Effects of CBD-Enriched Cannabis sativa Extract on Autism Spectrum Disorder Symptoms : An Observational Study of 18 Participants Undergoing Compassionate Use
Paulo Fleury-Teixeira, Fabio Viegas Caixeta, Leandro Cruz Ramires da Silva, Joaquim Pereira Brasil-Neto and Renato Malcher-Lopes
Frontiers in Neurology, October 2019, Volume 10, Article 1145
doi : 10.3389/fneur.2019.01145
Autism Spectrum Disorders comprise conditions that may affect cognitive development, motor skills, social interaction, communication, and behavior. This set of functional deficits often results in lack of independence for the diagnosed individuals, and severe distress for patients, families, and caregivers. There is a mounting body of evidence indicating the effectiveness of pure cannabidiol (CBD) and CBD-enriched Cannabis sativa extract (CE) for the treatment of autistic symptoms in refractory epilepsy patients. There is also increasing data support for the hypothesis that non-epileptic autism shares underlying etiological mechanisms with epilepsy. Here we report an observational study with a cohort of 18 autistic patients undergoing treatment with compassionate use of standardized CBD-enriched CE (with a CBD to THC ratio of 75/1). Among the 15 patients who adhered to the treatment (10 non-epileptic and five epileptic) only one patient showed lack of improvement in autistic symptoms. Due to adverse effects, three patients discontinued CE use before 1 month. After 6–9 months of treatment, most patients, including epileptic and non-epileptic, showed some level of improvement in more than one of the eight symptom categories evaluated: Attention Deficit/Hyperactivity Disorder; Behavioral Disorders; Motor Deficits; Autonomy Deficits; Communication and Social Interaction Deficits; Cognitive Deficits; Sleep Disorders and Seizures, with very infrequent and mild adverse effects. The strongest improvements were reported for Seizures, Attention Deficit/Hyperactivity Disorder, Sleep Disorders, and Communication and Social Interaction Deficits. This was especially true for the 10 non-epileptic patients, nine of which presented improvement equal to or above 30% in at least one of the eight categories, six presented improvement of 30% or more in at least two categories and four presented improvement equal to or above 30% in at least four symptom categories. Ten out of the 15 patients were using other medicines, and nine of these were able to keep the improvements even after reducing or withdrawing other medications. The results reported here are very promising and indicate that CBD-enriched CE may ameliorate multiple ASD symptoms even in non-epileptic patients, with substantial increase in life quality for both ASD patients and caretakers.
Keywords : autism spectrum disorders, cannabidiol, epilepsy, Cannabis sativa, endocannabinoid system
According to the DSM 5 (2013), Autism Spectrum Disorder (ASD) is characterized by functional deficits in three areas : mental development, social interaction, and behavior (1). In a multicenter epidemiological study done in 2012, involving nine countries, the median estimate of prevalence of ASD was 62/10.000 inhabitants (2). In clinical practice, the term ASD comprises a broad group of syndromes, diseases, and disorders (3, 4), that can affect cognitive development, motor skills, social interaction, communication, and behavior (frequently including auto and hetero-aggressiveness) (5–15). Often, this set of functional deficits results in incapacitation, lack of independence and severe distress for patients, families, and caregivers. For a recent review on this topic, refer to (16).
It is believed that ASD has multifactorial causes, generally associated with chromosomal or epigenetic changes in many different genes, which are often associated with neuronal function (17–24). Currently, there are no drugs or psychotherapeutic approaches capable of comprehensively improving life quality, social skills, and cognitive development of the most severe ASD patients (25–31). Currently available drugs may mitigate some specific symptoms, but generally speaking, they do so with a narrow range of effectiveness, and are often associated with important side effects (32, 33). Antipsychotic, antidepressant, or anxiolytic drugs, for example, may soothe autistic patients who display self-aggressive behavior (33–36). Antiepileptic drugs may be effective for seizure control and may even improve sleep quality and behavioral aspects (37). However, these drugs are known to cause major side effects (38–46). Moreover, none of these drus has been shown to significantly improve the lack of social interaction and communication skills that characterize and impose great impact on the lives of patients with ASD and their families.
Recent observational studies and trials reporting the use of pure CBD or CBD-enriched cannabis extracts for the treatment of syndromes characterized by refractory epilepsy and regressive autism suggest therapeutic potential of cannabinoids for autistic symptoms (47–60). These studies, which include extracts with a CBD/THC ratio of up to 20/1, showed that, even in children and adolescents, the side effects of these extracts are infrequent and less damaging than those reported for drugs traditionally used either for ASD, ADHD, sleep disorders, or epilepsy.
Changes in the expression of peripheral cannabinoid receptors were verified in autistic patients, suggesting possible deficiencies in the production and regulation of endogenous cannabinoids in ASD (61). This hypothesis has been recently confirmed specifically for anandamide, a major endo-cannabinoid, which is reduced in ASD patients (62). The understanding of the possible mechanisms involving the endocannabinoid system in the etiology of ASD has been derived from basic research in animal models. Special attention has been given to the neuronal hyperexcitability hypothesis and its possible relationship with the endocannabinoid system, which may also explain the higher incidence of epilepsy among ASD patients (63–68).
Significant epileptform EEG activity has been recorded even in the central nervous system of non epileptic autistic children (69), which is consistent with the “intense world hypothesis,” that relates autistic symptoms to excessive neuronal activity and connectivity (70). Together, these findings strongly support the need for testing Cannabis sativa extracts (CEs) and isolated phytocannabinoids as pharmacological approaches to control severe symptoms in both epileptic and non-epileptic ASD patients (68). Furthermore, CBD has been shown to have anxiolytic (71–75) and antipsychotic effects (76–79) in humans. It is plausible to assume that such effects are, at least in part, mediated by CBD induced accumulation of the endocannabinoid anandamide (80). Although the mechanisms underlying CBD-induced antiepileptic effects are not entirely clear, anandamide modulation is likely to play an important role (68). In this context, it is interesting to note that anandamide accumulation, caused by inhibitors of its metabolic degradation, leads to reduction of social interaction deficits in the valproate treated animal model of autism (81).
Here we report an observational study analyzing the effects of the compassionate use of Cannabis sativa extract (CE) containing a 75/1 CBD/THC ratio, which was given to a group of 18 ASD patients. The participant group includes 11 patients with no history of epilepsy, two previously diagnosed with epilepsy but seizure-free for over a year, and 5 currently diagnosed with epilepsy who had seizures during the month preceding treatment with CE. Treatment results were assessed by means of monthly questionnaires and clinical evaluation. The results after 6–9 months of treatment were extremely promising for both epileptic and non-epileptic patients. For the latter, observed improvements were much more comprehensive with fewer adverse effects than it would have been expected from currently available therapies. These preliminary results indicate, therefore, the urgent need for more extensive and detailed clinical studies to further validate the use of ECs and cannabinoids for the treatment of severe ASD symptoms.