Cannabinoids also regulate appetite and food intake via dopamine

(Endo)cannabinoids have a major influence on appetite and food intake.
Appetite and food intake are also controlled by dopamine with regard to the reward and motivation aspect. Food intake is controlled in particular

• from the brain regions:¹
  • Hypothalamus (there: Nucleus paraventricularis, nucleus arcuatus, dorsomedial nucleus, lateromedial nucleus for the integration of peripheral and central afferents)^{23 4}
  • ventral palladium (especially for hedonic valuation)⁵⁶
• via the messenger substances⁴
  • Neuropeptide Y⁷
    • increases appetite and food intake via Orexine
    • controls fat balance
    • controls motility of the gastrointestinal tract
    • controls circadian rhythm
    • controls stress and anxiety response
    • regulates vascular resistance
    • controls sexual function
  • Insulin⁸
    • regulates glucose uptake in body cells
    • reduces blood sugar
    • Increase in blood sugar (high), fatty acids (low) and amino acids (low) increases insulin release
    • accelerates glucose uptake in muscle and fat cells
    • accelerates the absorption of amino acids and potassium in muscle and fat cells
    • accelerates the uptake of triglycerides in muscle and fat cells
    • increases glycogen synthesis and storage in liver and muscle
    • increases triglyceride synthesis in liver and fatty tissue
    • promotes storage of amino acids in the muscle
    • inhibits hepatic gluconeogenesis
    • inhibits proteolysis
    • inhibits glycogenolysis
    • inhibits lipolysis
    • Insulin mediates endocannabinoid–mediated LTD in dopamine neurons in the VTA⁹
      • Insulin suppresses glutamatergic input
      • The reduced arousal drive reduces the interest in food
  • Leptin¹⁰
    • has an appetite suppressant effect and increases the feeling of satiety
      • only in normal-weight people, not in obese people (where leptin resistance is common)
        • In the case of abnormal leptin levels (e.g. in obesity)¹¹
          • increases 2-AG synthesis in the lateral hypothalamus by binding to CB1R
          • Endocannabinoids inhibit orexin-A
          • this eliminates the inhibitory signaling effect of orexin-A
          • increased orexin A release
          • Consequences are hyperphagia
          • Leptingabe normalized these Consequences
      • reduces synthesis of appetite-increasing (orexigenic) substances
        • reduces neuropeptide Y synthesis and release in the hypothalamus.
    • Leptin controls food intake via Endocannabinoids²
      • Leptin reduces AEA¹²
    • Leptin can cross the blood-brain barrier
    • Leptin blood level represents tissue fat percentage
  • Α-melanocyte-stimulating hormone (α-MSH)¹³
    • α-MSH is an appetite-inhibiting (anorexigenic) regulatory hormone in the melanocortin system
      • (only) In a saturated state after food intake:
        • Leptin and insulin can cross the blood-brain barrier
        • then activate POMC neurons in the arcuate nucleus
        • these produce α-MSH
        • α-MSH binds to MC-4 in the paraventricular nucleus
        • the latter reduces appetite and increases energy consumption
      • to unsaturated state (fasting period)
        • Ghrelin inhibits POMC neurons (and increases the feeling of hunger)
        • reduced leptin levels inhibit POMC neurons
        • Agouti-like peptide (AgRP) is synthesized
        • Neuropeptide Y is synthesized
  • Cholecystokinin¹⁴
    • conveys a feeling of satiety
    • inhibits gastric emptying
  • Melanin-concentrating hormone¹⁵
    • Release during sleep in the hypothalamus
    • increases appetite (important regulator)
    • Excess causes weight gain
    • Deficiency causes anorexia
  • Orexine¹⁶
    • increase the desire to eat
    • increase the amount of food consumed
    • suppress the feeling of satiety
      • Orexin A suppresses satiety 100 times more strongly than orexin B
    • Release during the waking state in the hypothalamus
    • Activate ghrelin Orexine
    • Leptin inhibits orexins

In addition to the neuronal circuits of the hypothalamus, these messenger substances also control brain regions that are involved in reward, motivation, learning, emotions and stress and probably modulate food intake: NAcc, ventral striatum, VTA, PFC, amygdala and hippocampus.³

The question arises as to whether endocannabinoids could be a key to understanding the appetite-suppressing effects of ADHD medications.

The CB1R (cannabinoid 1 receptor) regulates appetite.¹⁷¹⁸¹⁹

The CB1R agonists THC, anandamide and 2-AG promote appetite and cravings²⁰ also in animals^{121 22} via
CB1R binding in the hypothalamus and limbic forebrain.¹²

• Endocannabinoids modulate appetite and energy expenditure via CB1R. AEA has different effects on feeding behavior depending on the state of satiety and the CB1R location (peripheral or central):²³
  • Peripheral: The AEA reuptake inhibitor AM404 reduced food intake in partially satiated animals, not in unsatiated animals
  • Central: AM404 induced unrestrained eating (hyperphagia) in unsatiated animals. The inverse CBR agonist SR141716A suppressed this.

CB1R antagonists have an appetite-inhibiting effect.²⁴
The only CB1R antagonist that had received approval (rimonabant)²⁵ was withdrawn from the market due to rare but serious side effects.

• Rimonabant inhibited the effect of appetite stimulants (cocaine, morphine and food) and reduced interest in sucrose, beer and alcohol²⁶

The CB1R regulates the baby’s milk intake

• CB1R antagonists prevent the milk intake of infants on the first to fourth day and lead to death.²⁷
• CB1R-KO mice do not take milk on the first day of life²⁷

The following presentation in this section is based on the review by Sagheddu et al (2015).³⁰

Endocannabinoids also regulate food intake and perception of palatability via limbic forebrain areas such as the nucleus accumbens, which regulate the evaluation of sensory pleasure. The nucleus accumbens, a crucial structure of the brain’s reward system, is also a fundamental center for the non-homeostatic control of eating.³⁰
Endocannabinoids have a dose-dependent effect via CB1R in the hypothalamus and limbic forebrain to stimulate appetite (orexigen) and increase food intake.³⁰ In contrast, several studies report an effect on appetite and food intake by AEA, 2-AG and CB1R antagonists exclusively with peripheral administration and not with central administration.³¹³²

• Increased 2-AG in the nucleus accumbens increases food intake via CB1R³³³⁴
• Increased AEA in the nucleus accumbens enhances the natural liking of rats to sweet substances³⁵
• AEA promotes food intake via CB1R in the brain at low doses and reduces it at high doses^3637382
• Food deprivation
  • increased AEA and 2-AG in the limbic forebrain³³
  • increased 2-AG in the hypothalamus (lower)³³
  • increased AEA in the small intestine sevenfold, while AEA in the brain and stomach remained unchanged³¹
• Resumption of food intake
  • reduced 2-AG in the hypothalamus³³
    . - normalized the intestinal AEA values³¹
• The “satiety hormone” leptin lowers the AEA level²
• ADHD medications (stimulants) reduce AEA and 2-AG. More on this at MPH reduces anandamide and 2-AG in the article Cannabinoids for ADHD and stress. Stimulants have a significant appetite-suppressing effect.
• Leptin deficiency (as occurs in obesity) increases 2-AG synthesis in the lateral hypothalamus. Consequences are:¹¹
  • CB1R-mediated reduction of inhibitory orexin-A signaling
  • increased orexin A release
  • Hyperphagia (binge eating)
  • Leptingabe normalized these Consequences

CB1R agonists

• can trigger further food intake in fully eaten animals³⁰
• strengthen, even at low doses, the corticostriatal-hypothalamic signaling pathway (including the nucleus accumbens), which is highly important for the motivational drive to eat³⁹
  Within this circuit, dopamine is the key to both the rewarding and addictive properties of food.³⁰
  The CB1R antagonist rimonabant
• prevents the increase in dopamine levels in the nucleus accumbens that would otherwise be triggered by the presentation of novel tasty foods⁴⁰
• inhibits the release of dopamine in the mPFC, which occurs during food anticipation and eating in hungry rats⁴¹

CB1R antagonists
possibly only peripheral, not when administered to the brain³²
- reduce food intake motivation in rats in a dose-dependent manner.¹⁴²
- reduce appetite and consumption of rewarding (sweet) foods/drinks^{4344 45 46}
- suppress food intake, conditioned place preference for food, preference for sucrose and the reinforcing properties of chocolate¹
- reduce reactions to pleasant stimuli (e.g. tasty food) in important reward areas of the brain (e.g. VStr and OFC) and trigger anhedonia and anxiety when taken chronically⁴⁷
- CB1R-KO mice show a hypophagic phenotype (reduced interest in sucrose as a reward, lower motivation to obtain food, lower body fat percentage, increased leptin sensitivity)⁴⁸⁴⁹⁵⁰

MPH has a different effect on CB1R depending on the dose.⁵¹

Δ9-THC acid A (Δ9-THCA-A) is a carboxylated, non-narcotic native prodrug of Δ9-THC. Δ9-THCA-A acts as a partial and selective PPARγ modulator. Δ9-THCA-A showed in a mouse model of HFD-induced obesity:⁵²

• significantly reduced fat mass
• significantly reduced body weight gain
• significantly improved glucose intolerance
• significantly improved insulin resistance
• largely prevented hepatic steatosis, adipogenesis and macrophage infiltration in adipose tissue
• strong anti-inflammatory effect