Medicinal Herbs and ADHD


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Herbal Constituents and Relevant Biochemistry

For over three billion years, plants have evolved in response to the needs and challenges required of their environment. Through these constant biochemical pursuits, humankind has also greatly benefited.1 Herbal constituents are the active ingredients of plants. They are plant metabolites (phytochemicals) which when consumed, have a definable physiological and potentially medicinal effect on the body.

Plant cells produce two types of metabolites, both of which are derived from carbohydrates synthesized through the process of photosynthesis. Primary plant metabolites, which are involved directly in a plant’s growth and metabolism, and secondary plant metabolites, which are most often considered to be responsible for a plant’s medicinal effects.2 When a plant produces significant amounts of secondary metabolites, it is then generally categorized as a medicinal herb.

Herbal constituents are usually classified by their chemical structure or biosynthetic pathway, and within each grouping, various subgroupings or classifications can exist. Some are ubiquitous (e.g., flavonoids), while others will be unique to a single herb (e.g., curcumin) or only a few herbs of which herbalists are aware (e.g., alkylamides). Herbal constituents will also vary in their ability to be extracted into different solvents (e.g., fat, water, or ethanol) and distribution throughout body tissues (e.g., ability to cross the blood brain barrier).

Major Classes of Herbal Constituents
Alkaloids: synthesized from amino acids and all contain nitrogen

Polyphenols: have multiple aromatic rings and often occur as glycosides

  • Flavonoids
  • Tannins
  • Anthraquinones
  • Coumarins
  • Salicylates
  • Lignans

Terpenoids: synthesized from isoprene/mevalonate

  • Saponins (steroidal/furanosterol and triterpene)
  • Volatiles oils
  • Resins
  • Mono-, di-, and sesquiterpenes

Carbohydrates: mucilage and other polysaccharides


  • Note: Many of the above constituents are found combined with a sugar moiety and are thus considered glycosides within plants.



Standardization of Herbal Constituents

Pharmacognosy is the field of study focused on the identification and extraction of singular phytochemicals for the development of pharmaceuticals, and much modern research conducted with plants applies a similarly reductionistic approach. Although this can be helpful to further the understanding of a plant’s mechanism of action, it is important to recognize that studying individual plant constituents in isolation cannot be considered a complete representation of the activity of the plant as a whole. The concept of plant synergy is crucial to understanding the complexity of how plant medicines work.

Thousands of plant constituents have been discovered, and though our scientific understanding has grown immensely within the last few decades, many of their individual and combined effects are yet to be uncovered. Nonetheless, having a sound knowledge of some key plant constituents is particularly helpful when it comes to understanding a plant’s pharmacological activity. This is essential for developing quality assurance methods, extraction procedures, and ascertaining potential toxicity concerns and drug interactions.

Herbal products often include individual constituents to “standardize” or provide a marker of either quantifiable activity or consistency of active ingredients from batch to batch. It is ideal to achieve a certain accepted amount of an active phytochemical being present when based on the clinical data. It is equally useful to ensure that the “whole herb” is included alongside it and that a full spectrum of the plant’s other naturally occurring compounds are present in the product as well.


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Withanolides belong to a phytochemical class of constituents called steroidal saponins which are found mainly within the root of Ashwagandha (Withania somnifera) and are often regarded as key markers of the plant’s quality and therapeutic activity.

Approximately 900 withanolides have been discovered and though their chemical structure will vary, some bear a similar resemblance to the body’s endogenous hormones and can have modulating effects upon cortisol and reproductive functions.3 It is likely that Ashwagandha’s adaptogenic effects may result from the complex of withanolides, which have glucocorticoid-like effects – helping with the adaptive stress response.4


Withania somnifera

Many withanolides have also demonstrated significant immunomodulatory effects, with both immunostimulatory and inhibitory actions being attributed to different types. Withaferin A is perhaps the most most studied withanolide, and it has been shown to target multiple cellular signaling pathways simultaneously. In models of stress, it is able to shift toward a greater Th-1 immune response, activate cytotoxic natural killer (NK) cells, and recover depleted T-cells.5

Though the precise mechanism of action has yet to be fully elucidated, in vitro studies using methanolic extract of the root have demonstrated GABA-mimetic activity of withanolides. These studies indicate a possible rationale for its role in the treatment of disorders associated with GABAergic signaling dysfunction such as general anxiety disorders, sleep disturbances, and muscle spasms.6

Withanolides appear to have rapid absorption after oral administration in animal models. Extracts of Ashwagandha containing 30 mg of withanolides and used daily have been clinically demonstrated to:7

  • Benefit chronic stress anxiety and insomnia8-13
  • Improve sperm parameters and sex hormone levels in infertile men14,15
  • Improve cognitive function in healthy volunteers and patients with mild cognitive impairment16
  • Benefit muscle strength and recovery17
  • Potentially improve thyroid function in subclinical hypothyroidism18

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Alkylamides are a class of stable, fatty acid-like molecules produced by a number of medicinal plants often known for their pungent taste and tingling sensation within the mouth.19 They are particularly concentrated within the roots of Echinacea angustifolia (Narrow leaf purple coneflower) and are considered to be the most clinically relevant active constituents and major markers of quality in regards to Echinacea species.20


Echinacea angustifolia

Plant alkylamides are structurally diverse with a wide range of biological effects; however, they are usually lipophilic and will have various pharmacological activities including immunomodulatory, antimicrobial, antiviral, and anti-inflammatory activity.21  The roots of E. angustifolia appear to be higher in alkylamides overall and particularly in the 2-ene type structure versus other species such as E. purpurea (Eastern purple coneflower). Synergy between combining species of Echinacea has been demonstrated, with the 2-ene structure in E. angustifolia showing a protective effect against the degradation of 2,4, diene alkylamides via the P450 enzyme system.21 Therefore combining these species together may result in greater alkylamide bioavailability and activity within the body.

Alkylamides in Echinacea species have also been observed to resemble the structure of the endogenous cannabinoid anandamide (AEA) and interact at CB2 receptors, inhibiting AEA reuptake in vitro, and having anxiolytic effects in humans and animal models.22,23

The immunomodulatory activities of Echinacea spp. are in large part attributed to their alkylamides, and their ability to exert cannabimimetic responses, modulate innate and adaptive immunity, and contribute towards potent anti-inflammatory effects.24-26 Further interactions with the endocannabinoid system include inhibiting fatty acid amide hydrolase (FAAH) which may be linked to other central nervous system activities.27 Alkylamides from Echinacea have also shown potential in alleviating symptoms of atopic eczema and restoring the epidermal lipid barrier when applied to the skin, as the endocannabinoid system is known to regulate various aspects of cutaneous barrier and immune functions.25

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Kavalactones are lipophilic compounds found in the resinous portion of Kava roots (Piper methysticum), and they are considered responsible for its main pharmacological effects and numbing sensation in the mouth. Over 29 different kavalactones have been identified; however, some of the most researched include kavain, methysticin, dihydromethysticin, and yangonin.28 Kava extracts are often standardized to their kavalactone content and dosed between 100 to 200 mg kavalactones per day.

The content and profile of kavalactones appear to vary with the age and variety of the plant, geographical origin, and growing conditions, and may contribute to its medicinal properties, solubility, and potential for adverse effects.29,30 “Noble” cultivars of Kava appear related with respect to their kavalactone composition, having relatively higher levels of kavain and synergistically acting water-soluble constituents – compared to more fat-soluble constituents with potentially harmful effects such as dihydromethysticin.31


Piper methysticum

Kavalactones appear to be responsible for Kava’s anxiolytic properties via modulation of GABA channels, with kavain and dihydrokavain possessing the most significant GABAergic activity.32,33 The lipophilic nature of kavalactones allows for them to access the brain and remain within lipid membranes, potentially effecting a variety of cell surface receptors and increasing the number of GABA binding sites rather than changing an affinity to bind GABA directly.32,34 Numerous studies suggest a range of other possible mechanisms of kavalactones related to Kava’s anxiolytic, analgesic, and anesthetic effects, including:

  • Blockage of voltage-gated sodium ion channels35,36
  • Binding of brain opioid receptors at high concentrations37
  • Reduced excitatory neurotransmitter release due to blockade of calcium ion channels38
  • Affinity for CB₁ receptors within the endocannabinoid system39
  • Enhanced ligand binding to gamma-aminobutyric acid (GABA)(A) receptors and suppression of the synthesis of thromboxane A(2), which antagonizes GABA(A) receptor function34,40
  • Reduced neuronal reuptake of noradrenaline (norepinephrine) and dopamine41

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Curcumin is a bright yellow flavonoid isolated from the rhizomes of turmeric (Curcuma longa).

It is considered the most abundant and potent antioxidant of a group of compounds found in the turmeric rhizome called curcuminoids, which includes related molecules demethoxycurcumin and bisdemethoxycurcumin.

Curcumin has a lipophilic nature (it is nearly insoluble in water) and is generally considered to have poor absorption and low systemic bioavailability, as evidenced by low serum levels after oral doses, limited tissue distribution, and a rapid liver metabolism.42 Many methods to improve curcumin bioavailability have been utilized such as combining with fat or other adjuvants (e.g., Black pepper), using curcumin analogues, and formulating alongside galactomannosides, phospholipid complexes, and/or nanoparticles.

Curcumin is one of the most extensively studied plant constituents, whose main properties include antioxidant, anti-inflammatory, and anti-cancer effects.43 Its mechanism of action has been evaluated in thousands of studies at equivalents of approximately 200 to 300 mg of curcuminoids demonstrating effects upon diverse molecular targets including altered gene expression and signaling pathways such as:44,45

  • Transcription factors, such as nuclear factor-kB (NF-kB)
  • Signal transducer and activator of transcription (STAT) proteins
  • Nuclear factor erythroid 2-related factor 2 (Nrf2)
  • Growth factors (such as vascular endothelial cell growth factor)
  • Inflammatory cytokines such as tumour necrosis factor (TNF)-alpha, interleukin 1 (IL-1), and IL-6
  • Protein kinases, such as mitogen-activated protein kinases (MAPKs) and Akt
  • Cyclooxygenase-2 (COX-2), hemeoxygenase-1 (HO-1), and NAD(P)H:quinone oxidoreductase 1 (NQO1).

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Constituent Table

Constituent Class Secondary Metabolite Herbal Examples
Alkaloids Berberine Goldenseal (Hydrastis canadensis)

Oregon Grape (Berberis spp.)

Phellodendron amurense

Polyphenolics Flavonoids Proanthocyanins

(Condensed tannins)

Grapeseed (Vitis vinifera)

Green Tea (Camellia sinensis)


Vitexin-2-rhamnoside Hawthorne (Cratageus spp.)
Silybin Milk Thistle (Silybum marianum)
Flavonylglycosides Ginkgo (Ginkgo biloba)
Rosavins (e.g., salidroside)


Rhodiola (Rhodiola rosea)
Curcumin Turmeric (Curcuma longa)
Eleutheroside E Eleuthero (Eleutherococcus senticosus)
Terpenoids Saponins Withanolides


Ashwagandha (Withania somnifera)
Ginsenosides Asian/Korean Ginseng (Panax ginseng)
Glycyrrhizin Licorice (Glycyrrhiza glabra)
Gymnemic acids


Gymnema (Gymnema sylvestre)
Aescin Horse chestnut (Aesculus hippocastanum)
Bacosides Bacopa (Bacopa monnieri)



Tribulus (Tribulus terrestris)

Wild Yam (Dioscorea villosa)

Actein Black Cohosh (Actea racemose)


Volatile Oils Various Rosemary, Holy Basil, Oregano, Sage
Resins Kavalactones Kava (Piper methystium)
Mono, Di, and Sesquiterpenes Ginkgolide, bilobides


Ginkgo (Gingko biloba)
Labdane Diterpene Forskolin Coleus (Coleus forskohlii)
Fatty Acids Alkylamides Echinacea (Echinacea angustifolia and E. purpurea)
Various Saw Palmetto (Serenoa repens)
Carbohydrates Mucilage Marshmallow (Althea officinalis)
Minerals Iodine Kelp/Bladderwrack (Fucus vesiculosis)

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