INTRODUCTION:

Autism spectrum disorder (ASD) refers to a group of symptoms that range from communication deficits to disturbance in sensory-motor function. This disorder has a vital genetic factor, though other factors also contribute. The word spectrum denotes that this disorder ranges in severity from mild to severe, though individuals with ASD require at least support throughout their life¹.

Research in the past few decades has shown that ASD is prevalent among different populations worldwide. ASD is characterized by problems in social communication and restricted, repetitive behaviors². ASD occurs due to altered brain development and reorganization of neural circuits³. The diagnosis is made mainly on the basis of behavior⁴.The prevalence of ASD is increasing throughout the world⁵.

The pharmacotherapy of ASD is not very effective and is used only for symptomatic treatment of altered behavior, such as disruptive repetitive behaviors, and many of the drugs used, such as antipsychotics, have profound adverse effects⁶. Hence, behavioral therapies are the first-line treatment for ASD⁷.

The professionals involved in the management of ASD includes occupational therapist, speech pathologist, clinical psychologist, special educators based on individual needs and pediatricians⁸.

Apart from conventional pharmacological therapy and behavioral therapies, herbal medicine is used to manage ASD symptoms^9,10. It is estimated that about 28% of children with ASD have received alternative medicine ¹¹. Despite this, the use of herbal medicine in the management of ASD has not gained much attention. The current review describes the different herbs, phytoconstituents, and polyherbal formulations that have been reported for the treatment of ASD. Brief information about the diagnosis is also mentioned in the review to understand the effectiveness of treatment.

Management of ASD:

Altered Brain Development:

The behavioural traits observed in ASD arise because of alterations in brain development and changes in neural connections within the brain. However, a characteristic brain structure in ASD has not been identified because different individuals with ASD exhibit dissimilar results. Based on altered brain development and structure, ASD individuals have been categorized into different subsets. These subsets help to predict behaviour in ASD and also assist in designing treatments for different subsets¹².

The brain regions that differ in autistic children in comparison to non-autistic children include an enlarged hippocampus, a region of the brain involved in the creation and storage of memory. However, it is not known if this difference exists in adolescent and adult autistic people. Apart from this, structural changes are also seen in the amygdala, but different authors have reported different changes. It has been reported that autistic individuals have a smaller amygdala compared to people without autism, but some authors report that the size is reduced only in individuals with anxiety. On the contrary, some reports suggest that autistic children have a larger amygdala, and its size levels off with growth. An important difference has been observed in the cerebellum, where the amount of brain tissue has been reported to be less than normal in autistic individuals. This explains the difficulty in muscular coordination, cognition, and social interaction¹³.

The most striking difference is observed in the thickness pattern of the cerebral cortex. It has been observed that infants who are later diagnosed with ASD have faster expansion of cerebral cortex surface area from 6 to 12 months of age, and from year 2, the brain volume is larger compared to non-autistic infants. This explains why some autistic individuals have distended heads. This growth continues until childhood, but the brains of some ASD individuals shrink in adulthood around the age of 25. The enlarged head observed in autistic children is also due to excess cerebrospinal fluid, which starts at the age of 6 months and continues till the age of 3 years. Individuals with ASD usually have reduced or no corpus callosum, a structure that connects the cerebral hemispheres. This difference is seen in all ages in ASD individuals¹⁴.

Behavioural characteristics in ASD:

The characteristic behaviour observed in ASD is unusual, repetative mannerism such as hand clapping, bouncing, biting arm, avoiding eye contact etc.,) that increases with anxiety, anger, or fear. They display increased sensitivity to normal stimuli and display unusual emotions that are inappropriate to the situation. Under stress, ASD individuals do not respond to others, run away, or cause self-harm, and sometimes, they are unaware of their surroundings that may cause them harm ¹⁵.

Behavioural therapy in ASD:

The behavioural therapy includes applied behavioural analysis (ABA). Different types of ABA are used. These are positive behaviour and support (PBS), pivotal response training (PRT), the early intensive behavioural intervention (EIBI), and discrete trial training (DTT). The PBT identifies behavioural change and uses teaching and environment change to correct the altered behaviour. The PRT basically improves skills such as communication and motivates individuals to learn other skills. The EIBI gives individual instructions in one-on-one sessions, while the DTT uses a controlled step-wise teaching methodology to impart new skills. Hence, the management of ADS involves a multidisciplinary approach. The main role is played by clinical psychologists and speech therapists. Clinicians are involved in clinical observations and the symptomatic treatment¹⁶.

DRUG AND HERBAL TREATMENT FOR ASD:

ASD was believed to be a genetic disease, and genetic syndromes such as Fragile X and Rett syndrome have been associated with this disease¹⁷. However, several evidences indicate that environmental factors contribute to the development of ASD. Some of these environmental factors may not directly affect the brain but rather contribute to the disease through impairment of the immune system, disruption of detoxification mechanisms, generation of reactive oxygen species, alteration in energy generation, and inflammation^18,19. These factors may singly contribute to the development of ASD or aggravate the disease formation in individuals with gene defects that directly lead to ASD. Furthermore, polymorphism in genes involved in the metabolism and detoxification of environmental pollutants is also known to contribute to ASD^20,21.

The genetic component of ASD is not affected by pharmacotherapy. However, other factors that directly or indirectly contribute to the development and progression of ASD can be attenuated by the use of drugs and herbs. Symptomatic treatment of ASD is based on individual patients and is carried out using several agents. Since metabolism and detoxification are key factors for ASD, drugs and herbs that affect these directly or indirectly are used to improve the patient’s response²². Herbs that are believed to be beneficial in the treatment of ASD have neuroprotective, cognitive enhancing, or strong antioxidative actions²³.

Pharmacotherapy in ASD:

Pharmacotherapy involves the symptomatic treatment of ASD. Antipsychotics such as risperidone and aripiprazole are used to mitigate irritation, aggregation, and hyperactivity. Antidepressants such as citalopram are used to control obsessive-compulsive behavior. Anticonvulsants such as sodium valproate and lamotrigine are given to control epileptic attacks, and sleep dysregulation is addressed using melatonin and clonidine. Methylphenidate, a CNS stimulant, is used for attention-deficit hyperactivity disorder. Antihistamines and laxatives are used in the treatment of allergic rhinitis and constipation, respectively. Apart from this, vitamin supplements are given to attenuate the adverse effects of the used drugs²⁴. Melatonin is given to correct the sleep cycle²⁵. It is well known that drugs acting on the central nervous system, such as antipsychotics, anticonvulsants, and CNS stimulants, possess a wide range of adverse effects that range from changes in blood pressure, bowel movements, and urine retention to muscular movements. None of the above-mentioned pharmacological agents treats ASD, and the drugs are used only as symptomatic treatment depending on the symptoms manifested by the patients. Hence, the use of herbal drugs and other alternative treatments has seen phenomenal growth due to the belief that these treatments may help in curing the disease.

Herbal drugs and their extracts used in the treatment of ASD:

Ginkgo biloba:

Gingko biloba belongs to the family Ginkgoaceae. It is one of the oldest plants native to China and India. Japan, Korea, New Zealand, America, and many countries in Europe ²⁶

This herb is reported to improve memory and stabilize cognition. There are several reports on the effect of Ginkgo biloba on memory enhancement. It has been evaluated for its effect on memory enhancement in Alzheimer’s disease ¹⁹. It has been used for several centuries in China to improve memory, and it was one of the first drugs to be used for treating memory problems in the United States ²⁷. It is also reported to have neuroprotective effects due to its potent antioxidant action ²⁸. Furthermore, Ginkgo biloba is reported to affect the neurotransmitter levels in the brain, and it is reported to possess antidepressant and antianxiety effects ²⁹. The most widely used form of Ginkgo biloba is called ‘‘Ginkgo biloba EGb761’ which is a standardized extract containing 24% flavonoids (quercetin, kaempferol, and isorhamnetin), 6% terpene lactones;ginkgolides A, B, C, and bilobalide (figure 1), and various other constituents such as glucose, proanthocyanidins, and organic acids ³⁰.

Ginkgolide A

Ginkgolide B

Ginkgolide C

Bilobalide

Figure 1: Chemical structures of terpene lactones in Ginkgo biloba

A few clinical studies have been reported on the effect of Ginkgo biloba on ASD. In one study, Ginkgo biloba was added to risperidone for the treatment of ASD in children aged between 4 and 12 years. No significant difference was observed in the Aberrant Behavior Checklist-Community (ABC-C) rating scale, though no adverse drug reactions due to Ginkgo biloba were observed³¹. However, another study reported that the herbal extract of Ginkgo biloba ‘EGb761’ administration as an add-on drug is beneficial in reducing the symptoms of autism³². Both these studies are old, and there is no recent report on the effectiveness of Ginkgo biloba in ASD that raises doubts about the efficacy of this herb. The belief about its effectiveness in ASD is probably due to its memory-enhancing effect. It is known that children with ASD have poor memory³³. Though Ginkgo biloba is used widely for the treatment of psychiatric and neurodegenerative disorders, more studies should be carried out on the use of this herb for the treatment of ASD, either alone or as an add-on drug. Any traditional claims for the effectiveness of this herb in ASD should be ignored unless supported by clinical studies.

Zingiber officinale:

Zingiber officinale (Ginger), belonging to the family Zingiberaceae, is another herb that is claimed to be beneficial in the treatment of ASD. The beneficial effects are believed to be due to its antioxidant effects and its ability to increase blood floS⁴². Brahmi contains several chemical constituents that include alkaloids (brahmine, nicotine, herpestine), glycosides, steroidal saponins (mannitol, hersaponin, bacopasides I-XII, bacosides), tannins and flavonoids. Chemical structures of important phytoconstituents are given below (figure 2). Many of the biological effects of this herb are attributed to bacosides⁴³. One of the widely used Bacopa monnieri extracts for evaluation of its effect is ‘BacoMind,’ which is a standardized methanolic containing about 29% of the active constituents: Bacoside I and Bacoside A (29.1% w/w)⁴⁴. An experimental study conducted using valproic acid-induced ASD in rats showed that a standardized extract called ‘BacoMind’ is effective in ameliorating abnormal behavioral paradigms in rats ⁴⁵. There are no clinical studies to show the effectiveness of Bacopa monnieri on ASD.

Bacoside A

Bacoside B

Bacoside A₁

Bacoside A₃

Bacopaside I

Figure 2: Chemical structure of important phytoconstituents in Bacopa monnieri.

Green tea (Camellia sinensis):

Green tea is a good antioxidant. It contains flavonoids that are known to possess strong antioxidant actions, which are known to cause neuroprotection from reactive oxidative species⁴⁶. Administration of green tea extract to animals at doses of 75−300mg/kg is reported to possess neuroprotective effects due to the scavenging of free radicals in the brain⁴⁷. l-theanine present in green tea is also reported to enhance the levels of dopamine and serotonin neurotransmitters that elevate mood (figure 3)⁴⁸. Constituents present in green tea are reported to have antistress effects, and it is reported to protect the cortex, cerebellum, and hippocampus against alcohol-induced damage in diabetic rats⁴⁹. Finally, it is also reported to reduce the development of valproic acid-induced autism in experimental animals⁵⁰.

Figure 3: Chemical structure of l-theanine

Luteolin:

This is a flavonoid with strong anti-inflammatory and immunomodulatory effects ^50,51. Both these actions of luteolin are reported to be beneficial in autistic patients ⁵². Immunological stimulation and subsequent inflammation in the mother leading to dysfunction of microglia in the offspring is responsible for autism ⁵³. Luteolin is reported to reduce inflammatory processes in the microglial system ⁵⁴. It is also reported to reduce activation of STAT3, a marker of inflammation. Luteolin also reduces the elevated levels of inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor (TNF) ⁵⁵. Supplementation of luteolin in autistic children has been reported to increase their social behavior and reduce levels of different inflammatory cytokines ^56,57

Piperine:

Piperine (N-acylpiperidine) is an alkaloid found in many herbs, including pepper (figure 4) ⁵⁸. It is known to possess anticonvulsant and strong antioxidant effects ⁵⁹. It is also known to enhance memory and cognition ⁶⁰. Furthermore, it has been reported to reduce valproic acid autism in experimental animals ⁶¹. Additionally, it has antistress and anxiolytic properties ⁶². All these actions are reported in experimental animals, but it is believed that these effects may benefit autistic individuals.

Figure 4: Chemical structure of piperine

Curcumin:

Curcumin is a constituent that is mainly present in turmeric (Curcuma longa), and like many other herbs and phytoconstituents, it has neuroprotective effects that are mediated through its antioxidant effect (figure 5)⁶³. Furthermore, it also has an anti-inflammatory effect⁶⁴. In rats, neonatal curcumin treatment has been shown to improve hippocampal neurogenesis and improve autism-related behavior⁶⁵. Furthermore, curcumin was reported to suppress oxidative-nitrosative stress and restore neurological, behavioral, and biochemical parameters in rats, indicating its usefulness as an adjunct in ASD⁶⁶. Regular curcumin intake has been shown to enhance cognitive skills⁶⁷, though there are no direct clinical studies to prove its beneficial effects in autistic patients.

Figure 5: Chemical structure of curcumin

Cannabinoids:

Cannabis (Cannabis sativa) is being explored for the treatment of various neurological disorders⁶⁸. Cannabidiol, one of the constituents in cannabis, possesses neuroprotective, immunomodulatory, and antioxidant effects that may be beneficial in the management of autism⁶⁹. Though cannabis and cannabinoid use has been recommended for use in ASD ⁷⁰, a clinical study carried out over three months proved that findings about its efficacy are mixed and insufficient⁷¹. Cannabidivarin, another constituent of cannabis, improves behavior in autistic patients⁷². In a clinical study, cannabidivarin was shown to modulate neurotypical functions that could benefit autistic patients ⁷³. It was also reported to ameliorate autistic behavior in valproic acid-induced autism in rats⁷⁴. A study on the safety of cannabidivarin in a 12-week period has shown that it is safe at a dose of 10mg/kg/day. The Cannabinoid system in the brain is neuromodulatory, and it is believed that activating this system with cannabis or its constituents may help to ameliorate autistic symptoms through immunological and antioxidative mechanisms.

POLYHERBAL FORMULATIONS FOR THE MANAGEMENT OF ASD:

Traditional Chinese polyherbal formulations have been evaluated for their effectiveness in the management of ASD. Some of these polyherbal formulations contain the herbs mentioned above, such as Ginkgo biloba and Zingiber officinale, while other formulations contain several other herbs. Furthermore, many of these polyherbal formulations have been evaluated for their effectiveness with conventional pharmacological agents or physical and psychological interventions used in ASD. These clinical studies have been carried out using a smaller sample size, and many of the findings have been reported in journals that are non-reputable and difficult to access. These formulations have Chinese names. Some of these formulations are Jiawei Wendan decoction, Modified Yinhuo decoction, Suhe Ditan decoction, Jingshuaikang capsule, Congnaoyizhi capsule, and Ukgansangajinpibanha granule ¹⁰. However, a few of these formulations have been tested for safety and efficacy in clinical trials, and these are mentioned below.

The Ukgansangajinpibanha granule, a formulation containing nine herbs, is used to control angry and nervous autistic children and has been reported to be safe⁷⁵. The Jiawei Wendan decoction contains nine different herbs, including Zingiber officinale, and is used traditionally for the treatment of ASD¹⁰. Clinical studies have shown its effectiveness in migraine through the modulation of several cytokines⁷⁶. Modified Yinhuo decoction was reported to enhance applied behavior and communication in autistic children after 30 30-day courses with treatment on alternate days⁷⁷. The supplemented Lizhong decoction, which is prepared using six herbs including Zingiber officinale, was reported to increase the adaptation of autistic children to social life⁷⁸.

FUTURE DIRECTIONS FOR THE USE OF PHYTOCHEMICALS AND PLANTS IN THE TREATMENT OF ASD:

The use of herbal medicine for the management of ASD is growing, and some of these herbs have shown promising effects in attenuating altered behaviour and motor function. However, many of these herb or phytoconstituents have not been tested directly on the autistic children. Some of these herbal extracts and phytoconstituents have been reported only to enhance cognitive function in humans, while many of these have been evaluated using experimental animals. Hence, clinical studies with the required sample size may help to determine their effectiveness in the management of ASD. Furthermore, the isolation of active constituents and determination of the structure-activity relationship leading to the synthesis and evaluation of more effective agents may lead to the discovery of novel molecules that are more effective with fewer adverse effects. The Chinese polyherbal formulations containing several herbs have shown good effects in clinical studies that were carried out using low sample sizes and published in journals that are difficult to access. More studies using herbal formulations on autistic children from different ethnicities are required to confirm their activity. The effectiveness of Chinese formulations suggests that holistic approaches using herbal formulations mentioned in ancient texts are an effective alternative to conventional pharmacotherapy. Hence, other ancient texts such as Ayurveda, Unani, and other traditional medicines must be evaluated to identify potential polyherbal treatments for the management of ASD.

The potential long-term effects and sustainability of the herbs in management of ASD looks promising. However, many studies have been conducted on the use of herbal drugs in the management of ASD, and a direct beneficial effect of the herbs without other interventions is lacking. Nevertheless, the beneficial effects of herbs on ASD are promising, and further investigations on the use of herbs in other parts of the world and the isolation of active constituents from already reported herbs may lead to the development of novel molecules in the management of ASD.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

The author would like to thank the Deanship of Scientific Research at Shaqra University for supporting this work.

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Received on 26.11.2023 Modified on 07.02.2024

Research J. Pharm. and Tech 2024; 17(7):3459-3466.

DOI: 10.52711/0974-360X.2024.00541