Abuse Liability Assessment

Academic focus on drug abuse research and education from 1985 to 1996. Experience in Safety Pharmacology from 1997 to 1999 at a contract research organization (CRO) with a focus on neurobehavioral assessments including abuse potential. Responsible for the nonclinical development program for a cannabinoid receptor subtype 2 (CB2) immunology program from 2000 to 2005. Served as a subject matter expert (SME) on abuse liability assessment advising all drug development programs advancing to the NDA or BLA stage for a large pharmaceutical company (2005-2020) as well as a small biotech company (2020-2023). Was a planner and/or active participant in numerous Dialogue sessions held publicly between the FDA Controlled Substance Staff (CSS) and industry representatives from 2007 to 2023. Founding member of the Cross-Company Abuse Liability Council (CCALC), served on the Board of CCALC, served as Lead of the Preclinical Abuse Liability (PAL) specialty subgroup of CCALC, and serves on the CCALC Membership Committee. Served as a corporate representative to PhRMA providing industry feedback to FDA on the Draft Guidance for Abuse Liability Assessment. Chapter author and Editor of Nonclinical Assessment of Abuse Potential for New Pharmaceuticals. 1st Edition (01 August 2015); Academic Press, New York.

Book Chapters & Book Editor:

  • Martin, B.R., Compton, D.R., Little, P.J., Martin, T.J., and Beardsley, P.M. (1987) Pharmacological evaluation of agonistic and antagonistic activity of cannabinoids. NIDA Res Monograph 79: 108 -22.
  • Compton, D.R., Little, P.J., and Martin, B.R. (1988) Cannabinoid behaviors: specific versus nonspecific actions in Marijuana '87: Proceedings of the Melbourne Symposium on Cannabis. Melbourne, Australia: NCADA Monograph, Australian Gov't. Publishing Service, Canberra.
  • Compton, D.R., Dewey, W.L., and Martin, B.R. (1990) Cannabis dependence and tolerance production. Adv Alcohol Subst Abuse. 9: 129 -47.
  • Compton, D.R. and Martin, B.R. (1995) Marihuana Neurotoxicology. In: Handbook of Neurotoxicology. Eds. Louis W. Chang and Robert S. Dyer. Marcel Dekker, Inc., New York, p. 871 -890.
  • Compton, D.R., Harris, L.S., Lichtman, A.H., and Martin, B.R. (1995) Marihuana. In: Handbook of Experimental Pharmacology, Pharmacological Aspects of Drug Dependence. Eds. C. R. Schuster, S.W. Gust and M.J. Kuhar, Springer -Verlag, Heidelberg, Vol. 118, ch. 5.
  • Martin, B.R. and Compton, D.R. (1997) Contemporary Drug Abuse. In: Modern Pharmacology with Clinical Applications. Eds. C.R. Craig and R.E. Stitzel. Little, Brown, and Co., Fifth Edition, ch. 37, p. 429 -451.
  • Compton, D.R. and Hudzik, T.J. (2015) Chap. 2: Neurochemistry of Drug Abuse. In: Nonclinical Assessment of Abuse Potential for New Pharmaceuticals. 1st Edition (01 August 2015); Eds. Carrie G. Markgraf. Thomas J. Hudzik, and David R. Compton, Academic Press, New York, p. 9 -48.

Peer Review Manuscripts:

  • Compton, D.R., Bagley, R.B., Katzen, J.S., and Martin, B.R. (1987) (+) and ( -)N -allynormetazocine binding sites in mouse brain: in vitro and in vivo characterization and regional distribution. Life Sci. 40: 2195 -206.
  • Martin, B.R., Compton, D.R., Little, P.J., Martin, T.J., and Beardsley, P.M. (1987) Pharmacological evaluation of agonistic and antagonistic activity of cannabinoids. NIDA Res Monogr. 79: 108 -22.
  • Little, P.J., Compton, D.R., Johnson, M.R., Melvin, L.S., and Martin, B.R. (1988) Pharmacology and stereoselectivity of structurally novel cannabinoids in mice. J Pharmacol Exp Ther. 247: 1046 -51.
  • Lyddane, J.E., Thomas, B.F., Compton, D.R. and Martin, B.R. (1988) Modification of phencyclidine intoxication and biodisposition by charcoal and other treatments. Pharmacol Biochem Behav. 30: 371 -7.
  • Compton, D.R. and Johnson, K.M. (1989) Effects of acute and chronic clozapine and haloperidol on in vitro release of acetylcholine and dopamine from striatum and nucleus accumbens. J Pharmacol Exp Ther. 248: 521 -30.
  • Compton, D.R., Little, P.J., Martin, B.R., Saha, J.K., Gilman, J., Sard, H., and Razdan, R.K. (1989) Synthesis and pharmacological evaluation of mercapto and thioacetyl analogues of cannabidiol and delta -8 -tetrahydrocannabinol, Eur. J. Med. Chem. 24(3): 293 -298. (Note: Not indexed in PubMed/Scopus as of 2022)
  • Little, P.J., Compton, D.R., Mechoulam, R., and Martin, B.R. (1989) Stereochemical effects of 11 -OH -delta 8 -THC -dimethylheptyl in mice and dogs. Pharmacol Biochem Behav. 32: 661 -6.
  • Compton, D.R., Little, P.J., Martin, B.R., Gilman, J.W., Saha, J.K., Jorapur, V.S., Sard, H.P., and Razdan, R.K. (1990) Synthesis and pharmacological evaluation of amino, azido, and nitrogen mustard analogues of 10 -substituted cannabidiol and 11 - or 12 -substituted delta 8 - tetrahydrocannabinol. J Med Chem. 33: 1437 -43.
  • Compton, D.R. and Martin, B.R. (1990) Pharmacological evaluation of water -soluble cannabinoids and related analogs. Life Sci. 46: 1575 -85.
  • Compton, D.R., Dewey, W.L., and Martin, B.R. (1990) Cannabis dependence and tolerance production. Adv Alcohol Subst Abuse. 9: 129 -147.
  • Reggio, P.H., Seltzman, H.H., Compton, D.R., Prescott, W.R., Jr., and Martin, B.R. (1990) Investigation of the role of the phenolic hydroxyl in cannabinoid activity. Mol Pharmacol. 38: 854 -62.
  • Thomas, B.F., Compton, D.R., and Martin, B.R. (1990) Characterization of the lipophilicity of natural and synthetic analogs of delta 9 -tetrahydrocannabinol and its relationship to pharmacological potency. J Pharmacol Exp Ther. 255: 624 -30.
  • Compton, D.R., Prescott, W.R., Jr., Martin, B.R., Siegel, C., Gordon, P.M., and Razdan, R.K. (1991) Synthesis and pharmacological evaluation of ether and related analogues of delta 8, delta 9 -, and delta 9,11 -tetrahydro -cannabinol. J Med Chem. 34: 3310 -6.
  • Charalambous, A., Lin, S., Marciniak, G., Banijamali, A., Friend, F.L., Compton, D.R., Martin, B.R., and Makriyannis, A. (1991) Pharmacological evaluation of halogenated delta 8 -THC analogs. Pharmacol Biochem Behav. 40: 509 -12.
  • Martin, B.R., Compton, D.R., Thomas, B.F., Prescott, W.R., Little, P.J., Razdan, R.K., Johnson, M.R., Melvin, L.S., Mechoulam, R., and Ward, S.J. (1991) Behavioral, biochemical, and molecular modeling evaluations of cannabinoid analogs. Pharmacol Biochem Behav. 40: 471 -8.
  • Reggio, P.H., McGaughey, G.B., Odear, D.F., Seltzman, H.H., Compton, D.R., and Martin, B.R. (1991) A rational search for the separation of psychoactivity and analgesia in cannabinoids. Pharmacol Biochem Behav. 40: 479 -86.
  • Thomas, B.F., Compton, D.R., Martin, B.R., and Semus, S.F. (1991) Modeling the cannabinoid receptor: a three -dimensional quantitative structure -activity analysis. Mol Pharmacol. 40: 656 -65.
  • Compton, D.R., Prescott, W.R., Siegel, C.S., Gordon, P.M., Razdan, R.K., and Martin, B.R. (1990) Evaluation of ether and free hydroxyl analogs of delta -8, delta -9, and delta -9 -11 -THC as cannabinoid antagonists. NIDA Res. Monogr. 105: 297 -298.
  • Compton, D.R., Gold, L.H., Ward, S.J., Balster, R.L., and Martin, B.R. (1992) Aminoalkylindole analogs: cannabimimetic activity of a class of compounds structurally distinct from delta 9 -tetrahydrocannabinol. J Pharmacol Exp Ther. 263: 1118 -26.
  • Compton D.R., Johnson, M.R., Melvin, L.S., and Martin, B.R. (1992) Pharmacological profile of a series of bicyclic cannabinoid analogs: classification as cannabimimetic agents. J Pharmacol Exp Ther. 260: 201 -9.
  • Charalambous, A., Yan, G., Houston, D.B., Howlett, A.C., Compton, D.R., Martin, B.R., and Makriyannis, A. (1992) 5' -Azido -delta 8 -THC: a novel photoaffinity label for the cannabinoid receptor. J Med Chem. 35: 3076 -9.
  • Compton, D.R., Rice, K.C., DeCosta, B.R. Razdan, R.K., Melvin, L.S., Johnson, M.R. and Martin, B.R. (1993) Cannabinoid structure -activity relationships: correlation of receptor binding and in vivo activities. J Pharmacol Exp Ther. 265: 218 -226.Martin, B.R.,
  • Compton, D.R., Semus, S.F., Lin, S., Marciniak, G., Grzybowska, J., Charalambous, A., and Makriyannis, A. (1993) Pharmacological evaluation of iodo and nitro analogs of delta -8 -THC and delta -9 -THC. Pharmacol Biochem Behav. 46: 295 -301.
  • Huffman, J.W., Dai, D., Martin, B.R., and Compton, D.R. (1994) Design, Synthesis and Pharmacology of some cannabimimetic indoles. Bioorganic Med Chem Lett. 4(4): 563 -566. (Note: Not indexed in PubMed as of 2019)
  • McLaughlin, C.R., Martin, B.R., Compton, D.R. and Abood, M.E. (1994) Cannabinoid receptors in developing rats: Detection of mRNA and receptor binding. Drug and Alcohol Dependence 36: 27 -31.
  • Smith, P.B., Compton, D.R., Welch, S.P., Razdan, R.K., Mechoulam, R., and Martin, B.R. (1994) The pharmacological activity of anandamide, a putative endogenous cannabinoid, in mice. J Pharmacol Exp Ther. 270: 219 -227.
  • Yan, G., Yin, D.L., Khanolkar, A.D., Compton, D.R., Martin, B.R., and Makriyannis, A. (1994) Synthesis and pharmacological properties of 11 -hydroxy -3 -(1',1' -dimethylheptyl) hexahydrocannabinol: A high affinity cannabinoid agonist. J Med Chem. 37: 2619 -2611.
  • Fan, F., Compton, D.R., Ward, S., Melvin, L., and Martin, B.R. (1994) Development of Cross -Tolerance between delta -9 -THC, CP 55,940 and WIN 55,212. J Pharmacol Exp Ther. 271: 1383 -1390.
  • Dutta, A.K., Sard, H., Ryan, W., Razdan, R.K., Compton, D.R. and Martin, B.R. (1995) The synthesis and pharmacology of the cannabinoid antagonist SR141716A. Med. Chem. Res. 5: 54 -62. (Note: Not indexed in PubMed/Scopus [as of 2022] for period prior to 1996 and no volumes available on -line prior to 2004)
  • Huffman, J.W., Banner, W.K., Zoorob, G.K., Joynber, H.H., Reggio, P.H., Martin, B.R., and Compton, D.R. (1995) Stereoselective synthesis of the epimeric delta -7 -tetrahydrocannabinols, Tetrahedron 51: 1017 -1032. (Note: Not indexed in PubMed/Scopus as of 2022)
  • Martin, B.R., Compton, D.R., Prescott, W.R., Barrett, R., and Razdan, R.K. (1995) Pharmacological evaluation of dimethylheptyl analogs of delta -9 -THC: reassessment of the putative three -point cannabinoid -receptor interaction. Drug and Alcohol Dependence 37: 231 -240.
  • Adams, I.B., Ryan, W., Singer, M., Razdan, R.K., Compton, D.R., and Martin, B.R. (1995) Pharmacological and behavioral evaluation of alkylated anandamide analogs. Life Sciences 56: 2041 -2048.
  • Ryan, W., Singer, M., Razdan, R.K., Compton, D.R., and Martin, B.R. (1995) A novel class of potent tetrahydrocannabinols (THCs): 2' -yne -delta -8 - and delta -9 -THC. Life Sciences 56: 2013 -2020.
  • Woodward, J.J., Compton, D.R., Balster, R.L., and Martin, B.R. (1995) In vitro and in vivo effects of cocaine and selected local anesthetics on the dopamine transporter. European Journal of Pharmacology 277: 7 -13. (Note: Authorship typographical error “David M. Compton” in original publication instead of ‘David R Compton)
  • Lainton, J.A.H., Huffman, J.W., Martin, B.R., and Compton, D.R. (1995) 1 -Alkyl -3 -(1 -naphthoyl) -pyrroles: A new cannabinoid class. Tetrahedron Lett. 36: 1401 -1404. (Note: Not indexed in PubMed as of 2019)
  • Adams, I.B., Thomas, B.F., Compton, D.R., Razdan, R.K., and Martin, B.R. (1995) Evaluation of cannabinoid receptor binding and in vivo activities for anandamide analogs. J Pharmacol Exp Ther. 273: 1172 -1181.
  • Mechoulam, R., Ben -Shabat, S., Hanus, L., Ligumsky, M., Kaminski, N.E., Schatz, A.R., Gopher, A., Almog, S., Martin, B.R., Compton, D.R., Pertwee, R.G., Griffin, G., Barg, J., Bayewitch, M., and Vogel, Z. (1995) Identification of an endogenous 2 -monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol. 50: 83 -90.
  • Compton, D.R., Aceto, M.D., Lowe, J., and Martin, B.R. (1996) In vivo characterization of a specific cannabinoid antagonist (SR141716A): Inhibition of delta -9 -tetrahydrocannabinol -induced responses and apparent agonist activity. J Pharmacol Exp Ther. 277: 586 -594.
  • Showalter, V.M., Compton, D.R., Martin, B.R., and Abood, M.E. (1996) Evaluation of binding in a transfected cell line expressing a peripheral cannabinoid receptor (CB2): Identification of cannabinoid receptor subtype selective ligands. J Pharmacol Exp Ther. 278: 989 -999.
  • Huffman, J.W., Yu, S., Showalter, V., Abood, M.E., Wiley, J.L., Compton, D.R., Martin, B.R., and Reggio, P.H. (1996) Synthesis and Pharmacology of a Very Potent Cannabinoid Lacking a Phenolic Hydroxyl with High Affinity for the CB2 Receptor. J Med Chem. 39: 3875 -3877.
  • Pertwee, R.G., Fernando, S.R., Griffin, G., Ryan, W., Razdan, R.K., Compton, D.R., and Martin, B.R. (1996) Agonist -antagonist characterization of 6' -cyano -hex -2' -yne -delta 8 -tetrahydrocannabinol in two isolated tissue preparations. Eur. J. Pharmacology 315: 195 -201.
  • Moore, K.A., Mirshahi, T., Compton, D.R., Poklis, A., and Woodward, J.J. (1996) Pharmacological characterization of BNMPA (alpha -benzyl -N -methylphenethylamine), an impurity of illicit methamphetamine synthesis. Eur. J. Pharmacology 311: 133 -139.
  • Wiley, J.L., Compton, D.R., Gordon, P.M., Siegel, C., Singer, M., Dutta, A., Lichtman, A.H., Balster, R.L., Razdan, R.K., and Martin, B.R. (1996) Evaluation of agonist -antagonist properties of nitrogen mustard and cyano derivatives of delta 8 -tetrahydrocannabinol. Neuropharmacol 35: 1793 -1804.
  • Compton, D.R. and Martin, B.R. (1997) The effect of the enzyme inhibitor phenylmethylsulfonyl fluoride on the pharmacological effects of anandamide in the mouse model of cannabimimetic activity. J Pharmacol Exp Ther. 283: 1138 -1143.
  • Reggio, P.H., Wang, T., Brown, A.E., Fleming, D.N., Seltzman, H.H., Griffin, G., Pertwee, R.G., Compton, D.R., Abood, M.E. and Martin, B.R. (1997) Importance of the C -1 substituent in classical cannabinoids to CB2 receptor selectivity: Synthesis and characterization of a series of O,2 -propano -delta 8 -tetrahydrocannabinol analogs. J Med Chem. 40: 3312 -3318.
  • Lake, K.D., Compton, D.R., Varga, K., Martin, B.R., and Kunos, G (1997) Cannabinoid -induced hypotension and bradycardia in rats is mediated by CB1 -like cannabinoid receptors. J Pharmacol Exp Ther. 281: 1030 -1037.
  • Huffman, J.W., Lainton, J.A.H., Banner, W.K., Duncan, S.G., Jordan, R.D., Yu, S., Dai, D., Martin, B.R., Wiley, J.L., and Compton, D.R. (1997) Side Chain Methyl Analogues of delta -8 -THC. Tetrahedron 53: 1557 -1576. (Note: Not indexed in PubMed/Scopus as of 2022)
  • Dutta, A.K., Ryan, W., Thomas, B.F., Singer, M., Compton, D.R., Martin B.R., and Razdan, R.K. (1997) Synthesis, pharmacology, and molecular modeling of novel 4 -alkyloxy indole derivatives related to cannabimimetic aminoalkyl indoles (AAIs). Bioorganic and Medicinal Chemistry 5: 1591 -1600.
  • Seltzman, H.H., Fleming, D.N., Thomas, B.F., Gilliam, A.F., McCallion, D.S., Pertwee, R.G., Compton, D.R., and Martin, B.R. (1997) Synthesis and pharmacological comparison of dimethylheptyl and pentyl analogs of anandamide. J. Medicinal Chem. 40: 3626 -3634.
  • Adams, I.B., Compton, D.R., and Martin, B.R. (1998) Assessment of anandamide interaction with the cannabinoid brain receptor: SR141716A antagonism studies in mice and autoradiographic analysis of receptor binding in rat brain. J Pharmacol Exp Ther. 284: 1209 -1271.
  • Thornton, S.R., Compton, D.R., and Smith, F.L. (1998) Ontogeny of mu opiate agonist antinociception in postnatal rats. Developmental Brain Research. 105: 269 -276.
  • Wiley, J.L., Compton, D.R., Dai, D., Lainton, J.A.H., Phillips, M., Huffman, J.W., and Martin, B.R. (1998) Structure -activity relationships of indole - and pyrrole -derived cannabinoids. J Pharmacol Exp Ther. 285: 995 -1004.
  • Jarai, Z., Wagner, J.A., Varga, K., Lake, K.D., Compton, D.R., Martin, B.R., Zimmer, A.M., Bonner, T.I., Buckley, N.E., Mezey, E., Razdan, R.K. Zimmer, A., and Kunos, G. (1999) Cannabinoid -induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors, Proc Natl Acad Sci USA. 96: 14139 -14141.
  • Kang, J., Compton, D.R., Vaz, R.J., and Rampe, D. (2016) Proarrhythmic mechanisms of the common anti -diarrheal medication loperamide: Revelations from the opioid abuse epidemic. Naunyn -Schmiedeberg's Arch Pharmacol 389:1133-1137. (NOTE: manuscript not listed in Scopus; number of citations not available; not included in h -index)
  • de Zafra, C.L.Z., Markgraf, C.G., Compton, D.R., and Hudzik, T.J. (2018) Abuse liability assessment for biologic drugs - All molecules are not created equal. Regulatory Toxicology and Pharmacology 92: 165 -172.

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