cbd oil for cushing& 39

Can CBD Oil Treat Horses With Cushing's?

Equine Cushing’s disease, medically known as pituitary pars intermedia dysfunctions (PPID), is an endocrine (hormone) disease affecting the pituitary gland in horses.

The pituitary gland is located at the base of the brain, and it’s the master gland responsible for hormone production for brain signaling which affects the whole body. It can be a devastating diagnosis for horse owners. The disease primarily affects horses over the age of 10, with 19 years being the average age of diagnosis [1].

As more research about the benefits of CBD oil emerges for humans and animals, vets and equestrians alike are turning to CBD to support their horses’ health.

In this article, we’ll take an in-depth look at what the current research says about CBD and this metabolic syndrome.

Symptoms Of Cushing’s Syndrome In Horses

Pituitary pars intermedia dysfunctions (PPID) or Cushing’s disease is an example of metabolic syndrome that increases the risk of heart disease and strokes. It’s a very slow and progressive disease, so early veterinary intervention can help to improve your horses’ quality of life.

In PPID, the pituitary gland—also known as the master hormone gland—becomes overactive and produces large amounts of the adrenocorticotropin hormone (ACTH). Not much is known about what causes PPID, but it has been observed to occur from a benign pituitary tumor most prevalent in older horses.

One of the functions of ACTH is to stimulate the release of the stress hormone, cortisol. When left untreated, elevated ACTH increases cortisol levels in your horses’ body that can lead to very serious consequences.

Clinical signs that a horse may have Cushing’s syndrome include:

  • A pot-bellied appearance
  • Drastic changes in weight
  • Abnormal fat distribution, especially in the face
  • Lethargy
  • Muscle loss
  • Increased coat length, and failure to shed coat in summer
  • Slow wound healing
  • Prone to infections
  • Excessive drinking and urinating
  • Development of laminitis

If you notice these changes in your horse’s body and see a noticeable difference in its mood, you should seek professional advice from your vet to get a proper diagnosis.

Cushing’s is a very slow and progressive disease, so early veterinary intervention can help to improve your horses’ quality of life.

Diagnosing Cushing’s In Horses

The most common way to test for Cushing’s is with the low-dose dexamethasone suppression (LLD) test.

This test is typically conducted overnight and requires a baseline blood sample for cortisol levels. The vet will then administer a dose of dexamethasone and test blood samples 18–20 hours later. In a healthy horse, the cortisol levels will decrease from the injection of dexamethasone. However, horses with Cushing’s will still have elevated cortisol levels.

Insulin resistance is common in equines diagnosed with Cushing’s so a blood glucose or insulin test is also recommended in conjunction with testing for Cushing’s.

What Are Conventional Treatments For Cushing’s Disease In Horses

A Cushing’s diagnosis is devastating. While there is no cure for PPID, with veterinary treatment, a balanced nutrition plan, and careful management, many horses and ponies can live comfortable and active lives for many years after their diagnosis.

Most vets will recommend a focus on a low-carb diet to maintain healthy blood sugar levels and weight in your horse and careful monitoring every six to eight months to track the progression of PPID.

When it comes to medications, your vet may prescribe dopamine, serotonin, and cortisol agonists. The most common medication for PPID is dopamine agonists, which help to control the overactive pituitary gland.

Some of the negative side-effects of dopamine agonist medications include:

  • Colic
  • Digestive issues
  • Depression
  • Weight loss

What Is CBD?

CBD or cannabidiol is a naturally derived compound from cannabis plants. It’s one of over a hundred compounds in a class called cannabinoids.

These cannabinoids look very similar to neurotransmitters in mammal bodies called endogenous cannabinoids in a system called the endocannabinoid system (ECS). The ECS is responsible for maintaining homeostasis (balance) in a wide variety of functions, including the sleep-wake cycle, stress, metabolism, mood, and the immune system.

CBD is not to be confused with its more notorious cousin, THC (tetrahydrocannabinol). Unlike THC, CBD does not produce intoxicating effects, which makes it a more reliable compound in terms of supporting one’s health with daily use.

Hemp crops have high concentrations of CBD, and that’s where legal CBD comes from. Thanks to the US Farm Bill in 2018, hemp crops that contain up to 0.3% THC were legalized, while marijuana plants (anything with over 0.3% THC) remain federally illegal.

CBD is incredibly versatile and can be found in anything from capsules, sublingual oils, topical treatments, and even pet treats and food.

How Does CBD Work For Horses?

The endocannabinoid system (ECS) is a major signaling system that exists in humans and our furry pets. There’s still limited research surrounding horses for cannabis-related studies. However, researchers agree that CBD appears to stimulate horse’s ECS in the same way it does in humans.

CBD, even in high doses, is well-tolerated and can provide positive uses to support health and wellness with very few adverse effects.

Cannabinoids such as CBD, CBG, CBN, and THC from hemp and naturally produced cannabinoids in the body (endogenous) communicate in the intricate endocannabinoid system’s receptors to turn on key functions to maintain homeostasis (balance) for optimal body function.

When we become out of balance in one system for too long, such as poor stress levels, irregular sleep cycles, or disrupted hormone function, horses and humans become prone to serious health issues. Supplementing your equine’s diet with CBD allows the endocannabinoid system to function more effectively to help deal with stress better for improved wellness.

CBD For Horses And Its Profound Benefits

Support ECS For Healthy Inflammatory Response

One of the roles of the endocannabinoid system is to regulate healthy levels of inflammation.

CBD products help to increase the body’s levels of endocannabinoids and slows the breakdown of these neurotransmitters to improve the ECS function.

Horses with a Cushing’s diagnosis are susceptible to insulin resistance, obesity, and cardiovascular disease, which are all linked with inflammation.

The CB2 receptor plays an important role in regulating healthy inflammation. CBD may help to improve the levels of endogenous cannabinoids for improved communication with CB2 receptors for gentle and natural-based support in the immune system [2].

Support ECS For Comfort Levels In Your Horse

Equines with a Cushing’s diagnosis are more susceptible to laminitis, a condition that affects the tissues binding the hoof wall to the pedal bone. Since PPID affects hormone function and can result in excessive weight gain, it can put a lot of pressure on these joints causing tremendous pain.

CBD oil may help to support comfort levels in your horse. As we mentioned in the previous point, CBD helps the ECS regulate inflammation. While inflammation is a healthy response to support wound healing and fight off infection, too much inflammation can result in pain and tissue damage as seen in laminitis.

Support Healthy Recovery Post-Exercise

For horses that undergo a lot of training, CBD may help to support your equine’s muscle recovery, to keep them in their healthiest form. Adding CBD oil to your horses’ wellness regime may help with their performance as it may help to support post-exercise recovery and maintain healthy levels of stress.

Calm Your Horse

CBD has been studied for its calming and relaxing benefits, which may help to combat the negative effects of stress.

Stress is an important protective mechanism for the fight-or-flight response, but it was never meant to be turned on 24/7. Chronic stress leads to a wide host of health conditions that presents themselves in Cushing’s syndrome in horses.

Many trainers reach for CBD oil to keep their horses calm in stressful situations like transportation or when adapting them to a new environment.

Frequently Asked Questions About Horses & CBD

How Much CBD Should I Give My Horse?

Dosing CBD for humans and animals is always a tricky subject as it depends on many different factors and can take some experimentation to find the ideal dose. CBD is typically dosed depending on weight, so you’ll need much more CBD for your horse than you would for yourself or your dog.

Look for CBD products marketed for horses, as they will have more appropriate strengths suited to the size of your horse, and follow the instructions with the lowest dose and monitor your horses’ behavior before increasing the dose.

If you plan on giving CBD products to your horse to support a health condition, we strongly advise that you speak with your veterinarian to ensure that it’s the right thing to do. We want to underscore that there is no evidence that CBD can treat horses with Cushing’s.

How Do I Give My Horse CBD?

Edible CBD oil and treats are the most common products marketed for horses, one of the easiest ways to give your horse CBD is to disguise it in their feed or to give it to them straight in their mouths if they’re not fussy.

At Neurogan, we offer CBD hemp pellets for horses. These palettes are made with one simple ingredient, high-quality, sun-grown hemp. They provide the benefits of the cannabinoids and terpenes from hemp and are an excellent source of fiber and antioxidants that may help reduce oxidative stress.

Will CBD Show Up On A Drug Test For Competition Horses?

CBD and other metabolites from hemp-based cannabinoids may be detected in blood and urine samples for up to 2 weeks after taking it and may result in a failed drug test.

When it comes to racing horses, this may disqualify them from competing, but more ongoing research is underway to clarify the rules surrounding legal hemp extractions and horse racing as more benefits emerge supporting CBD for equine health.

What Are The Side-Effects Of CBD In Horses?

CBD has been shown in multiple studies to be a well-tolerated compound even at high doses, so it’s relatively safe [3]. That being said, it’s not completely without potential side effects.

Luckily, the adverse effects of CBD wear off when it leaves your system, and it’s more likely to happen when you give your horse too much CBD.

Some of the side-effects of CBD to look out for in your horses include:

  • Drowsiness
  • Diarrhea
  • Dry mouth

Our pets can’t let us know when something’s wrong, so always monitor your horse after giving them CBD to ensure there are no negative interactions and to mitigate the chances of inducing a negative experience.

How To Buy CBD For Horses

When it comes to shopping for pet products in the CBD space, it can be even trickier to decipher the legitimate products from snake oil.

The food packaged for animals typically comes from off-cuts and isn’t as high of quality or nutrient-dense as food for humans. When you love animals as much as we do, we make sure our animals are getting the best quality possible when it comes to food and CBD products.

Here’s what you can do to make sure you’re buying the highest-quality CBD products for your horses.

1. Know Where The Hemp Was Grown

Look to make sure the source of hemp was grown using the best farming practices. High-quality CBD oil starts with a clean hemp source. Unfortunately, not all brands take hemp sourcing seriously. While the United States is known for its high agricultural standards, the same can’t be said for other countries’ hemp crops.

Hemp is highly sensitive to its growing environment. It can absorb many contaminants such as heavy metals and pesticides in the soil and surrounding area, which is why farming practices and hemp sourcing is critical when shopping for CBD products to support your animal’s health.

2. Buy Full Spectrum Or THC-Free Broad Spectrum Extracts

There is more than one beneficial compound found in hemp. In fact, there are over a hundred cannabinoids and dozens of terpenes in hemp that can support the effects of CBD in the endocannabinoid system.

To leverage the full benefits that hemp has to offer, you want to give your horses a CBD product that works as hard as they do. Full spectrum extracts are the least processed and more natural form of hemp extracts, they contain as much of the natural plant profile, which means it can include up to 03% THC.

If you’re looking for a THC-free option, broad spectrum CBD is your best bet. It undergoes further processing to filter out THC, while still providing whole-plant synergy for a more potent CBD product.

CBD isolate or distillate products only contain one active ingredient from hemp—CBD. It also tends to be cheaper as it requires less careful extraction methods from the cannabis plant, and manufacturers can sell it in bulk at cheaper prices. CBD isolate on its own can still provide holistic wellness benefits, but it won’t be as potent and increase the risk of inducing adverse effects.

3. High Potency CBD

CBD oil is typically dosed based on size. Since horses way much more than humans do, make sure the CBD products you’re buying have the appropriate strength to support a horse’s endocannabinoid system. Shop with brands that have a line of CBD products for horses as the potency tends to be much higher (upwards of 4000 MG/1 oz bottle).

The Takeaway: Can CBD Oil Help With Cushing’s?

There is no cure for Cushing’s syndrome in horses, but CBD may help improve your equine’s quality of life. With veterinary care and changes in nutrition, horses can enjoy a comfortable life for years to come after a diagnosis.

CBD does show a lot of promise for supporting a healthier lifestyle in humans and animals, but we always recommend you speak with your veterinarian before giving CBD to your horse with Cushing’s.

If you’re looking for more articles like this on how to give your pet a happier life with CBD, be sure to check out our other blog posts or sign up for our newsletter to receive the Inside Scoop on the latest findings in the CBD industry straight to your inbox.

Marijuana Use and Hypothalamic-Pituitary-Adrenal Axis Functioning in Humans

Preclinical studies suggest cannabinoids affect functioning of the hypothalamic-pituitary-adrenal (HPA) axis, but little is known about the effects of marijuana (MJ) use on HPA axis functioning in humans. Since previous work indicates substances of abuse may dysregulate the HPA axis, it is critical to understand how MJ use affects HPA axis activity. Here, we review studies that (a) examined the effects of acute MJ administration on HPA axis functioning, (b) investigated the impact of stress on HPA axis functioning in MJ users, (c) examined the effect of chronic MJ use on basal cortisol levels, and (d) studied the relationship between MJ use and the cortisol awakening response (CAR). Findings indicate acute MJ administration typically raises cortisol levels, but this increase is blunted in MJ-dependent users relative to controls. Frequent MJ users have blunted adrenocorticotropic hormone and cortisol reactivity in response to acute stress. These findings suggest HPA axis activity may be dysregulated by heavy MJ use. Alternatively, dysregulation of the HPA axis may be a risk marker for heavy MJ use. There is mixed evidence for how MJ use affects basal cortisol levels and the CAR. Future studies should consider MJ use characteristics, method of hormone collection, time when samples are collected, and environmental factors that may influence HPA axis activity in MJ users. By examining existing studies we provide one of the first reviews aimed at synthesizing the literature on HPA axis functioning in MJ users.


Marijuana (MJ) is the most commonly used illicit substance worldwide, with

147 million past year users (1). Within the United States, MJ use has significantly increased during the past decades. Between 2001 and 2002, 4.1% of adults reported past year MJ use compared to 9.5% between 2012 and 2013, 30% of whom met criteria for cannabis use disorder (2). These increases in MJ use coincide with a time of MJ decriminalization, legalization, and changing attitudes regarding risk of MJ use (3). While multiple risk factors contribute to heavy MJ use, cumulative stress is one pathway that may be linked to chronic MJ use as individuals report using MJ to reduce stress (4).

Several studies indicate that the hypothalamic-pituitary-adrenal (HPA) axis, the major neuroendocrine system that responds to stress (5), is dysregulated in substance users (6, 7). In response to acute stress as well as substances of abuse, the HPA axis releases corticotropin-releasing hormone (CRH) from the hypothalamus, which promotes release of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland, ultimately resulting in cortisol secretion from the adrenal cortex. However, chronic stress and heavy substance use can lead to allostatic load, HPA axis dysfunction, and adverse effects on stress responsivity (8, 9). Despite the worldwide prevalence of MJ use, little is known about HPA axis response in heavy MJ users. Understanding how MJ use affects HPA axis functioning in humans is critical to informing studies on the role of the neuroendocrine stress system in chronic MJ users and in individuals at risk for heavy MJ use.

The purpose of this review is to provide a descriptive overview of prior research on the effects of acute MJ administration on HPA axis activity, the impact of stress on HPA axis functioning in MJ users, and the role of chronic MJ use on basal cortisol levels and the cortisol awakening response (CAR). Additionally, we compare methodological differences among studies that may have contributed to discrepant findings, and comment on future directions for advancing research in this field. Articles for this mini review were included based on combinations of keywords searched on Pubmed, including “marijuana”, “HPA axis”, “cortisol”, “tetrahydrocannabinol (THC)”, and “endocannabinoid.” Titles and abstracts were reviewed for relevance to the topic on human MJ users. Additional articles were found through citations included within the manuscripts found using the keyword search.

Effects of THC administration and acute marijuana use on HPA axis functioning in marijuana users

Several studies have investigated the effects of acute MJ administration on HPA axis response by examining ACTH and/or cortisol levels in a laboratory setting (Table ​ (Table1). 1 ). Cone et al. (11) found that MJ administration raised serum cortisol levels in MJ users compared to baseline. Similar results were reported by Kleinloog et al. (15), who reported that THC inhalation increased cortisol compared to baseline in infrequent MJ users. These findings were replicated in a resting state functional magnetic resonance imaging (fMRI) study, such that THC administration elevated cortisol levels compared to placebo in MJ users, but as there were no changes in hypothalamic connectivity observed, cortisol levels were not examined in relation to functional connectivity (16). In another study, De souse Fernades perna et al. (17) examined the effects of vaporized THC administration on cortisol response before and after an implicit association task displaying aggressive behavior, in which participants self-reported how aggressive they felt after viewing each image. MJ administration significantly elevated cortisol levels compared to placebo prior to aggression exposure. Cortisol levels were also higher after inhalation of MJ vs. unintoxicated baseline levels in an fMRI study examining the aphrodisiacal effects of MJ in MJ users. However, there were no differences in cortisol levels between MJ users with or without prior aphrodisiacal experiences, so its effect on brain activity was not examined further (18). Considering the lack of standardization of MJ administration, caution should be used when drawing conclusions based on these results. Overall, increases in cortisol after MJ administration may have both advantageous and disadvantageous effects. For example, as HPA axis activity mobilizes the body to face challenges, increased cortisol levels could be related to enhanced attention after acute MJ administration in heavy users (35), but could also be associated with impairments in other cognitive domains, such as working memory and inhibition (35), and increased anxiety (36). Thus, the increased cortisol response may be beneficial in certain contexts, but detrimental in others.

Table 1

Studies of HPA axis functioning in marijuana users.

Study Participants Sample size Age (mean ±SD) Study design ACTH or cortisol analysis Main findings
Benowitz et al. (10) Regular MJ users (only male users) n = 6 21–30 210 mg oral THC for 14 days,.15 U/kg IV insulin Plasma cortisol No acute effect of THC on cortisol; following THC treatment, insulin administration ↓ cortisol compared to pre-THC treatment levels
Cone et al. (11) Frequent MJ users (only male users) n = 4 33.75 a Inhaled 2 MJ cigarettes (2.8% THC), 1 MJ and one placebo cigarette, or 2 placebo cigarettes (one condition per day) Plasma cortisol ↑ cortisol compared to baseline
Dax et al. (12) Abstinent heavy and occasional MJ users (only male users) n = 7 oral THC
n = 6 inhaled THC
n = 5 placebo
Age statistics not reported 10 mg oral THC (Marinol) or 18 mg/1.2 g inhaled MJ cigarette for 3 days (once on day 4) Plasma ACTH and cortisol No effect on cortisol for either method of administration
D’ Souza et al. (13) Abstinent MJ-dependent users and HC n = 30 MJ users
n = 22 HC
MJ = 24.8 ± 5.5
HC = 29 ± 11.6
0, 2.5, or 5 mg IV THC (one condition per day, test days separated by ≥1 week) Plasma cortisol Dose-dependent ↑ cortisol compared to placebo, blunted in frequent MJ users
Ranganathan et al. (14) Abstinent MJ-dependent users and HC n = 40 MJ users
n = 36 HC
MJ = 28.28 ± 10.2
HC = 24.58 ± 4.9
Study 1: Placebo, 0.0357 mg/kg, 0.0714 mg/kg IV THC Study 2: placebo, 0.0286 mg/kg IV THC Serum cortisol Dose-dependent ↑ cortisol, blunted in frequent MJ users
Kleinloog et al. (15) Mild MJ users (only male users) n = 49 mild MJ users 18–45 2-, 4-, and 6 mg inhaled THC at 90 min intervals Serum cortisol ↑ cortisol compared to baseline
Klumpers et al. (16) Occasional MJ users n = 12 22.17 ± 2.95 Day 1: 3 doses placebo Day 2: 2, 6, and 6 mg inhaled THC Serum cortisol ↑ cortisol compared to placebo
De Sousa Fernandes Perna et al. (17) Regular MJ users; heavy alcohol users; HC n = 21 regular MJ users
n = 20 alcohol users
n = 20 HC
MJ = 21.9 ± 2.2
Alcohol = 22.7 ± 2.4
HC = 22.9 ± 2.3
300 μg/kg vaporized MJ (12% THC), aggression implicit association task (IAT) Serum cortisol ↑ cortisol compared to placebo in MJ users administered THC prior to IAT
Androvicova et al. (18) Casual MJ users n = 12 aphrodisiac
n = 9 non-aphrodisiac
Aphrodisiac = 29.08 ± 5.37
Non-aphrodisiac = 23.78 ± 3.03
Inhaled socially relevant doses of personal MJ 30 min prior to study visit Serum cortisol ↑ cortisol compared to baseline
Childs et al. (19) occasional MJ users, ≤ 1 use per week n = 14: 0 mg THC
n = 15: 7.5 mg THC
n = 13: 12.5mg THC
0 mg THC = 23.8 ± 1.4
7.5 mg THC = 23.2 ± 0.9
12.5 mg THC = 23.9 ± 1.3
0, 7.5, or 12.5 mg oral THC (Marinol), Trier Social Stress Task Salivary cortisol No effect of THC on pre- or post- TSST cortisol levels
Van Leeuwen et al. (20) Lifetime abstainers; lifetime tobacco users; and lifetime MJ users; users were also classified as repeated or lifetime users only n = 219 lifetime abstainers
n = 168 lifetime tobacco users
n = 204 lifetime MJ users
16.27 ± 0.73 Groningen Social Stress Test Salivary cortisol ↓ cortisol in lifetime MJ users vs. lifetime abstainers or lifetime tobacco users; similar finding in repeated MJ users vs. lifetime MJ or tobacco only users
Mcrae-Clark et al. (21) MJ-dependent n = 87 MJ stress group = 25.5 ± 9.2 MJ no stress group = 26.2 ± 8.0 Trier Social Stress Task; MJ cues Plasma ACTH and cortisol ↑ ACTH and cortisol in stress group; ↑ cortisol in response to neutral vs. MJ cues
Somaini et al. (22) Active MJ-dependent; abstinent MJ-dependent; HC n = 14 MJ-dependent
n = 14 abstinent MJ-dependent
n = 14 HC
MJ = 24.1 ± 2.7
HC = 25.4 ± 3.6
Unpleasant and neutral pictures from IAPS Plasma ACTH and cortisol Active MJ-dependent ↑ basal ACTH and cortisol vs. other groups, but smallest ↑ in ACTH and cortisol after viewing unpleasant images
Fox et al. (23) Treatment-seeking MJ, alcohol, cocaine dependent; alcohol/cocaine dependent; social drinking HC n = 30 MJ, alcohol, cocaine- dependent
n = 29 alcohol, cocaine- dependent
n = 26 social drinking HC
MJ/alcohol/cocaine = 33.7 ± 6.9
alcohol/cocaine = 37.1 ± 6.4
HC = 28.1 ± 1.4
Guided imagery (stress, alcohol/cocaine cue, relaxing) Plasma ACTH and cortisol MJ-dependent polysubstance users ↑ ACTH and cortisol to stress vs. relaxing imagery; effect not seen in other groups
Tull et al. (24) MJ-dependent PTSD; MJ-dependent no PTSD, PTSD only; no PTSD/no MJ-dependence n = 18 PTSD/MJ
n = 32 MJ no PTSD
n = 27 PTSD only
n = 91 no PTSD/no MJ
34.32 ± 10.1 Trauma cues Salivary cortisol No effect of trauma cues on cortisol
Cuttler et al. (25) Daily or near-daily MJ users; HC n = 40 daily MJ users
n = 42 HC
MJ users in stress condition = 26.05 ± 1.44
MJ users in no stress condition = 25.14 ± 1.86
HC in stress condition = 26.95 ± 2.23
HC in no stress condition = 25.24 ± 1.19 b
Maastricht Acute Stress Test Salivary cortisol ↓ cortisol in daily MJ users vs. HC
Nusbaum et al. (26) Daily or near-daily MJ users; HC n = 39 daily MJ users
n = 40 HC
MJ users in stress condition = 25.85 ± 6.19
MJ users in no stress condition = 25.35 ± 8.71
HC in stress condition = 27.25 ± 10.4
HC in no stress condition = 25.25 ± 5.57
Maastricht Acute Stress Test Salivary cortisol ↓ cortisol in daily MJ users vs. HC
Chao et al. (27) Non-treatment seeking daily MJ users with and without trauma exposure n = 125 Age range 18–50 (more detailed demographics of the six subgroups in table of manuscript) Trier Social Stress Task Salivary cortisol ↑ cortisol before, during, after TSST in daily MJ users with trauma exposure vs. daily MJ users without trauma exposure
Block et al. (28) Frequent, moderate, infrequent, or non-Users of MJ n = 27 frequent MJ users
n = 18 moderate MJ users
n = 30 infrequent MJ users
n = 74 non-users
23.5 ± 0.4 b , more detailed demographics divided by user group and sex in table of manuscript Morning or afternoon blood draw Serum cortisol No difference between groups
King et al. (29) Daily or near daily MJ users; HC n = 30 MJ users
n = 30 HC
M MJ users = 21
F MJ users = 22.5
M HC = 23
F HC = 24.5 d
Morning saliva collection Salivary cortisol ↑ cortisol in MJ group compared to HC
Cloak et al. (30) Heavy MJ users; light MJ users; HC n = 43 heavy MJ users
n = 37 light MJ users
n = 42 HC
Heavy MJ users = 19.4 ± 0.3
Light MJ users = 19.1 ± 0.4
HC = 18.3 ± 0.4 c
Late morning or afternoon saliva collection f Salivary cortisol No difference between groups
Carol et al. (31) UHR youth with current MJ use; UHR youth without current MJ use; HC n = 17 UHR with MJ use
n = 26 UHR without MJ use
n = 29 HC
UHR with MJ use = 19.59 ± 0.87
UHR without MJ use = 18.46 ± 1.92
HC = 17.34 ± 2.82
Three saliva samples every 60 min between 8:45 a.m.−2 p.m. Salivary cortisol ↑ cortisol in MJ group compared to HC
Lisano et al. (32) Physically active regular MJ users; physical active HC (males only) n = 12 regular MJ users
n = 12 HC
MJ = 23.33 ± 4.14
HC = 24.08 ± 5.5
Blood samples collected between 7 and 9 a.m. Serum cortisol No difference between groups
Huizink et al. (33) Early (9–12 years old), late (13–14 years old), and non-users of MJ n = 59 late MJ users
n = 44 early MJ users
n = 1338 non-users
Cortisol collected between ages 10 and 12, age breakdown for groups not reported Saliva collected at awakening, 30 min later, and 8 pm Salivary cortisol ↓ cortisol 30 min post-awakening in early MJ users vs. late MJ users; MJ users ↑ evening cortisol vs. non-users
Montelone et al. (34) SCZ with MJ use prior to psychotic symptoms; SCZ with no MJ use prior to psychotic symptoms; HC n = 16 SCZ with MJ use
n = 12 SCZ without MJ use
n = 15 HC
SCZ with MJ use = 39.1 ± 7.2
SCZ without MJ use = 43.6 ± 7.3
HC = 37.6 ± 6.9 c
Saliva collected at awakening, and 15, 30, and 60 min later Salivary cortisol ↑ baseline cortisol in SCZ with MJ use vs. HC; ↓ CAR in SCZ with MJ use vs. HC

ACTH, adrenocorticotropic hormone; CAR, cortisol awakening response; HC, healthy controls; IV, intravenous; MJ, marijuana; PTSD, post-traumatic stress disorder; SCZ, schizophrenia; THC, tetrahydrocannabinol; TSST, Trier Social Stress Task; UHR, ultra-high risk; ↑, increase/increased/greater; ↓, decrease/decreased/less.

In other studies, cortisol levels were compared between abstinent MJ-dependent individuals and non-users following intravenous THC administration. MJ-dependent individuals exhibited a blunted cortisol increase after THC administration compared to non-users (13, 14). Preclinical research has linked this blunted cortisol response to MJ tolerance (37), while other research suggests differences in MJ response may be influenced by genetics (38).

Some studies have found no significant effect of acute MJ administration on cortisol levels. In a study conducted by Benowitz et al. (10), the effects of insulin-induced hypoglycemia in MJ users were examined. Participants were given insulin prior to and after oral THC was administered. No difference in cortisol was observed between baseline and post-THC treatment but insulin administration decreased cortisol compared to pre-THC treatment levels. In a study by Dax et al. (12) abstinent MJ users were administered oral or inhaled THC. No differences were observed in ACTH or cortisol between baseline and post-treatment levels. Small sample sizes may have resulted in the lack of significant findings in these studies. Childs et al. (19) also found no relationship between acute administration of oral THC and cortisol response. The authors suggest their lack of findings could have been the result of collection of salivary rather than serum cortisol, the latter possibly being a more sensitive measure of cortisol. Moreover, in studies that found no effect of MJ on cortisol levels, greater time elapsed between MJ administration and cortisol assessment. It is possible the acute effects of MJ on cortisol could have diminished before cortisol assessment. Since studies that found an association between acute MJ administration and HPA axis response collected cortisol samples closer to the time of acute MJ use, it may be necessary for future studies to measure cortisol within 2 h following MJ administration. In sum, the majority of research examining acute MJ administration on cortisol reactivity has indicated MJ significantly increases cortisol, and some studies report that abstinent MJ-dependent users show a blunted increase in cortisol relative to non-users.

Effects of stress on HPA axis functioning in marijuana users

A number of studies in MJ users have examined the effects of acute stressors on HPA axis activity (Table ​ (Table1). 1 ). A study by Somaini et al. (22) presented neutral and unpleasant images to MJ-dependent individuals, abstinent MJ-dependent individuals, and healthy controls. Interestingly, active MJ users had generally high basal stress hormone levels but reduced responsivity of the HPA axis, potentially due to dysregulation of the stress system by MJ use. These findings are in contrast to another study in which MJ-dependent polysubstance users had significantly higher levels of plasma cortisol and ACTH following exposure to stress imagery relative to relaxing imagery, a finding not present in non-MJ-dependent polysubstance users or social drinkers (23). Since participants in this study were abstinent treatment-seeking polysubstance users, the elevated cortisol and ACTH levels could reflect a “rebound” upregulation of the HPA axis following abstinence (23).

Two recent studies examined salivary cortisol in chronic adult MJ users using the Maastricht Acute Stress Test, which includes both physiological stress (placing hand in ice water) and psychosocial stress (solving math problems). The acute stress manipulation resulted in blunted cortisol response in the daily MJ users compared to healthy controls (25, 26). For individuals who may be characterized by an overactive HPA axis, a reduction in cortisol activity may be beneficial. Alternatively, cortisol release usually serves to motivate adaptive responses during stressful situations and a blunted response could impair one’s ability to act appropriately (8, 25). In particular, a blunted cortisol response to psychosocial stress has been associated with anxiety and depression in women (39), suggesting female MJ users may be at increased risk for anxiety and depression symptoms. Similar findings were reported in a study with a large sample (N = 591) of adolescent MJ users who had lifetime or repeated MJ use (20). The authors reported lower salivary cortisol levels during the Groningen Social Stress Task (involving both a speech and math problems) in adolescents who had ever used MJ relative to non-users or participants who reported lifetime tobacco use. This finding was also seen when the authors compared adolescents who used MJ at least five times in the past year with lifetime users of MJ or tobacco. These results were interpreted as a reduction in HPA axis response in adolescents who are at risk for using MJ repeatedly, possibly to stimulate their HPA axis response. Finally, another study that utilized the Trier Social Stress Task found that stress increased plasma ACTH and cortisol levels in MJ-dependent participants (21). However, in response to MJ cues, cortisol levels were significantly lower in MJ-dependent participants than in response to neutral cues. As the purpose of this study was to examine the effects of stress and drug cues on physiological reactivity in MJ-dependent individuals, no control group was included.

Other types of stress, such as previous trauma exposure, which may influence cortisol response in MJ users, was examined in a study of non-treatment seeking daily MJ users (27). Daily MJ users who experienced trauma had higher overall cortisol levels before, during, and after the Trier Social Stress Task than those who had never experienced trauma. However, as there was no control group of non-using participants in this study, it is uncertain whether the effects of trauma on cortisol reactivity would be similar to or different from the daily MJ users. Contrary to the findings of this study, Tull et al. (24) found no effects on cortisol reactivity in participants with or without post-traumatic stress disorder who were either MJ-dependent or non-dependent, even though MJ-dependent participants reported less subjective emotional reactivity in response to trauma cues.

Taken together, the findings to date suggest that stress exposure in adult heavy MJ users (22, 25, 26), or adolescents at risk for heavy MJ use (20) is mostly related to blunted reactivity of the HPA axis. This could suggest both dysregulation as result of MJ use or increased vulnerability toward frequent MJ use as individuals may engage in MJ use to increase responsivity of an underactive HPA axis. As there is currently limited research in this area, future studies should carefully consider the following variables, which could impact study findings: method of obtaining cortisol sample [plasma: (21–23) vs. saliva: (20, 24, 25, 27)], time of day of cortisol measurement, duration of time between stress administration and cortisol measurement, MJ use criteria (frequency of use, MJ-dependent or non-dependent sample, treatment seekers vs. non-treatment seekers), and co-occurring mental health conditions, such as previous trauma exposure (24, 27) or psychopathology (23).

Marijuana use and basal HPA axis activity

Studies have measured cortisol levels in frequent MJ users and non-users to determine whether the groups differ in basal cortisol levels, and findings suggest MJ has either no effect or increases basal cortisol (Table ​ (Table1). 1 ). Block et al. (28) found that there was no difference in serum cortisol levels between frequent, moderate, and infrequent MJ users and controls. However, only one blood sample was taken and time of day for blood draws varied among participants. There was also no difference in serum cortisol response in physically active MJ-using adults compared to non-using controls, suggesting that heavy MJ use may not affect stress hormone levels in individuals with high levels of physical activity (32). Since previous studies report that MJ may be used to reduce stress and anxiety symptoms (4), Cloak et al. (30) examined the relationship between MJ use, anxiety symptoms, and cortisol levels in adolescent and young adult heavy, light, and non-MJ users. There was no effect on mid-day salivary cortisol despite greater MJ use being associated with more anxiety symptoms, indicating a disconnect between psychological, and physiological stress reactivity.

Contrary to the findings above, an fMRI study examining psychomotor function found that chronic MJ users had higher levels of salivary cortisol compared with controls and greater superior frontal gyrus (SFG) but reduced visuomotor activity relative to controls (29). The authors propose that this increased cortisol in MJ users may impair visuomotor function during psychomotor tasks, resulting in greater reliance on brain regions involved in attention and motor planning, such as the SFG. A recent study of adolescents at ultra-high risk for schizophrenia reported that youth who used MJ in the past month had higher levels of salivary cortisol than healthy controls, suggesting a potential link between risk for psychosis and HPA axis functioning (31). Previous research indicates high basal cortisol levels are associated with hypertension and obesity (40), as well as hippocampal atrophy and memory impairment in aging populations (41). The potential effect of frequent MJ use on basal cortisol levels requires further investigation to clarify inconsistencies in the literature. Variations in participant characteristics, MJ use parameters, and method of cortisol assessment may have contributed to the inconsistent findings.

Cortisol awakening response in marijuana users

Cortisol levels exhibit diurnal variation, such that levels rise during the morning hours, peak 30 min after awakening, and are lowest in the evening. This increase of cortisol in the morning, known as the CAR is believed to be a reliable marker for individual differences in HPA axis activity (42). Studies have reported that the CAR is influenced by substance use, such as heavy alcohol use (43, 44). Surprisingly, little is known about the CAR in MJ users (Table ​ (Table1). 1 ). To our knowledge, only one study to date has examined diurnal cortisol response in MJ users, and found blunted levels of cortisol 30 min after awakening in a large sample of children (10–12 years old) who began using MJ during early adolescence (9–12 years old) relative to those who initiated use in later adolescence (13–14 years old) (33). These findings may indicate that blunted cortisol response could be a risk factor for initiating MJ use. The study also found that participants who initiated MJ use regardless of age at first use, had higher levels of evening cortisol relative to non-users. The authors believed this finding may be explained more by environmental influences on cortisol levels in the evening, such as ongoing stressful events rather than genetic vulnerability toward MJ use. Similar findings were reported in another study, albeit in a sample of participants diagnosed with schizophrenia who were also MJ users (34). These participants had higher baseline levels of cortisol, but a flattened CAR relative to healthy controls. These findings may indicate that MJ use in schizophrenics contributes to dysregulation of the HPA axis, although it is possible that blunted CAR in MJ-using schizophrenics predated and increased their vulnerability toward substance use. Given the lack of research investigating the CAR in MJ users, significant work is needed to characterize how MJ use affects the CAR and whether dysregulation of HPA axis functioning is a risk factor for and/or further drives MJ use.

Conclusions and future directions

The purpose of the current mini review is to highlight and integrate the existing, albeit limited literature on the effects of MJ use and stress on HPA axis functioning in adult MJ users and youth at risk for heavy MJ use. Understanding these findings comes at an important time when MJ decriminalization and legalization has made MJ increasingly available, while the perceived risk of MJ use has declined (3). Preclinical research has indicated that cannabinoids affect functioning of the HPA axis [for review, see Steiner and Wotjak (45)], and it appears that the current findings suggest that overall, acute MJ administration elevates cortisol levels, but to a smaller degree in MJ-dependent users. Further, acute stress exposure in heavy MJ users also appears to largely blunt cortisol reactivity. The findings on basal cortisol levels are mixed, likely due to diurnal fluctuations of cortisol and because cortisol is sensitive to changes in daily stress. These findings suggest that MJ use may dysregulate normal functioning of the HPA axis, perhaps as individuals develop tolerance to MJ, which could further drive MJ use. An alternative explanation is that individuals at risk for MJ use seek out MJ to stimulate an underactive HPA axis. Further research, including longitudinal studies of MJ users to examine long-term effects on HPA axis functioning are needed. While there is a growing literature on the effects of MJ use on brain structure and functioning in humans (46, 47), few studies have measured HPA axis activity in neuroimaging studies of MJ users, an important avenue for future research. This could provide information on how biological markers related to stress reactivity are associated with neurocognition in MJ users. Additionally, to our knowledge only two studies have examined the CAR in MJ-using participants, thus necessitating significant work in understanding how MJ use affects diurnal HPA axis rhythms. Work is currently underway in our laboratory to examine the effects of adult heavy MJ use on the CAR.

Author contributions

All authors contributed to the article search for this review. AC and JD-B wrote the Introduction, SL wrote the section on acute THC and MJ effects on HPA axis functioning, and AC wrote the sections on stress, basal cortisol, cortisol awakening response, and conclusions and future directions. AC and SL created the table. AC edited and finalized the manuscript.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


This work was supported by the Oregon State University Center for Humanities and College of Liberal Arts Research Grant to AC.

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A cannabinoid is of a class of diverse chemical compounds that acts on cannabinoid receptors, also known as the endocannabinoid system in cells that alter neurotransmitter release in the brain.

The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis. Cannabidiol (CBD) is another major constituent of the plant. There are at least 113 different cannabinoids isolated from cannabis, exhibiting varied effects.


A terpenoid, sometimes called isoprenoid, are a large and diverse class of naturally occurring organic chemicals derived from terpenes.

Plant terpenoids are used for their aromatic qualities and play a role in traditional herbal remedies. Terpenoids contribute to the scent of eucalyptus, the flavors of cinnamon, clove and ginger, the yellow color in sunflowers, and the red color in tomatoes among many others. Different strains of Cannabis naturally produce different Terpenoids.

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