Adaptogen Complex: Ashwagandha and Rhodiola
HPA Axis, Stress Regulation, and Resilience
What are adaptogens, how do ashwagandha and rhodiola modulate the HPA axis through complementary mechanisms, and what does the most recent literature say about their action in dogs, cats and humans?
By Stefan Veenstra DVM
What are adaptogens: a scientific framework
The term “adaptogen” was coined in 1947 by Soviet toxicologist Nikolai Lazarev to describe substances that increase the organism’s physiological resistance to stressors without interfering with normal biological functions. The modern pharmacological definition requires three properties: the substance must act nonspecifically (broad spectrum of stressors), it must have a normalizing effect (lowering in case of overactivity, stimulating in case of exhaustion), and it must not have significant side effects at therapeutic doses. [1]
Research by Panossian and Wikman (2009) in Annals of the New York Academy of Sciences described the molecular mechanism of action of adaptogens in detail for the first time: intervention at multiple points in the HPA axis cascade, modulation of stress-activated proteins (Hsp70, SAPK/JNK), and normalization of neuroendocrine stress responses. This mechanistic framework makes it clear why adaptogens are effective in both acute overstimulation and chronic exhaustion: they address the regulation of the stress response system, not the symptom itself. [2]
NGD Care Behavioral Protocol: Adaptogens as the Core of HPA Axis Repair
NGD Care Old Age Protocol: Stress Regulation in Aging Animals
NatuurlijkGezondeDieren.nl: behaviour and stress-related complaints in dogs and cats
The HPA axis: the central stress system
The hypothalamic-pituitary-adrenal axis (HPA axis) is the central neuroendocrine stress regulation mechanism in all mammals. In the event of a stressful stimulus, the hypothalamus secretes CRH (corticotropin-releasing hormone), which activates the pituitary gland to ACTH secretion, which stimulates the adrenal cortex to produce cortisol. Cortisol prepares the body for the stress response via gluconeogenesis, immune modulation, and activation of the sympathetic nervous system. [3]
In chronic stress activation, the negative feedback loop of the HPA axis is disrupted: cortisol receptors in the hypothalamus and pituitary gland become less sensitive, cortisol secretion dysregulates and the system loses its adaptive flexibility. This leads to chronically elevated or chronically decreased cortisol levels (when exhausted), both of which are pathological for the immune system, gut microbiome, behavior, and energy management. The same mechanism plays a role in dogs and cats with chronic behavioural problems, chronic illness or long-term kennel or home situation stress.
Ashwagandha: the most researched adaptogen
Ashwagandha (Withania somnifera) is the best-documented adaptogen in modern literature. The active ingredients are withanolides, steroid lactone compounds with broad pharmacological activity. Withanolides modulate the HPA axis via lowering of CRH sensitivity in the hypothalamus and inhibition of the adrenal cortex response to ACTH, leading to normalization of cortisol levels in chronic overactivation. [4]
The clinical evidence has grown significantly in recent years. A meta-analysis of nine RCTs with 558 patients (Zahra et al., 2024) showed significant reductions in perceived stress, anxiety scores, and serum cortisol with ashwagandha compared to placebo. A systematic review and meta-analysis in BJPsych Open (Akhgarjand et al., 2025) confirmed that ashwagandha is safe and effective in stress reduction in adults with statistically significant cortisol reductions. [5]
Bharani et al. (2024) published in Veterinary Medicine and Science the first randomized, double-blind, placebo-controlled trial of ashwagandha extract in healthy geriatric dogs. The study showed improvement in aging-related parameters, including cognitive function, immune markers, and stress response. This is the first direct veterinary RCT for ashwagandha in dogs and provides the clinical basis for veterinary application. [6]
In addition to the HPA axis modulation, ashwagandha has GABAergic properties via direct binding to GABA-A receptors, which explains its direct anxiolytic effect. Withanolides protect mitochondrial membrane potential and inhibit oxidative stress in neurons, which gives neuroprotective effects in chronic stress load. [4]
Rhodiola rosea: energy, performance and serotonergic modulation
Rhodiola rosea has a mechanistic profile that is complementary to that of ashwagandha. The primary active components, rosavines and salidroside, act through three pathways: inhibition of the stress-activated protein kinase SAPK/JNK that mediates the cellular stress response, modulation of serotonergic and dopaminergic neurotransmission, and enhancement of monoamine oxidase inhibitory activity. [7]
Where ashwagandha primarily has a calming and anxiolytic effect through cortisol normalization and GABAergic activity, rhodiola primarily supports energy management, mental performance and resilience in fatigue. A double-blind crossover study (Darbinyan et al., 2000) showed significant improvement in cognitive test scores and reduction in stress-related fatigue in rhodiola group compared to placebo. Stojcheva et al. (2022) confirmed the effectiveness of rhodiola preparations in life stress symptoms and stress-induced conditions in a review in Molecules. [8]
Rhodiola also has adaptogenic action on the cardiovascular system via modulation of myocardial oxygen consumption and coronary blood flow, documented in animal studies including in dogs.[7]
Synergy: why the combination offers more than each individual
The combination covers both dimensions of stress-related dysfunction: the overactivity component (anxiety, cortisol, overstimulation) via ashwagandha and the exhaustion component (fatigue, reduced resilience, cognitive decline) via rhodiola. In chronic stress in dogs and cats, both components are almost always present at the same time: the animal is hyper-reactive and exhausted at the same time. A single adaptogen can only primarily address one dimension.
Clinical applications in dogs, cats and humans
Behavioral problems and situational stress
In dogs and cats with chronic anxiety, separation stress, fear of fireworks, kennel stress or overstimulation due to environmental changes, HPA-axis dysregulation is the physiological core of the problem. Adaptogen Complex modulates this dysregulation via cortisol normalization (ashwagandha) and serotonergic balance (rhodiola). As part of the Behavioral Protocol, it works complementary to Relax Support (neurotransmitter precursors), Myco Adaptogen Complex (mushroom-based adaptogens) and CBD (endocannabinoid modulation).
Aging and cognitive recovery in senior animals
In aging dogs and cats, HPA axis flexibility decreases and stress responses become dysregulatory. The veterinary RCT by Bharani et al. (2024) showed direct improvement in cognitive and immune parameters in geriatric dogs after ashwagandha supplementation. In the Aging Protocol, Adaptogen Complex strengthens the stress regulation component that systematically declines with aging.
Recovery after illness or intense training
Rhodiola is particularly well documented in fatigue and reduced performance after physical exertion. In working dogs (tracking, sports or assistance dogs) and in animals in the recovery phase after serious illness or surgery, rhodiola supports energy metabolism and the neurotransmitter balance that is disturbed by prolonged physical or emotional strain.
Scope of application Adaptogen Complex: dog, cat and human
Chronic and situational stress in dogs, cats and humans. HPA axis dysregulation and adrenergic overload. Anxiety, overstimulation and sleeping problems. Fatigue and reduced resilience in chronic loads. Senior animals with increased stress sensitivity and cognitive decline. Recovery after illness, surgery or intense training. As a core component of the NGD Care Behavioral Protocol. As a stress regulation component of the Old Age Protocol.
Conclusion
Adaptogen Complex combines two mechanistically complementary adaptogens: ashwagandha for HPA axis normalization, cortisol regulation, and anxiolyz, and rhodiola for serotonergic/dopaminergic support, SAPK/JNK inhibition, and energy enhancement. Together, they cover both dimensions of stress-related dysfunction. Clinical evidence has grown significantly in recent years, with meta-analyses from 2024 and 2025 and the first veterinary RCT for ashwagandha in dogs.
Liposomal encapsulation improves the bioavailability of the fat-soluble active components and makes the product suitable also in animals with stress-related digestion inhibition. Always as part of an integral protocol for serious behavioural problems, in consultation with an (integrative) veterinarian or behavioural therapist.
View Adaptogen Complex in the NGD Care webshop
Literature
- Brekhman II, Dardymov IV. New substances of plant origin which increase nonspecific resistance. Annu Rev Pharmacol. 1969;9:419-430.
- Panossian A, Wikman G. Evidence-based efficacy of adaptogens in fatigue and molecular mechanisms related to their stress-protective activity. Curr Clin Pharmacol. 2009; 4(3):198-219.
- Tsigos C, Chrousos GP. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res. 2002; 53(4):865-871.
- Sprengel M, et al. Withania somnifera (Ashwagandha) supplementation: a review of its mechanisms, health benefits, and role in sports performance. Nutr Metab (Lond). 2025; 22(1):9. [Most Recent Mechanistic Review Ashwagandha 2025]
- Zahra K, et al. Effects of Ashwagandha (Withania somnifera) on stress and anxiety: A systematic review and meta-analysis. Explore. 2024; 20(6):101055. [Meta-analysis 9 RCTs, Significant Cortisol and Anxiety Reductions, 2024]
- Bharani KK, Devarasetti AK, Carey L, et al. Effects of Ashwagandha (Withania somnifera) root extract on aging-related changes in healthy geriatric dogs: a randomized, double-blinded placebo-controlled study. Vet Med Sci. 2024; 10(5):E1556. [First Veterinary RCT Ashwagandha in Dogs, 2024]
- Darbinyan V, Kteyan A, Panossian A, et al. Rhodiola rosea in stress induced fatigue a double blind cross-over study of a standardized extract. Phytomedicine. 2000; 7(5):365-371.
- Stojcheva EI, Quintela JC. The effectiveness of Rhodiola rosea L. preparations in alleviating various aspects of life-stress symptoms and stress-induced conditions. Molecules. 2022; 27(12):3902.
This information is educational in nature and based on available scientific literature. The studies mentioned are not always directly veterinary or specific to the formulation described here. This text does not replace a veterinary consultation and does not contain any therapeutic claims.