Alberto Caddeo, Roberto Trampetti, Giusy Messina, Enrica Porta, Giuseppe Di Fede*, Rosanna Tartarelli, Olga Tartarelli, Alejandra Monzon,Giorgio Porro and Paolo Lissoni

Institute of Biological Medicine, Milan, Italy.

^*Corresponding Author: Giuseppe Di Fede, Institute of Biological Medicine, Milan, Italy.

Published Date: 02-24-2020

Copyright^© 2020 by Caddeo A, et al. All rights reserved. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

After several years of researches to identify possible neurochemical alterations, at present it is known that autism is characterized and induced by at least three neuroendocrine deficiencies, involving the pineal function and the secretion of its most investigated hormone, melatonin (MLT), brain cannabinoid system, and the neurohypophyseal production of oxytocin (OT). Because of the fundamental role of MLT in sleep regulation, brain cannabinoid system in pleasure perception and control of anxiety, and OT in the affective life, these three neuroendocrine deficiencies might explain at least in part the symptomatology of autism.  Therefore, autism-related neurochemical anomalies would involve the same main brain structures responsible for the conscious and the affective life, as well as for pleasure perception. On these bases, a preliminary study was performed to evaluate the influence of a progressive neuroendocrine. Substitutive treatment in autistic children. The study included 30 consecutive patients, by treating the first 12 subjects with the only MLT (100 mg/day in the dark period), the next 12 subjects with MLT plus cannabidiol. (CBD) (10 mg twice/day), and the remaining 6 subjects with MLT plus CBD plus OT (2 mg twice/day). All therapies were orally administered.  MLT alone was mainly active in the treatment of sleep disorders. The association with CBD improved the control of anxiety. Finally, the further association with OT was also effective in improving the social and affective relationships. These preliminary results would suggest the possibility to treat the autism spectrum disorders by correcting their main neuroendocrine deficiencies through an exogenous administration.

Keywords

Autism; Cannabidiol; Cannabinoid System; Melatonin; Oxytocin; Pineal gland.

Introduction

The recent advances in the investigation of the neuro-chemical processes involved in emotions, social relationship and consciousness status, have demonstrated the fundamental importance of the pineal gland in regulating the relationship between single living organism and universal information’s through the light/dark circadian secretion of its most investigated hormone, melatonin (MLT) [1], and its connection with the endogenous cannabinoid system (ECS) in the perception of pleasure and consciousness expansion [2], as well as with the neurohypophyseal oxytocin (OT) in modulating social, affective and sexual behavior [3], namely by acting at amygdala level, which is one of brain areas characterized by a high expression of OT receptors [4]. The autistic syndrome, which affects about 1/70 children, is characterized by social and communications impairments, restrictive interest and repetitive behavior, mood disorders, epilepsy and possible disruptive behavior. The great number of symptoms of the autistic syndrome would be the consequence of complex alterations involving both brain anatomic and biochemistry features. In more detail, from a neuro-chemical point of view, at present autism-related neuro-bio-psychological disturbances have been proven to depend on at least three major deficiencies, including hypofunction of the endocrine activity of the pineal gland with a following diminished secretion of its indole hormone MLT [5,6], a diminished or an altered activity of brain ECS [7], and abnormally low levels of OT [8]. Because of its important anxiolytic and antidepressant activity, as well as its fundamental role in sleep induction namely through its connection with the GABA ergic intra neuronal system [1], the pineal deficiency would be responsible at least in part for autism-related sleep disturbances, anxiety and depression [5]. On the same way, because of its importance in sensory sensitivity, pleasure perception and self-consciousness [2], the hypofunction of brain ECS observed in autism would allow autism-related consciousness disorders [7]. Finally, autism-associated disturbances in social relationships could depend on the deficiency in the secretion of OT [8], since it has been proven to play an important role in promoting the affective and social life, including the sexual behaviour [3]. Several anomalies of brain structure have been observed by magnetic resonance imaging in autism spectrum disorders (ASD), consisting of a diminished grey and white matter density in some brain areas, including lateral occipital lobe, medial temporal lobe, basal ganglia and right parietal operculum [9], as well as a decreased functional connectivity involving ventral medial prefrontal cortex and ventral anterior cingulate cortex in association with reduced dimensions of bilateral inferior parietal lobule, posterior cingulate cortex, and temporal-parietal junction [10]. However, since the main ASD-related symptoms involve self-consciousness, sensory sensitivity and social affective relationships [11-13], the well documented fundamental importance of amygdala in regulating the emotional life [14] has allowed to identify the main anomaly responsible for the autistic syndrome into a functional alteration of the amygdala, by representing the so-called amygdala theory of autism [15,16], as also suggested by the evidence of reduced dimensions of amygdala in autistic subjects with severe anxiety [13], which could also influence the main types of the sensory processing problems, consisting of hypo-responsivity to sensory stimulations, hyper-responsivity to sensory stimulations, and no interest in sensory aspects of the environment [11-13].Unfortunately, despite the great interest for the ASD because of its severe existential and social implications, at present no clear integrate psychoneurochemical therapeutic approaches has been proposed, since most therapeutic strategies generally consist of psychotherapeutic, or psycho-pharmacological approaches in a separate manner, which in contrast may play a same importance. In fact, the recent discoveries in the area of Psycho-Neuro-Endocrino-Immunology (PNEI) [17] have shown a reciprocal bidirectional influence between psychotherapeutic and psycho pharmacological strategies, since changes in brain biochemistry may affect the psycho spiritual status of subjects, and on a same way the psychotherapeutic approach may induce changes in the psychochemical mediations of emotions and consciousness states. Then, by considering the three major neuro-endocrine alterations occurring in ASD, consisting of pineal endocrine deficiency, reduced OT secretion, and brain ECS hypofunction, it is probable that the pharmacological correction of one or more autism- related neuro-endocrine deficiencies may allow some benefits in ASD symptomatology, obviously with results depending on the beginning of therapy, and the degree of ASD severity. Pineal deficiency may be corrected by the exogenous administration of MLT during the night according to its physiological circadian rhythm [1], even though it is not the only hormone produced by the pineal gland. In fact, preliminary clinical results would suggest that MLT therapy may improve sleep disorders, anxiety, pain, depression and gastrointestinal dysfunctions [6].On the same way, OT diminished secretion may be corrected by an exogenous administration of OT itself. Finally, as far as autism-related ECS deficiency is concerned, its clinical correction is apparently more complex, since the two main endogenous cannabinoids, represented byarachidonoyl-ethanol-amide (AEA), and 2-arachidonylglycerol (2-AG), namely produced respectively during the night and during the day [18], are not at present available for clinical use. However, since the endogenous cannabinoid content depends on the concentrations of fatty acid amide hydrolase (FAAH), the enzyme responsible for cannabinoid degradation [2], the decline in blood concentrations of FAAH would allow an increased endogenous cannabinoid content, including in the brain. The non-psychoactive product of Cannabis Indica cannabidiol (CBD), which is a vanilloid receptor agonist, and which is not active on cannabinoid CB1 and CB2 receptors, has been proven to inhibit FAAH activity, with a following increase in brain cannabinoid content, by contributing to replace the ECS deficiency. The present preliminary study was performed to evaluate the subjective and clinical effects of a progressive replacement therapy with MLT alone, or in association with CBD, or CBD plus OT as MCO regimen in the treatment of ASD, irrespectively of the clinical stage of disease, to correct the three main autism-related neuro-endocrine deficiencies, consisting in pineal endocrine activity, endocannabinoid functionless and OT secretion.

Patients and Methods

The study included 30 consecutive autistic subjects (M/F: 21/9; median age 16 years, range 6-27). The substitutive therapy consisted of MLT alone in the first 12 subjects, MLT plus CBD in the successive 12 subjects, and MLT plus both CBD and OT in the remaining last 6 subjects. All therapies were given orally. MLT was administered at a dose of 10 mg/ once day during the dark period of the day in relation to its natural light/dark circadian rhythm [1], generally 30 minutes before sleeping, by reaching the planned dose of 100 mg/day within few days. CBD was given at a dose of 10 mg twice/day (8:00 AM and 8:00 PM), starting with a dose of 2 mg twice/day. By considering that 1.7 mcg of OT corresponds to 1 IU, the administered dose consisted of about 1,850 IU twice/day. Finally, OT was given at a dose of 2 mg twice/day (8:00 AM and 8:00 PM), and because of its peptidergic nature, it was administered in gastric-protected pills. The clinical protocol was explained to all subjects and to their relatives, and written consent was obtained. Moreover, all subjects were concomitantly followed with a psychotherapeutic approach. The clinical results were evaluated in relation to the three main autism-related symptoms, consisting of sleep disturbances, excessive anxiety, and disorders of social and affective relationships. For the clinical evaluation, subjects were followed for a minimum follow-up period of 6 months. Data were statistically analyzed by the chi-square test. 

Results

The clinical results are reported in Table 1. An improvement in the quality of sleep was achieved within the first week of therapy in 7/12 (58%) subjects treated with MLT alone. The percentage of MLT-induced improvement in sleep disturbances was enhanced by the concomitant association with CBD alone (8/12 (67%)), and CBD plus OT (5/6 (83%)), even though the difference was not statistically significant. A clear improvement in anxiety-related symptoms was progressively observed in 3/12 (25%) subjected treated with the only MLT, in 8/12 (67%) subjects treated with MLT plus CBD, and in 5/6 (83%) subjects, who received MLT plus CBD and OT. Then, the percentage of the control of anxiety achieved by both MLT plus CBD (P<0.05) and MLT plus CBD and OT (P<0.01) was significantly higher than that obtained by the only MLT. Finally, an improvement in the social and affective relationships occurred in only 2/12 (17%) subjects, who received MLT alone, in 4/12 (33%) subjects treated by MLT plus CBD, and in 4/6 (67%) subjects, who received the complete replacement therapy with MLT, CBD and OT. Then, the percentage of improvement in the social affective relationships achieved in subjects concomitantly treated with OT, MLT and CBD was statistically significantly higher with respect to that observed in MLT (P<0.01) and in MLT plus CBD groups (P<0.05).Moreover, the improvement in the emotional reactivity and social relations obtained by a concomitant administration of OT was more rapid than that found in subjects treated with the only MLT and CBD. The compliance to therapy of both subjects and their relatives was optimal, and no therapy-related Biological toxicity occurred. Finally, psychotherapy itself was apparently more effective, because of the major emotional reactivity of subjects under the substitutive pharmacological therapy.

Table 1: Therapeutic effects with melatonin (MLT), MLT plus cannabidiol (CBD), and MLT plus CBD plus oxytocin (OT) in 30 autistic subjects.

Discussion

This preliminary clinical study, carried out to improve the main autism-related symptoms by correcting the major autism-related neuro-endocrine deficiencies, would suggest that the psychotherapeutic approach cannot be separated from a psychopharmacological strategy consisting of the replacement therapy of the main autism-related neuro-chemical deficiencies, since each single correction of the three main autism-related, represented by a diminished pineal endocrine function, a failure of brain cannabinoid system, and a reduced OT secretion, has appeared to induce a relief of some specific symptoms. In more detail, MLT deficiency would be mainly related to sleep disorders, since the symptom more influenced by the only MLT therapy has been shown to be sleep disturbance. Brain cannabinoid deficiency would be mainly connected with the anxiety, and may be improved by CBD, whose anxiolytic properties have been well demonstrated [3], whereas the disturbances of socialization and affective emotional life would mainly depend on OT deficiency, since the best benefits have been obtained in subjects concomitantly treated by OT. This evidence is not surprising by taking into consideration that the amygdala is one of the main target organs for OT action, which has been proven to exert a modulatory effect on the emotional stimulatory responsivity of amygdala itself, whose fundamental role in the modulation of the affective and interpersonal relationships [3,4], including the sexual and romantic life [14], is well known. Further double-blind randomized studies in a greater number of autistic subjects and with a more adequate clinical psychosocial evaluation will be required to confirm the need of a substitute pharmacological therapy with at least MLT, CBD and OT to correct the three main autism-related neuro-endocrine failures in the treatment of autistic children. In any case, it has to be remarked that MLT is not the only hormone produced by the pineal gland, then autism-related pineal failure could involve pineal hormones other than MLT, namely 5-methoxytryptamine [19] and the beta-carboline pinealine [20], whose fundamental importance in the regulation of emotions and consciousness states have been well demonstrated, and whose further concomitant administration could allow more therapeutic benefits with respect to the already interesting results achieved by MLT, CBD and OT, as shown by this preliminary study. 

Conclusion

This preliminary study would suggest and confirm that the exogenous pharmacological corrections of the main autism-related neuro-endocrine and neuro-chemical deficiencies, may impact on the prognosis of the autistic children, by justifying further clinical investigations.

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