Monday, 24.02.2020

Thomas A. Ban
Neuropsychopharmacology in Historical Perspective
Education in the Field in the Post-Neuropsychopharmacology Era

Background to An Oral History of the First Fifty Years
Addiction (Volume Six): 4b. Contributions of interviewees
(Bulletin 58)


            Of the remaining 11 interviewees in Volume Six, six (Blaine, Jaffe, Jasinsky, Kleber, Kreek and Wayner) were involved in the development of treatment for addiction (Ban 2011; Kleber 2011).

            In 1966, Mary Jeanne Kreek co-authored one of the two papers by Dole and Nyswander on methadone in opioid dependence that launched substitution therapy with methadone (Dole and Nyswander 1965; Dole, Nyswander and Kreek 1966).     In the late 1960s she described the role of µ and К opioid receptors in normal physiology, responsiveness to stress and in specific addictive diseases (Kreek 1969). In the 1990s, the focus of Kreek’s research shifted to genes associated with addiction (Kreek, Nielsen and LaForge 2004).  

            Donald R. Jasinsky was among the first to study the effects of naltrexone, a full antagonist, and of buprenorphine, a partial antagonist of µ and competitive antagonist of К opioid receptors, in the treatment of opioid dependence (Jasinsky, Fudala and Johnson 1989; Jasinsky, Pavnick and Griffith 1978; Martin, Jasinsky and Mansky 1973). A close collaborator of W.R Martin, one of the leaders of the Lexington group, Jasinsky coauthored the paper with Martin in which the concept of “protracted abstinence” was introduced (Martin and Jasinsky 1969).

            Jerome H. Jaffe was one of the first in 1970 to report on the effects of levoacetylmethadol (LAAM), a long-acting orally available opioid, in the treatment of chronic heroin users and compared its effect with methadone (Jaffe, Schuster, Smith and Blachly 1970; Jaffe and Senay 1971). In the late 1970s Jaffe’s interest turned to smoking as an addictive disorder (Jaffe and Kranzler 1979). 

            Findings with LAAM in the treatment of addiction received further substantiation by Jack D. Blaine in the late 1970s (Blaine, Renault, Levine and Whysner 1978). Blaine was a member of David Janowsky’s team which studied the effects of cannabis on simulated flying ability (Janowsky, Meacham, Blaine, Schoor and Bozzetti 1976).

            In the late 1970s, Herbert D. Kleber, in collaboration with Gold and Redmond, discovered that administration of clonidine, an α–adrenergic agonist, could ameliorate opiate withdrawal symptoms (Gold, Redmond and Kleber 1978). Ten years later, in the mid-1980s, he demonstrated that co-administration of clonidine and naltrexone significantly shortens the opioid withdrawal syndrome without substantially increasing patient discomfort (Kleber, Topazian and Gaspari 1987). Kleber was one of the first to show that dronabinol, a synthetic levoisomer of tetrahydrocannabinol, could mitigate the symptoms of marijuana withdrawal (Levin and Kleber 2008).

            In the mid-1990s Matthew J. Wayner demonstrated the effect of alcohol on lateral hypothalamic dentate granules and suggested a possible relationship between this effect and alcohol-induced memory changes. Wayner also showed that losartan, an angiotensin II inhibitor, improved performance in ethanol-intoxicated rats (Tracy and Wayner 1997; Wayner and Phenix 1993).  

            Three interviewees (Charalampous, Klee and Schoolar) were involved with psychomimetics in their research. In the late 1950s Gerald D. Klee studied the effects LSD-25 on mental performance and on time sense (Aronson, Silverstein and Klee 1959). In the early 1960s, he reported on the effect of the substance on ego functions (Klee 1963). Klee was among the first in 1960 to explore the effects of 5-hydroxytryptophan on schizophrenia and to question the relationship between the action of LSD on serotonin and the mental effects of the substance (Klee, Bertino, Callaway and Weintraub 1960; Klee, Bertino, Gudineau and Aronson 1960).

            The first autoradiogaphic study with LSD was carried out in the late 1960s by Joseph Schoolar in collaboration with Idenpään Heikkilä. By tracking the substance in mice, they found high concentrations in the brain, adrenals, hypophysis, kidney, liver and lung and demonstrated that LSD passes the placental barrier (Idenpään-Heikkilä and Schoolar 1969).

            Kanellos D. Charalampous was first, in the mid-1960s, to demonstrate the metabolic fate of mescaline in man (Charalampous, Walker and Kinross-Wright 1966). He was also first, in the mid-1970s, to show the effects of acute ethanol administration on brain cyclic nucleotides and of chronic morphine administration on cerebellar cAMP levels (Charalampous and Askew 1977a, b).

            Finally, two interviewees (Noble and Schuckit) contributed to genetic research in addiction. In the 1990s Marc Schuckit demonstrated an increased risk for alcoholism among sons of alcoholics (Schuckit 2000, 2009; Schuckit and Smith 1997). He identified patterns of drinking in the offspring and showed a different level of response to alcohol in the offspring of heavy drinkers (Kreikebaum, Hinnga and Allen 2008; Schuckit, Smith, Danko et al. 2007).

            In 1993 Ernest P. Noble and his team reported on an allelic association of the D2 dopamine receptor gene (DDR2) with cocaine dependence (Noble, Bloom, Khals et al. 1993). Subsequently, he found similar associations between DDR2 and other substances and hypothesized that DDR2 is a “reward gene” (Noble 2003; Noble, St. Jeor, Ritchie et al. 1994).

            Interviewees included in Volume Six entered the field at different stages in the development of the neuropsychopharmacology of addiction. Hence, the transcripts cover 50 years of history during which norepinephrine was replaced by dopamine as the molecular substrate of reinforcement; opiate receptors were identified in the brain; the site of brain structures involved with addiction was extended from the limbic lobe to the frontal cortex; and behavioral methodologies in the study of addiction were supplemented with brain imaging and molecular genetic techniques (Ban 2011).

            Herbert D. Kleber, the editor of this volume, has been one of the leaders of addiction psychiatry in the past decades. In his Introduction and Dramatis Personae he provides an overview of developments in the field and biographic information on the interviewees with a précis of their contributions.




Aronson H, Silverstein AB, Klee GD. The influence of lysergic acid diethylamide (LSD-25) on subjective time sense. Arch Gen Psychiatry 1959; 1: 469-72.

Blaine JD, Renault P, Levine GL, Whysner JA. Clinical use of LAAM. Annals of the New York Academy of Sciences 1978; 311: 214-31

Charalampous KD, Askew WE. Effects of acute ethanol administration on brain cyclic nucleotides. Res Comm Psychol Psychiatr Behav 1977a; 2: 287-96.                           

Charalampous KD, Askew WE. Cerebellar cAMP levels following acute and chronic morphine administration. Can J Physiol Pharm 1977b; 55: 117-20.

Charalampous KD, Walker KE, Kinross-Wright J. Metabolic fate of mescaline in man. Psychopharmacologia 1966; 9: 48-63.Dole VP, Nyswander ME. A medical treatment for diacetylmorphine (heroin) addiction JAMA 1965; 193: 646-50.

Dole VP, Nyswander ME, Kreek MJ. Narcotic blockade a medical technique for stopping heroin use by addicts. Trans Assoc Am Phys 1966; 9: 122-36.

Gold MS, Redmond DE, Kleber HD. Clonidine in opiate withdrawal. Lancet 1978; 11: 599- 602. 

Idenpään-Heikkilä JE, Schoolar J. LSD autoradiographic study and the placental transfer and tissue distribution  in mice. . Science 1969; 164: 1295-7.

Jaffe JH, Schuster CR, Smith B, Blachly P. A comparison of acetylmethadol and methadone in the treatment of chronic heroin users. A pilot study. JAMA 1970; 211: 1834-6.  

Jaffe JH, Senay EC. Methadone and 1-metadyl acetate use in the management of narcotic addicts. JAMA 1971; 216: 1303-5.

Jaffe JH, Kranzler M. Smoking as an addictive disorder. NIDA Research Monographs 1979; 23; 4-23. 

Janowsky DS, Meacham MP, Blaine JD, Schoor M, Bozzetti LP. Marihuana effect on simulated flying ability. Am J Psychiatry 1976; 133: 384 - 8.

Jasinsky DR, Fudala PJ, Johnson RE. Sublingual vs  subcutaneous buprenorphine  in opiate abusers. Clinical Pharmacol 1989; 45: 513-9.

Jasinsky DR, Pavnick JS, Griffith JD. Human pharmacological abuse potential of buprenorphine. Arch Gen Psychiatry 1978; 35: 501-16.

Kleber HD, Topazian M, Gaspari J. Clonidine and naltrexone in the outpatient treatment of heroin withdrawal. Am J Drug Alcohol Abuse 1987; 13: 1 – 17.

Klee GD. Lysergic acid diethylamide (LSD-25) and ego functions. Archives of General Psychiatry 1963; 8: 761- 4.

Klee GD, Bertino J, Callaway E, Weintraub W. Clinical studies with LSD and two serotonin related substances. J Ment Science 1960; 106: 301-8.

Klee JD, Bertino J, Goodineau  A,  Aronson H. The effects of 5-hydroxytryptophan (A serotonin precursor) in schizophrenic patients. J Ment Science 1960; 106: 309-16.

Kreek Opioid receptors: Some perspective from early studies of their role in normal physiology, stress responsivity and in specific addictive diseases.  Neurochem Research 1969; 21: 1469-88. 

Kreek MJ, Nielsen DA, LaForge KS. Genes associated with addiction. Neuromolecular Med 2004; 5: 85-108.

Kreikebaum S, Hinnga B, Allen R. Testing the level of response to alcohol-based model  of heavy drinking and alcohol problems  in the offspring from the San Diego prospective study. Journal of Studies on Alcohol and Drugs 2008; 69: 571-9.  

Levin FR, Kleber HD. Using dronabinol for marihuana withdrawal. Am J Addiction 2008; 17: 161 – 4.

Martin WR, Jasinsky DR. Physiological parameters of morphine dependence in man – tolerance and abstinence of protracted abstinence.  Journal of Psychiatric Research 1969; 7: 9-17.

Martin WR, Jasinsky DR, Mansky P. Naltrexone, an antagonist for the treatment of heroin dependence. Effects in man. Arch Gen Psychiatry 1973; 28: 764-91.

Noble EP. The D2 dopamine receptor gene in psychiatric and neurologic disorders and its phenotypes: a review. Am J Med Genet 2003; 116B: 103-25.

Noble EP, St. Jeor ST, Ritchie T, Syndulko K, St. Jeor P,  Fitch RJ,  Brunner RL, Sparkes RS. D2 dopamine receptor gene and cigarette smoking. A reward gene?  Medical Hypotheses 1994; 42: 257-60.

Schuckit MA Genetics of the risk for alcoholism. American Academy of Psychiatrists in Alcoholism and Addiction 2000; 9: 103-21.

Schuckit MA. An overview of genetic influences in alcoholism. Journal of Substance Abuse and Treatment 2009; 36: 55-64.

Schuckit MA, Smith TL. Assessing the risk for alcoholism among sons of alcoholics. Journal for Studies on Alcohol. 1997; 58: 141-5.

Schuckit M, Smith TL, Danko GP, Allen R, Kreikebaum S. Patterns and correlate of drinking  in offspring  from San Diego  prospective study. Alcoholism, Clinical and Experimental Research 2007; 31: 1681-91.

Tracy HA, Wayner MJ, Armstrong DL. Losartan improves the performance of ethanol-intoxicated rats in eight-arm radial maze. Alcohol 1997; 14: 5111-7.

Wayner MJ, Phenix CF, Armstrong DL. Lateral hypothalamic stimulation inhibits dentate granule cell LTP direct connections. Brain Research Bulletin 1997; 43: 5-15.


February 21, 2019