Cannabinoids for ADHD and stress

• 1. Cannabinoid system and ADHD
  • 1.1. CB1R reduced at SHR
  • 1.2. CB1 receptor and impulsivity
  • 1.3. CB2 receptor and hyperactivity/impulsivity
  • 1.4. Inhibition of sensory overload
  • 1.5. Attention and distractibility
  • 1.6. Anandamide levels (AEA) increased in ADHD
  • 1.7. 2-AG levels elevated in ADHD
  • 1.8. MPH reduces anandamide and 2-AG
  • 1.9. FAAH gene variants moderate the effect of amphetamine
  • 1.10. MAGL for ADHD
• 2. Endocannabinoids and stress
  • 2.1. Early childhood stress alters CB1R
  • 2.2. Endocannabinoids regulate stress
  • 2.3. Stress influences the cannabinoid system
  • 2.4. Cannabinoids in late adolescence can repair damage from early childhood stress

1. Cannabinoid system and ADHD¶

CB1Rs could be a helpful target in the treatment of ADHD.¹

1.1. CB1R reduced at SHR¶

SHR shows significantly reduced basal CB1R gene and protein expression in the brainstem ^{2 34}
Another study found increased receptor gene expression levels in an ADHD animal model⁵

A CB1R agonist also reduced your elective impulsivity (delay aversion)³
Amphetamine loses its dopamine and noradrenaline increasing effect when the CB1R is blocked.⁶ We are considering whether a lack of CB1R could be a possible cause of AMP non-responding.

It is unclear how a study in SHR that found that inhibition of CB1R in PVN could reduce high blood pressure is consistent with this.⁷

Chronic ingestion of methylphenidate (MPH) in drug dose decreased CB1R in rats after 4 weeks, while it increased it in drug dose.⁸

The synthetic CB2R agonist (weaker also CB1R) agonist WIN55,212-2 (WIN) elicited conditioned place preference in both juvenile and adult SHR rats, but conditioned place aversion in Wistar control animals only in adults. The behavioral effects of WIN were mediated via the CB1R. The contrasting effects of WIN in Wistar and SHR rats and the greater resistance of adolescent rats to the aversive and rewarding effects of WIN suggests that both adolescence and the ADHD-like profile of SHR are factors influencing the motivational properties of cannabinoids.⁹
WIN (0.25 and 1.25 mg/kg i.p.) only promoted the stimulation of locomotor activity in the open field in juvenile SHR, but not in adult SHR or juvenile or adult Wistar-Kontoll rats. Pretreatment with the selective CB1R antagonist AM 251 (0.25 mg/kg, i.p.) prevented the effect in juvenile SHR.¹⁰

One study found that the activation of cannabinoid receptors⁵

• risk behavior hyperactivity increased in adolescence, especially in female rats
• risk assessment worsened in adulthood, while hyperactivity remained unchanged

1.2. CB1 receptor and impulsivity¶

Reduced CB1R was found in SHR (the main model animal for ADHD). At the same time, a CB1R agonist reduced their elective impulsivity (delay aversion)³
In contrast, another study found that a CB1R antagonist reduced elective impulsivity, while a CB1R agonist increased it.¹¹
THC, a CB1R agonist, increased some, but not all, forms of impulsivity in humans.¹²
The CB1R antagonist rimonabant (SR141716A) reduced action impulsivity in rats, while the agonist WIN55,212-2 only slightly worsened it and did not affect choice impulsivity.¹³

Daily cannabis use is more common among people with ADHD-HI, i.e. those with hyperactivity and impulsivity.¹⁴ This is consistent with the data from the ADxS symptom test, in which around 650 test subjects answered the question about frequent cannabis use. Positive answers correlated with hyperactivity and impulsivity.

The effect of endocannabinoids on hyperactivity appears to follow an inverted-U curve.

Mice with a traumatic brain injury showed increased hyperactivity, which correlated with reduced levels of ethanolamide endocannabinoids (AEA, OEA, PEA) in the perilesional and subcortical ipsilateral brain tissue.¹⁵

1.3. CB2 receptor and hyperactivity/impulsivity¶

DAT-CNR2 mice have no cannabinoid CB2 receptors (CB2R) on midbrain dopamine neurons.
DAT-CNR2 mice show¹⁶

• Hyperactivity (males and females)
• Elective impulsivity
• reduced anxiety behavior
• increased risk behavior

Amphetamine in medication doses (2 mg / kg) reduces hyperactivity and ADHD symptoms. This corresponds to the typical paradoxical effect of stimulants in ADHD.

One study found increased receptor gene expression levels in an ADHD animal model⁵

1.4. Inhibition of sensory overload¶

By binding to CB1R, endocannabinoids (the body’s own cannabinoids) provide protection against sensory overload, among other things.¹⁷

1.5. Attention and distractibility¶

The AEA degradation inhibitor URB597 improved attention and reduced distractibility in healthy mice.¹⁸

1.6. Anandamide levels (AEA) increased in ADHD¶

Several studies suggest that anandamide (and 2-AG) are elevated in ADHD due to a lack of FAAH, which breaks down AEA.

In children with ADHD, peripheral blood mononuclear cells were found to have increased anandamide (AEA) levels due to decreased AEA degradation by decreased FAAH. The AEA synthetase NAPEPLD was unchanged.¹⁹²⁰ Another study also found increased AEA levels in children with ADHD.²²
FAAH deficiency in ADHD selectively altered synaptic glutamate transmission in the striatum, but not that of GABA. This could indicate that ADHD symptoms may be due, at least in part, to a differential dysregulation of excitatory and inhibitory synaptic transmission in the striatum²⁰

ADHD is largely characterized by a reduced ability to motivate oneself. AEA reduces motivation. More on this under AEA reduces reward-seeking behavior In the article Cannabinoids regulate dopamine in the chapter Neurological aspects / Neurotransmitters in ADHD / Cannabinoid system / What is regulated by cannabinoids.

Organophosphates reduce FAAH, thus increasing anandamide and causing ADHD symptoms in mice.²³²⁴

As endocannabinoids reduce the perception of pain via the CB1R, this is also the case with an increased AEA level. An extreme example is the FAAH-KO mouse. However, pain perception is often increased in ADHD.

The AEA reuptake inhibitor AM-404 reduced ADHD symptoms in mice.²⁵²⁶ In juvenile SHR, AM404 reduced hyperactivity.²⁷

Increasing anandamide (AEA) by reducing the degradation of AEA using a FAAH inhibitor normalized blood pressure in SHR.²⁸²⁹
The AEA reuptake inhibitors AM404 and VDM11 and the FAAH inhibitor AA5HT attenuated spontaneous hyperlocomotion in DAT-KO mice.³⁰
Prenatal administration of AM-404 to Naples rats (an ADHD model animal) reduced their hyperactivity by 20%.³¹

AM-404 (N-(4-hydroxyphenyl)-arachidonylamide) is an AEA reuptake inhibitor³²³³ , although there are those who disagree.³⁴³⁵ AM-404 also inhibits FAAH and thus the degradation of AEA.³⁶³³
A reuptake inhibition as well as an inhibition of the degradation substance lead to increased extracellular levels (here: of anandamide (AEA)). This initially collides with the hypothesis of increased AEA in ADHD, but only as long as AEA is considered the causal cause of the increased ADHD symptoms. If, on the other hand, the increased AEA (and 2-AG) were a compensatory or protective response of the brain in ADHD, this could conclusively explain why AEA and 2-AG are increased in ADHD, why a further increase in AEA reduces ADHD symptoms and why MPH leads to decreased AEA and 2-AG.

Increased AEA was also observed in tic disorder⁴⁶ and PTSD⁴⁷.
Endocannabinoids are also elevated in obesity.⁴⁸
AEA and 2-AG appear to be elevated in Parkinson’s disease.⁴⁹

No correlation was found between the FAAH gene polymorphism rs324420 (C385A) and ADHD.⁵⁰

1.7. 2-AG levels elevated in ADHD¶

2-AG in cerebrospinal fluid correlated with the severity of ADHD symptoms.⁴⁶

1.8. MPH reduces anandamide and 2-AG¶

MPH reduces the endocannabinoids anandamide and 2-AG in the limbic forebrain in a dose-dependent manner. An optimal dose reduced the anandamide level by 30 % and the 2-AG level by 45 %. At higher doses, anandamide and 2-AG increased again.⁵¹
The selective dopamine reuptake inhibitor GBR 12909 (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine) also significantly reduced anandamide levels and also tended to reduce 2-AG levels.
The D1 receptor antagonist SCH 23390 (R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) did not increase anandamide or alter 2-AG.
The D1 receptor agonist SKF 33939 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine) reduced anandamide
The D2 receptor antagonist eticloprid significantly increased 2-AG and did not alter anandamide.
The D2 agonist quinpirole at low doses (as preferred by autoreceptors) increased anandamide, higher doses reduced anandamide to approximately the level of controls. Quinpirole did not significantly affect 2-AG.

Endogenous dopamine appears to exert differential suppressive effects on anandamide and 2-AG levels via activation of D1 and D2 receptors, respectively, with modulation of endocannabinoid levels by dopamine thought to be secondary to changes in glutamatergic transmission.⁵¹

Seven days after the administration of methamphetamine at neurotoxic levels, both the dopamine level and the density of dopamine transporters in the limbic forebrain decreased. CB1R density and CB1R activity were unchanged. The 2-AG level was increased. MAGL activity was reduced.⁵²

• CBR1 antagonists block amphetamine-mediated LTD in the amygdala in a dose-dependent manner.⁵³ This indicates an increase in CB1R agonists by AMP.
  In another study, the amphetamine MDMA unexpectedly increased neither AEA nor 2-AG.⁵⁴

On the other hand, the cannabinoid system increases dopamine via the CB1R. For more on this, see above under CB1R and dopamine.
In ADHD, however, the pathway of action should not originate from the endocannabinoids. Since anandamide and 2-AG are elevated in ADHD, and both are CB1R agonists, this should have a dopamine-increasing effect (via CB1R kinetics on GABA as well as via DAT inhibition by AEA). The central problem with ADHD, however, is the reduced dopamine level.

Chronic ingestion of methylphenidate (MPH) at drug doses increased CB1R in rats after 4 weeks, while CB1R levels decreased 4 weeks after chronic low-dose MPH.⁸

1.9. FAAH gene variants moderate the effect of amphetamine¶

Depending on the FAAH gene variant, healthy volunteers responded differently to 0, 10 or 20 mg D-Amp ⁵⁵

One study found elevated FAAH gene expression levels in an ADHD animal model⁵

1.10. MAGL for ADHD¶

One study found elevated FAAH gene expression levels in an ADHD animal model.⁵

2. Endocannabinoids and stress¶

2.1. Early childhood stress alters CB1R¶

Stress influences the endocannabinoid system in an epigenetic way.⁵⁶
Early life stress caused reduced CB1R and FAAH as well as epigenetic changes in the mPFC of male rats.⁵⁷ Female rats also showed epigenetic changes, but no reduction in CB1R and FAAH⁵⁸

CB1R blockade led to a reversal of the otherwise usual decline in neuronal activation in corticostriatal regions in response to repeated stress exposure.⁵⁹ CB1R-KO mice showed inappropriate behavioral adaptation to repeatedly presented stressors.⁶⁰⁶¹

2.2. Endocannabinoids regulate stress¶

Endocannabinoids make a decisive contribution to the regulation of the stress response by modulating the sensitivity and activation of the HPA axis.⁶²⁶³⁶⁴
This regulation is carried out in particular via the CB1R.⁶⁵
Endocannabinoids are also involved in the process of stress adaptation.⁶⁶

Endocannabinoids significantly inhibit the HPA axis.⁶⁷⁶⁸

Stress reduces anandamide (AEA) and CB1R and increases AG-2⁶⁹
AEA and AG-2 mediate different adaptive responses to chronic stress:⁶²
After repeated stress it shows:

• AEA is permanently reduced in the entire corticolimbic stress cycle
• 2-AG is elevated, only in the amygdala, in a stress-dependent manner
• Inhibition of AEA hydrolysis prevented the development of basal hypersecretion of corticosterone after repeated stress
• CB1R antagonists before the last stress load reduced the decrease in corticosterone responses induced by repeated stress

AEA was reduced 30 min after acute and 24 hours after last chronic stress (30 min daily for 9 days) in:⁶²

• Amygdala
• Hypothalamus
• PFC
• Hippocampus
• Thalamus (decrease, but not significant)

Only in the PFC did chronic stress cause an increase in basal corticosterone secretion with a decrease in AEA content.⁶²

AG-2 was elevated 30 min after acute, but not 24 hours after last chronic stress (30 min daily for 9 days) only in:⁶²

• Amygdala
• unchanged in the hypothalamus, PFC, hippocampus, thalamus

The AG2 increase in the amygdala correlated with a reduced corticosterone response after the last chronic stress.⁶²

Chronic stress (30 min daily for 9 days) caused an increased basal corticosterone level.⁶²
The CB1R antagonist AM251 did not prevent this increase.
The AEA degradation inhibitor URB597 halved this increase.
The AEA reuptake inhibitor AM-404 prevented the increase.

However, the CB1R antagonist AM251, given before the daily stress, prevented the decline in the immediate corticosterone stress response. The AEA degradation inhibitor URB597 and the AEA reuptake inhibitor AM-404 did not prevent the decline.⁶²

The decrease in the corticosterone stress response in response to repeated restraint appears to be mediated by increased 2-AG-mediated activation of CB1 receptors in the basolateral amygdala.⁶²

Causes / mediates stress:⁶⁹

• the AEA decline
  • a manifestation of the stress response
  • Activation of the HPA axis
  • Increase in anxiety behavior
• the 2-AG increase
  • Termination and adaptation of the HPA axis
  • Changes in the perception of pain
  • Changes in memory
  • Changes in synaptic plasticity

CB1R agonists (such as THC) inhibit the reaction of the HPA axis to stress.⁷⁰

2.3. Stress influences the cannabinoid system¶

Chronic unpredictable stress causes a down-regulation of CB1R and 2-AG levels in the hippocampus. Both levels remained unchanged in the frontal brain.⁷¹
Chronic unpredictable stress leads to symptoms of depression and neuropathic pain, e.g.

• thermal hyperalgesia⁷² and cold allodynia⁷³ and correlated with decreased CB1R⁷⁴ and 2-AG in the hippocampus⁷¹, increased CB1R in the PFC⁷⁴ and decreased dopamine receptors⁷⁵ in the brain.⁷⁶

Acute stress as well as chronic (10 days) restraint stress increase AEA-degrading FAAH and decrease AEA.⁷⁷⁷⁸⁷⁹
The degree of reduction in CB1R activation by AEA in the basolateral amygdala appears to be the determining factor in how much stress activates the HPA axis and corticosterone release:⁷⁹

• 30-minute restraint stress increases endocannabinoid-degrading FAAH in the amygdala of rats and thereby reduces AEA
• in stressed rats, the amygdala AEA correlated negatively with serum corticosterone
• pharmacological inhibition of FAAH in the basolateral amygdala reduced stress-induced corticosterone secretion
  • simultaneous administration of the CB1R antagonist AM251 blocked this
• the stress-induced secretion of corticosterone was
  • significantly reduced by CB1R agonist administration into the basolateral amygdala and
  • increased by CB1R antagonist administration

Social stress appears to dampen the endocannabinoid system in vulnerable individuals, which could further increase the propensity to use cannabis, as CB1R agonists (such as THC) inhibit the HPA stress response⁷⁰

THC increased dopamine uptake and dopamine metabolism in the striatum in stressed rats, but not in non-stressed rats.⁸⁰⁸¹⁸² Cross-sensitization between THC and stress has been reported. Subjects with an increased risk of schizophrenia showed an unchanged dopamine stress response to a psychosocial stress task despite increased positive, attenuated psychotic symptoms.⁸³⁷⁰⁸⁴

2.4. Cannabinoids in late adolescence can repair damage from early childhood stress¶

The FAAH inhibitor URB597, when given in late adolescence (P45-60, equivalent to 18 to 25 years in humans), abolished the effects of early childhood stress (decreased social preference, impaired social recognition, increased learned helplessness and anxiety-like behavior) in rats. Given in early adolescence, URB597 did not eliminate these.⁸⁵ In the mPFC, early life stress downregulated miR-16 in males and miR-135a in females, which URB597 abolished in late adolescence. In females, early life stress increased CB2R and decreased FAAH in the mPFC. URB597 in late adolescence also abolished this.⁸⁶

Early childhood stress caused short-term memory performance deficits in spatial localization and social recognition tasks in male and female rats in adulthood. In males, recognition of novel objects was also impaired. The synthetic CB2R agonist (weaker also CB1R) agonist WIN55,212-2 in late adolescence (corresponding to 18 to 25 years in humans) prevented these stress-induced impairments and reduced anxiety. In females, WIN normalized the upregulation of glucocorticoid receptors in the PFC and CB1R in CA1 induced by early life stress. In males, WIN normalized the upregulation of glucocorticoid receptors in the PFC and downregulation of CB1R in the basolateral amygdala induced by early childhood stress.⁸⁷

Early childhood stress can increase the predisposition to depression. Male and female rats exposed to early childhood stress were injected with the FAAH inhibitor URB597 or the MAGL inhibitor JZL184 for two weeks during late adolescence (P45-60). FAAH and MAGL inhibitors in late adolescence prevented:⁸⁸

• the depression- and anxiety-like behavior in males and females induced by early childhood stress
• the impairment of social behavior and neuronal plasticity in males and females
• changes in MAGL activity induced by early childhood stress in the hippocampus of males and in the hippocampus and nucleus accumbens of females
• bDNF changes induced by early childhood stress in the hippocampus and nucleus accumbens of males and in the hippocampus of females

Another study on URB597 found similar results.⁸⁹

Escitalopram in PT 35 to 55 remedied anxiety and despair behavior in rats stressed by maternal deprivation in early childhood by altering the gene expression of CB1R, among others.⁹⁰

THC⁹¹, CBD⁹²⁹³ and a CB1R antagonist⁹³ during puberty corrected the increased CB1R, DRD2 and DRD3 expression in the PFC of rats treated prenatally with methylazoxymethanol acetate (MAM) and the resulting behavioral changes. Prenatal MAM causes brain developmental disorders that cause schizophrenia symptoms.⁹⁴