2014)

    Article  Google Scholar 

  13. Christophersen, A. S. Amphetamine designer drugs—an overview and epidemiology. Toxicol. Lett. 112–113, 127–131 (2000)

    Article  Google Scholar 

  14. United Nations International Drug Control Programme. World drug report. Trends Organ. Crime 3, 11–14 (1997)

  15. Keup, W. Use, indications and distribution in different countries of the stimulant and hallucinogenic amphetamine derivatives under consideration by WHO. Drug Alcohol Depend. 17, 169–192 (1986)

    Article  CAS  Google Scholar 

  16. Al-Imam, A. et al. Captagon: use and trade in the Middle East. Hum. Psychopharmacol. 32, e2548 (2017)

    Article  Google Scholar 

  17. Alabdalla, M. A. Chemical characterization of counterfeit captagon tablets seized in Jordan. Forensic Sci. Int. 152, 185–188 (2005)

    Article  CAS  Google Scholar 

  18. Wood, S., Sage, J. R., Shuman, T. & Anagnostaras, S. G. Psychostimulants and cognition: a continuum of behavioral and cognitive activation. Pharmacol. Rev. 66, 193–221 (2013)

    Article  Google Scholar 

  19. Shufman, E. & Dickman, M. Fenethyllin psychosis: description of two cases. Isr. J. Psychiatry Relat. Sci. 36, 129–131 (1999)

    CAS  PubMed  Google Scholar 

  20. Rasmussen, N. Medical science and the military: the Allies’ use of amphetamine during World War II. J. Interdiscip. Hist. 42, 205–233 (2011)

    Article  Google Scholar 

  21. Kinsey, B. Vaccines against drugs of abuse: where are we now? Ther. Adv. Vaccines 2, 106–117 (2014)

    Article  Google Scholar 

  22. Schlosburg, J. E. et al. Dynamic vaccine blocks relapse to compulsive intake of heroin. Proc. Natl Acad. Sci. USA 110, 9036–9041 (2013)

    Article  ADS  CAS  Google Scholar 

  23. Biała, G. & Kruk, M. Amphetamine-induced anxiety-related behavior in animal models. Pharmacol. Rep. 59, 636–644 (2007)

    PubMed  Google Scholar 

  24. Richards, H. J., Benson, V., Donnelly, N. & Hadwin, J. A. Exploring the function of selective attention and hypervigilance for threat in anxiety. Clin. Psychol. Rev. 34, 1–13 (2014)

    Article  Google Scholar 

  25. Gooyit, M., Miranda, P. O., Wenthur, C. J., Ducime, A. & Janda, K. D. Influencing antibody-mediated attenuation of methamphetamine CNS distribution through vaccine linker design. ACS Chem. Neurosci. 8, 468–472 (2017)

    Article  CAS  Google Scholar 

  26. Haile, C. N. et al. Altered methamphetamine place conditioning in mice vaccinated with a succinyl-methamphetamine-tetanus-toxoid vaccine. Am. J. Addict. 24, 748–755 (2015)

    Article  Google Scholar 

  27. Justinova, Z. et al. Involvement of adenosine A1 and A2A receptors in the adenosinergic modulation of the discriminative-stimulus effects of cocaine and methamphetamine in rats. J. Pharmacol. Exp. Ther. 307, 977–986 (2003)

    Article  CAS  Google Scholar 

  28. Franco, R. et al. Evidence for adenosine/dopamine receptor interactions: indications for heteromerization. Neuropsychopharmacology 23 (Suppl), S50–S59 (2000)

    Article  CAS  Google Scholar 

  29. Heller, A. R., Heger, J., Gama de Abreu, M. & Müller, M. P. Cafedrine/theodrenaline in anaesthesia: influencing factors in restoring arterial blood pressure. Anaesthesist 64, 190–196 (2015)

    Article  CAS  Google Scholar 

  30. Kimishima, A., Wenthur, C. J., Zhou, B. & Janda, K. D. An advance in prescription opioid vaccines: overdose mortality reduction and extraordinary alteration of drug half-life. ACS Chem. Biol. 12, 36–40 (2017)

    Article  CAS  Google Scholar 

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This work was supported by a grant from the NIH (DA024705-06). We thank M. Gooyit for supplying reagents, B. Ellis for assistance with tissue collection and M. Taffe for providing DEA licensing (RT0485537). This is manuscript 29481 from The Scripps Research Institute.

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Authors and Affiliations



C.J.W. designed and carried out the chemistry, enzyme-linked immunosorbent assays and in vivo behavioural experiments, analysed and interpreted the data and prepared the manuscript. B.Z. carried out and analysed the surface plasmon resonance experiments. K.D.J. oversaw design of the experiments, interpretation of the data and preparation of the manuscript.

Corresponding author

Correspondence to Kim D. Janda.

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The authors declare no competing financial interests.

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Reviewer Information Nature thanks P. Kenny, M. Pravetoni and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Figure 1 General schematic demonstrating the concept behind using DISSECTIV to isolate CNS activity of single chemical species within a complex chemical mixture that elicits psychoactive effects.

Mixtures of known (solid) and unknown (dashed) chemical species are frequently observed due to active metabolite generation from a parent compound, within natural products, toxins or their extracts, and in counterfeit or clandestine production of synthetic drugs. In DISSECTIV, incremental vaccination against individual known chemical species can identify effects due to the actions of those species (A/B), effects emerging from the interaction of multiple known species (C), effects due to actions of unknown species (D) or effects emerging from the interaction of known and unknown species (E). Furthermore, while five discrete ‘all or nothing’ effects are listed here for clarity, the approach can also be used to determine the impact of each compound in altering the magnitude of each discrete effect.

Extended Data Figure 2 Conjugation of FEN, THEO, 1-A1 and AMPH haptens to BSA.

a, BSA (m/z 66,134–66,284; ESI+ m/z 66,431). b, FEN–BSA (m/z 70,031–70,106). c, THEO–BSA (m/z 69,424–71,275). d, 1-A1–BSA (m/z 70,727–71,058). e, AMPH–BSA (m/z 69,563). Representative data shown for BSA, FEN–BSA, THEO–BSA and 1-A1–BSA; two replicates.

Extended Data Figure 3 Standard curves used to quantify the concentrations of drugs in biological tissue samples.

a, b, Standard curves for fenethylline (solid circles) at low (a, slope = 44,941 ± 1,026; r2 = 0.9806) and high (b, slope = 45,929 ± 143.1; r2 = 0.9998) concentrations in the presence of fenethylline-d3 (open circles) as an internal standard. c, d, Standard curve for theophylline (solid triangles) at low (c, slope = 93,380 ± 844.4; r2 = 0.9970) and high (d, slope = 83,746 ± 1,406; r2 = 0.9954) concentrations in the presence of theophylline-d6 (open triangles) as an internal standard. e, f, Standard curve for amphetamine (solid squares) at low (e, slope = 299,394 ± 1,980; r2 = 0.9995) and high (f, slope = 254,747 ± 16,197; r2 = 0.9898) concentrations in the presence of amphetamine-d11 (open squares) as an internal standard. All lines fit through the origin.

Source data

Extended Data Figure 4 Vaccination with FEN–KLH blunts the behavioural effects of amphetamine and methamphetamine.

a, Amphetamine (2 mg kg−1) locomotor behaviour in animals vaccinated with KLH or FEN–KLH (Pinteraction < 0.0001; F30,240 = 3.70); *P < 0.01 versus KLH, Bonferroni correction). n = 5, repeated-measures two-way ANOVA. b, Methamphetamine (2 mg kg−1) locomotor behaviour in animals vaccinated with KLH (n = 9) or FEN–KLH (n = 11) (Pinteraction = 0.0385; F30,540 = 1.52; *P < 0.01 versus KLH, Bonferroni correction). Repeated-measures two-way ANOVA. c, EPM in KLH-vaccinated animals following saline (n = 9), amphetamine (A., 2 mg kg−1, n = 10) or methamphetamine (M., 2 mg kg−1, n = 10) administration. One-way ANOVA (P = 0.1325; F2,26 = 2.187). d, EPM in FEN–KLH-vaccinated animals following saline (n = 9), amphetamine (2 mg kg−1, n = 10) or methamphetamine (2 mg kg−1, n = 10) administration. One-way ANOVA (P = 0.9588; F2,26 = 0.042). a, b, Data are presented as mean ± s.e.m. c, d, Data are shown as median with quartiles ± 10–90% CI; +, mean.

Source data

Extended Data Figure 5 Vaccination with AMPH–KLH generates ineffective antibodies.

a, Midpoint titres, day 35. Dotted line is mean 1-A1–KLH titre (n = 6). b, AMPH–KLH serum binding to AMPH–BSA with competing fenethylline or amphetamine. Data are pooled from n = 6, two replicates. Dotted line is mean 1-A1–KLH + amphetamine binding. c, Total hyperlocomotion (90 min) due to fenethylline (20 mg kg−1) in KLH-vaccinated (n = 6) and AMPH–KLH-vaccinated (n = 6) animals. Dotted line is mean 1-A1–KLH + fenethylline 20 mg kg−1 locomotor response, t-test (P = 0.3584, d.f. = 9). a, c, Data are shown as median with quartiles ± 10–90% CI; +, mean). b, Data are presented as mean ± s.e.m.

Source data

Extended Data Table 1 Fenethylline binding to CNS targets
Extended Data Table 2 Binding and behavioural activity summary for DISSECTIV results

Supplementary information

Supplementary Information

This file contains Supplementary Methods and Supplementary Figures 1-10. (PDF 524 kb)

Reporting Summary (PDF 69 kb)

Supplementary Data

This file contains source data for Extended Data Table 2. (XLSX 23 kb)

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Wenthur, C., Zhou, B. & Janda, K. Vaccine-driven pharmacodynamic dissection and mitigation of fenethylline psychoactivity. Nature 548, 476–479 (2017).

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