Low-dose naltrexone effects on plasma chemistries and clinical symptoms in autism: a double-blind, placebo-controlled study

Bouvard, Manuel; Leboyer, Marion; Launay, Jean‐Marie; Recasens, Christophe; Plumet, Marie‐Hélène; Waller-Perotte, Delphine; Tabuteau, F; Bondoux, Dominique; Dugas, Michel J.; Lensing, Patrick; Panksepp, Jaak

doi:10.1016/0165-1781(95)02601-r

Cited by 105 publications

(76 citation statements)

References 24 publications

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“…The Leboyer group found that naltrexone responses in autistic humans suggested opioid activity in the C-terminal fragment but not the N-terminal. In subjects whose autistic symptoms were markedly reduced under low-dose naltrexone treatment, their normally elevated plasma levels of C-terminal βE were also reduced to normal levels under naltrexone [4]. The N-terminal assay found no significant differences in plasma levels between autistic subjects and controls, nor any changes under naltrexone versus baseline conditions.…”

Section: The Relation Between Abnormal Behavior and Different Beta-enmentioning

confidence: 79%

“…However, it is not clear that our BEC-IR assay is sufficiently different from theirs to explain the differing C-terminal results. Their research has found markedly elevated BEC in 80% of autistic patients, many of which had SIB symptoms [4,23].…”

Section: The Relation Between Abnormal Behavior and Different Beta-enmentioning

confidence: 99%

“…The mu-opioid receptor coding region in rhesus is approximately 98% homologous to the corresponding human coding region [28]. Naltrexone antagonizes particularly mu-type opioid receptors [4]. The amino acid sequence for M.…”

Section: The Relation Between Abnormal Behavior and Different Beta-enmentioning

confidence: 99%

“…The trend toward significance of the sex factor in BET (Table 5) appears to be related to sex differences in the C-terminal, because the MANCOVA controlled for sex differences in abnormal behavior. It is possible that some human studies indicating opioid action in the C-terminal are confounded by uncontrolled sex differences, although this was not the case for Bouvard [4] in which five subjects were male and five were female. In our study, male macaques were more likely to have higher abnormal behavior rank scores than females.…”

Section: The Relation Between Abnormal Behavior and Different Beta-enmentioning

confidence: 99%

“…Some autistic subjects with SIB were reported to have normal ACTH levels but elevated levels of the C-terminally directed βE-immunoreactivity relative to the Nterminally directed immunoreactivity [23,24]. In another study, autistic subjects were found to have markedly elevated C-terminal βE concentrations compared to normal individuals, but did not differ significantly in N-terminal βE concentrations; six of the ten subjects had a history of mild SIB [4]. The possible opioid activity of the third fragment was suggested by an analysis of beta-endorphin fragment activity on human monocyte chemotaxis indicating that the Nterminal, but not the C-terminal, has opiate effects [39].…”

Section: Introductionmentioning

confidence: 99%

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Beta-endorphin levels in longtailed and pigtailed macaques vary by abnormal behavior rating and sex

et al. 2007

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Frequent or severe abnormal behavior may be associated with the release of endorphins that positively reinforce the behavior with an opiate euphoria or analgesia. One line of research exploring this association involves the superhormone, proopiomelanocortin (POMC). The products of POMC appear to be dysregulated in some human subjects who exhibit self-injurious behavior (SIB). Macaque monkeys have POMC very similar to humans, and some laboratory macaques display SIB or frequent stereotypies. We investigated associations between plasma levels of three immunoreactive POMC fragments with possible opioid action and abnormal behavior ratings in macaques. In 58 adult male and female macaques (24 Macaca fascicularis and 34 M. nemestrina), plasma levels of intact beta-endorphin (βE) and the N-terminal fragment (BEN) were significantly higher in animals with higher levels of abnormal behavior. The C-terminal fragment (BEC) was significantly higher in males but unrelated to ratings of abnormal behavior. Levels of ACTH, cortisol, and (βE-ACTH)/βE dysregulation index were unrelated to abnormal behavior. None of the POMC products differed significantly by subjects' species, age, or weight. The finding that intact betaendorphin is positively related to abnormal behavior in two species of macaque is consistent with some previous research on human subjects and nonprimates. The positive relation of the N-terminal fragment of βE to abnormal behavior is a new finding.

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Section: The Relation Between Abnormal Behavior and Different Beta-enmentioning

confidence: 79%

Section: The Relation Between Abnormal Behavior and Different Beta-enmentioning

confidence: 99%

Section: The Relation Between Abnormal Behavior and Different Beta-enmentioning

confidence: 99%

Section: The Relation Between Abnormal Behavior and Different Beta-enmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Beta-endorphin levels in longtailed and pigtailed macaques vary by abnormal behavior rating and sex

et al. 2007

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Proopiomelanocortin (POMC) disregulation and response to opiate blockers

Sandman

Spence

Smith

1999

Ment. Retard. Dev. Disabil. Res. Rev.

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Autism is a collection of disorders or subtypes with distinctive or prominent phenotypes and genotypes. The study of adults with autism offers a unique opportunity to examine its phenotypic diversity. Recent evidence has identified disturbances in specific neurochemical systems that are associated with primary autistic symptoms. Establishing biological markers, such as specific neurochemical disturbances, not only confers greater precision in phenotyping individuals but also provides the basis for rational intervention. Our initial studies in adult individuals exhibiting self-injurious behavior (SIB) generated evidence that the proopiomelanocortin (POMC) system, specifically the endogenous opioid system, may be disregulated in subgroups of autistic patients. These findings, corroborated in at least 15 other laboratories, indicated that treatment with an opiate blocker, naltrexone (NTX), reduced SIB in 30-70% of individuals observed. However, the effects of NTX on SIB were not simple. We and others have found that concentration of plasma POMC fragments, specifically opioid fragments, contributed to the symptoms of autism and to the response to treatment. Uncoupling of the release of POMC products predicted the efficacy of NTX treatment on the expression of SIB. Uncoupling of POMC fragments among autistic and SIB patients suggested a basic, underlying defect, perhaps in the POMC gene. The findings of a maternal influence on the C-terminal BE fragment among individuals with autism (Leboyer et al. [1999] Soc Biol Psychiatry 45:158-163) and our preliminary findings, reported here, of a mutation in the opioid region of the POMC gene in an autistic individual, were consistent with the prospect that a subgroup of patients will be identified who share a POMC genetic defect.1999 Wiley-Liss, Inc.

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