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published: 07 November 2018
doi: 10.3389/fpsyt.2018.00545
Frontiers in Psychiatry | www.frontiersin.org 1November 2018 | Volume 9 | Article 545
Edited by:
Valentina Bassareo,
Università Degli Studi di Cagliari, Italy
Reviewed by:
Miriam Goebel-Stengel,
HELIOS Klinik Rottweil, Germany
Nicholas T. Bello,
Rutgers, The State University of New
Jersey, United States
*Correspondence:
Pedro Rada
pedrorada6@gmail.com
Specialty section:
This article was submitted to
Psychosomatic Medicine,
a section of the journal
Frontiers in Psychiatry
Received: 12 April 2018
Accepted: 12 October 2018
Published: 07 November 2018
Citation:
Wiss DA, Avena N and Rada P (2018)
Sugar Addiction: From Evolution to
Revolution. Front. Psychiatry 9:545.
doi: 10.3389/fpsyt.2018.00545
Sugar Addiction: From Evolution to
Revolution
David A. Wiss 1, Nicole Avena 2and Pedro Rada 3
*
1Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, United States, 2Icahn School of
Medicine at Mount Sinai, New York, NY, United States, 3School of Medicine, University of Los Andes, Mérida, Venezuela
The obesity epidemic has been widely publicized in the media worldwide. Investigators
at all levels have been looking for factors that have contributed to the development of this
epidemic. Two major theories have been proposed: (1) sedentary lifestyle and (2) variety
and ease of inexpensive palatable foods. In the present review, we analyze how nutrients
like sugar that are often used to make foods more appealing could also lead to habituation
and even in some cases addiction thereby uniquely contributing to the obesity epidemic.
We review the evolutionary aspects of feeding and how they have shaped the human
brain to function in “survival mode” signaling to “eat as much as you can while you can.”
This leads to our present understanding of how the dopaminergic system is involved in
reward and its functions in hedonistic rewards, like eating of highly palatable foods, and
drug addiction. We also review how other neurotransmitters, like acetylcholine, interact
in the satiation processes to counteract the dopamine system. Lastly, we analyze the
important question of whether there is sufficient empirical evidence of sugar addiction,
discussed within the broader context of food addiction.
Keywords: obesity, food addiction, drug addiction, sucrose, feeding behavior, dopamine, acetylcholine, nucleus
accumbens
INTRODUCTION
Obesity has become one of the biggest health care burdens since the second World War ended,
increasing morbidity and lowering life expectancy (1,2). It is a major contributing factor to several
chronic conditions, including cardiovascular disease, diabetes, and cancer (3). Given the social and
economic burden associated with the “obesity epidemic” there has been considerable global interest
across many disciplines including medicine, nutrition, neuroscience, psychology, sociology, and
public health in order to reverse this trend. Numerous interventions have been proposed, but there
has been minimal progress to date. This obesity crisis affects not only developed countries but less
developed ones as well, with up to 30% or more of its population categorized as overweight or obese
(1,4). The disproportionate increase in body weight has intensified in the last 30 years (1,5,6).
Virtually all investigators have asked the question of what has changed in this relatively short
period of time? A common theory is an increase in sedentary lifestyles. Some contend that this
alone explains the epidemic, arguing that energy expenditure, rather than food consumption, has
significantly decreased in modern society compared to our hunter-gatherer ancestors (7). Multiple
studies support this concept of a direct correlation between physical inactivity, television watching
hours, and obesity (8–10). A second theory is the availability and consumption of highly palatable
foods, which has surged in the past few decades. Nestle reported the appearance of 11,000 new
food products added to the supermarket shelves every year in 1998 (11), introducing countless
new and attractive flavor combinations for food consumers. Investigations into the link between
Wiss et al. Sugar Addiction
the “food environment” and obesity have led to the conclusion
that ubiquitous access to relatively inexpensive and convenient
“snack” foods have changed normal eating behavior, including
less time spent preparing meals at home (12). Industrialization of
the food supply has decreased the cost of energy dense foods by
adding refined sugars, grains, and/or fats to their products (11).
Consumption of these processed foods has increased in children
(13) and toddlers (14).
While behavioral and lifestyle interventions remain the
mainstream “treatment” approach for obesity, dietary adherence
remains an obstacle (15). Recent research suggests that highly
processed foods are addictive and the hedonic mechanisms
(pleasure-seeking pathways) may play a critical role in the
pathogenesis of obesity (16). It has also been suggested that the
focus on calorie counting is misguided, and that future strategies
should emphasize dietary quality and individual factors such as
hormonal regulation of metabolism (17), and the gut microbiome
(18). Given the challenges that many people face controlling their
appetites in today’s “food environment” it appears that public
policy changes will be required to modify the conditions in
which food choices are made (19). According to Gearhardt and
Brownell (20) “it will be important to look at the widespread
subclinical impact of potentially addictive foods through the use
of public health approaches” (20). The goal of this paper is to
review the human predilection for refined sugars and how they
reshape the brain, with its implications for public health policy.
THE NUTRITION TRANSITION THEORY
The nutrition transition theory first emerged to describe global
trends toward a “Western diet” containing refined foods high
in fat and sugar, and low in fiber (21). Later the term
was used to capture a correlation with increased BMI and
changing economic and agricultural factors. Early identified
factors include urbanization, economic growth, technical change,
and culture (22) while more recent descriptions of the critical
underlying factors include technology, urbanization, economic
welfare relative to the cost of food, and expansion of global
trade (23). The nutrition transition theory is not a new
concept. Previous models have included the demographic and
epidemiological transitions. Popkin and Gordon-Larsen identify
that both historic processes precede the nutrition transition
(22). The epidemiological transition describes a shift from high
prevalence of disease associated with famine, malnutrition, and
poor sanitation, to a pattern of high prevalence of chronic and
degenerative disease associated with urban-industrial lifestyles
(24). This ecological framework analyzes changes at the societal
level, examining how agricultural and food supply chains impact
global dietary patterns. The theory suggests that “upstream”
interventions (supply-side) will be more effective than addressing
the lower hanging fruit (i.e., exercise, calorie restriction).
The nutrition transition theory is also supported by
compelling evidence suggesting that a wide range of animals
have also been gaining weight in recent years (25,26). Other
terms that support the “environmental theory of obesity” include
“globesity” at the most distal levels, and the “neighborhood
effect” at more proximal levels (27). Notwithstanding, the
“neighborhood effect” has far-reaching social implications, given
that the neighborhood where one lives is merely a proxy for
socioeconomic status. Recently, other research has suggested that
discussions of nutritional inequality emphasizing supply-side
factors are less indicative of consumption patterns than demand-
side differences (28), lending support to the food addiction (FA)
hypothesis.
EVOLUTIONARY AND GENETIC ASPECTS
OF FEEDING
Adipose tissue in mammals play an important role in survival
by preparing the body for periods of famine (29). From an
evolutionary perspective, the increase in body fat prepared
animals for times of food scarcity, in fact, those accumulating
body fat had an advantage compared to those that did not (30).
However, this occurred in times when humans had insecure
food supply (hunter-gatherer) and could spend many days on a
hypocaloric diet. During prehistoric times, the excessive increase
in body weight was dampened by physical activity needed in the
search of food, moreover, excessive fat would mean, as a predator,
lower chances of catching the prey and vice versa (29). So, even if
copious quantities of food were eaten, there was a natural brake
mediated by physical activity.
When did this panorama change? The first change was
the advent of agriculture and animal domestication ∼10,000
years ago, leading people to become producers by gathering
and securing food supply (31). Of course, farming depended
on climate and plagues which could decimate crops resulting
in famine (3). The second change was the industrialization
of food supply (industrial revolution of the nineteen century)
allowing for mass production of flour and sugar (32), with
the ulterior manufacturing, in the last decades, of processed
and ultra-processed foods that are inexpensive and highly
caloric (abundant sugars, salts, fats) (11,33). These two
developments are linked to food availability and how food
is refined and commercialized. Meanwhile, a third important
revolution happened over the past few decades: the arrival and
public accessibility of automobiles, television sets, and later the
computer leading us toward a sedentary lifestyle (7). When all
three transformations are combined, we can see that caloric
intake has risen while calorie expenditure has significantly
decreased, leading to the obesity epidemic.
Although humans have culturally and technologically evolved,
our genome has changed very little in the last 10,000 years
(4). This means that our brain circuitry is still programmed to
eat more in times of food abundance preparing for periods of
starvation (31). Recent genetic studies have focused on gene
polymorphisms related to specific nutrients and obesity (34–
37). This area of investigation has been called nutrigenetics
and suggests that epigenetic factors influence the expression of
predisposing genes in certain populations. For example, positive
associations have been found between the fat-mass and obesity
associated gene (FTO) and BMI (38). Many investigators are
interested in genes such as beta-adrenergic receptor 2 (ADRB2)
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Wiss et al. Sugar Addiction
and melanocortin receptor 4 (MCR4), since their expression may
be altered following ingestions of carbohydrates (sugar) (39–41).
Researchers have found a significant interaction between sugar-
sweetened beverages and genetic-predisposition score calculated
on the basis of 32 BMI-associated loci suggesting that people
carrying this trait, when exposed to sweetened beverages, BMI,
and adiposity will be augmented (35). In addition, other
investigators have found that at chromosome16p11.2 different
variations of this gene can affect consumption of sweet foods
(42,43). The question at this point is: how can we link sugar
ingestion to addictive behavior?
EVOLUTION OF ADDICTIVE DRUGS
When Charles Darwin postulated the evolution theory, he
suggested that a trait would emerge if it contributed to survival
and increase the reproductive success of a species. Plants have
evolved protective measures to prevent herbivores from eating
them. For example, some alkaloids that give the plant a bitter taste
cause avoidance by most species in the animal kingdom (44,45).
Nonetheless, many animal species including hominids, as well as
prehistoric humans, ingested lesser amounts of toxic substances
and obtained benefits for their own survival (45). Thus, a
coevolution occurred as different traits were evolving in animals
for the detection of caloric nutrients in foods (i.e., carbohydrates),
traits emerged that permitted the ingestion of small amount of
toxic plants to prevent diseases or to improve physical conditions
(45). This would explain the chewing of cocaine or tobacco leaves
by aborigines in the Americas allowing them better physical
fitness to cope with fatigue and a better chance to catch prey
or find food (44). One could argue that, like our dependency
on nutritive foods to survive, we were also partially dependent
on certain toxic plants. What made them addictive? Analogous
to nutrients, humans learned how to process these toxic plants,
increasing their potency, as it is done in modern times, conferring
drugs and foods with a salient rewarding response. Thus, in both
cases (food or drugs) an “evolutionary mismatch” has occurred
by which human technology has been able to alter environmental
conditions much faster than the changes that occur in our central
nervous system (46,47). Ultimately, early in our evolution the
ingestion of food or drugs emerged as positive reinforcement
and evolved common neural circuits for reward, and that has
not changed over time, owing to their sharing of similar neural
mechanisms in addictive behavior (48–50).
NEURAL CIRCUITS FOR REWARD
The limbic system consists of different brain regions engaged
in various aspects of emotions. Historically, it included a
bidirectional pathway between the hippocampus and the
hypothalamus (51). Over time, other structures have been added
to the circuit including: the amygdala, the nucleus accumbens
(ventral striatum) and the prefrontal cortex. The functions of
these structures are complex, and their diverse mechanisms of
action are still being elucidated. Various neurotransmitters in
this circuit (like GABA, glutamate, and opioids) are involved in
several aspects of reward (52,53), however, the dopaminergic
pathway from the ventral tegmental area (VTA) to the nucleus
accumbens (NAc) has received the most attention in the “reward”
cascade (54–60). To summarize, blocking the dopaminergic
pathway between the VTA and the NAc inhibits instrumental
responding for food and became the foundation of the dopamine
(DA) hypothesis of reward (61). Later, studies have demonstrated
that “reward” is a vague term (62) that consists of at least three
components: hedonics (“liking”), reinforcement (learning) and
motivation (incentive, “wanting”) (63). DA in the NAc seems to
have a preponderant role in the latter two components (learning
and incentive motivation) and less in the former (hedonics)
where the opioid and GABA system appear to play a stronger role
(64,65).
FOOD “REWARD” AND ACCUMBENS
DOPAMINE
Although the exact contribution of accumbens DA in reward
is still unclear, most researchers agree that it is involved in
feeding behavior. For instance, original studies in the 1970’s have
shown that a lesion in the striatonigral DA pathway with 6-OH-
dopamine provoked a profound aphagia and adipsia (66). This
finding was later corroborated in DA-deficient mice that also
became hypoactive, aphagic, and adipsic (67). Similarly, lever
pressing for food pellets in animals increases DA release in the
NAc (68–70), however, not during rat chow free-feeding (70,71)
suggesting that DA in the accumbens regulates instrumental
learning. Others have observed that accumbens DA increases
during rat chow feeding only if rats were food deprived (72,73)
or in the presence of palatable foods (74–81). Interestingly,
increased DA while eating highly palatable food wanes after
repeated exposure (74,75,79) and this returns if palatable
foods are switched to a different one (82) suggesting a role
of this neurotransmitter in the NAc for novelty recognition.
Additionally, it has been shown that DA neurons respond to
exposure of a novel food and if that novel food is paired with
a cue, in a subsequent exposure, food alone will not induce
neuronal firing while the cue alone does, suggesting that DA
neurons are involved in conditioned learning (83,84). Cue-
invigorating food-seeking may be considered adaptive, but the
maladaptive eating in the absence of hunger forms the basis for
the FA hypothesis. It has been shown that limited or intermittent
access to highly palatable foods increase cue-reactivity to these
foods, which has implications for the consequences of extreme
dieting behavior in humans (85).
Another preponderance of evidence for the engagement of
accumbens DA on feeding behavior comes from studies utilizing
orexigenic peptides. It is well known that some peptides in
various brain sites are capable of initiating feeding behavior, for
instance, paraventricular injection of galanin, ghrelin, or opioids
will promote food intake even if rats are satiated (86–92). These
peptides, systemically or locally injected in the paraventricular
nuclei, increased NAc DA (93–95). Inversely, local injection
of cholecystokinin (CCK), an anorexigenic peptide, decreased
DA release in the NAc (96). It appears that accumbens DA
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Wiss et al. Sugar Addiction
plays more of a role in the anticipatory behavior than in the
consummatory behavior. Stomach-derived ghrelin has known
action on orexigenic neurons in the hypothalamus, and receptors
have been identified in the VTA, hippocampus, and amygdala
(97,98). Ghrelin appears to be implicated in rewarding aspects
of eating distinct from homeostatic mechanisms that promote
food consumption when energy stores are low, thus may be a
key driver in the motivational aspects (“wanting”) of consuming
palatable foods beyond metabolic need (99,100).
Finally, pharmacological manipulation of the DA system has
led to contradictory results. On the one hand, DA injected
directly into the NAc is capable of increasing ingestive behavior
(101,102). However, others have not been able to modify feeding
behavior when specific DA agonists or antagonists were used
(103,104). Recently, chemogenetically activating DA neurons
in the VTA that project to the NAc disrupted feeding patterns
(105). In part, these dissimilar findings show that it is very
hard to propose that only one neurotransmitter or hormone is
responsible for driving behavior.
DYSFUNCTION OF THE DOPAMINERGIC
SYSTEM IN OBESE SUBJECTS
Investigators can identify animals that have propensity to become
obese in a 5-day weight gain on a high-fat diet (OP rats) (106).
In these OP rats, a deficit of exocytosis mechanisms in the DA
neuron was found, as well as a decrease in accumbal DA basal
levels (107,108). Similarly, rats made obese with a “cafeteria diet”
exhibited decreased basal levels of DA in the NAc, and show a
blunted DA response to the taste of rat chow, while increasing
DA release in response to a highly-palatable food (109). Human
studies using neuroimaging determined that obese patients had
a lower sensitivity of the accumbens DA (110) and a decrease
in DA-D2 receptor availability (111,112). Several studies have
used the term “reward deficiency syndrome” to describe a genetic
dysfunction of the DA-D2 receptor leading to substance-seeking
(food, drugs) behavior in humans (113–115). Variations in the
DA-D2 gene have also been associated with impulsivity and a
preference for smaller more immediate rewards compared to
larger but delayed ones (delay discounting) (116). It is possible
that obese subjects compensate for the depressed DA basal levels
by overeating palatable foods (57). Conversely, optogenetical-
induced increase in basal DA release inhibits consumption
behavior (117). How can these results be reconciled with other
studies? DA is released phasically and tonically with possible
divergent tasks (118,119). Basal DA levels are likely to determine
the tonic response of the system, thus could confer a complete
opposite response.
DRUGS OF ADDICTION AND ACCUMBENS
DOPAMINE
Most drugs of addiction activate the VTA-NAc pathway whether
they are systemically injected (120) or locally applied in the
accumbens (121,122). Furthermore, drugs that increase DA
release in the NAc are also self-administered (123–126). Thus,
drugs of addiction, like food, increase DA release in the NAc,
however with drugs, this increment occurs repeatedly every
time it is given, compared to a decline in release observed
with palatable food. Blunted striatal DA and decreased DA-
D2 receptor availability (measured using radiotracers as binding
potential relative to nonspecific binding) have been repeatedly
identified in position emission tomography (PET) scans of drug-
addicted human subjects and is likely to be both a result and
a cause of an addictive disorder (127). Given the similarities
in human PET scans between drug abusers and obese subjects
(128), additional research is needed to identify neurobiological
risk factors for addiction-like eating. Animal studies suggest that
overconsumption of each can be a predisposing factor for the
other (129,130).
ACCUMBENS ACETYLCHOLINE AND
SATIETY SIGNALING
Acetylcholine (ACh) is released by local interneurons that
compromise less than 2% of neurons in the NAc (131,132). They
have an extensive axonal arborization and form synapses in the
medium spiny output neuron (133). The idea that ACh opposes
DA function in the striatum comes from research on Parkinson’s
disease (PD). It is known that anticholinergic (antimuscarinic)
drugs were the first medications used in the treatment of PD
antagonizing mainly M1 receptors (134,135). This indicates
that DA normally exerts an inhibitory action on striatal ACh
interneurons as demonstrated in rats (136). In addition, L-dopa
induced hyperlocomotion in DA-deficient mice is suppressed by
cholinergic agonists (137). Separately, anticholinergic drugs are
abused (138) probably by increasing DA activity in the striatum
(139), thus, an antagonistic association probably exists between
DA and ACh in the NAc and striatum.
ACh in the NAc appears to have a modulatory effect on
feeding behavior. During free-feeding, ACh increased at the
end of a meal (72) and during ingestion of a palatable food it
reached a maximum after the animal stopped eating (79,140).
This increment disappeared in sham-fed animals that had a
gastric fistula opened compared to controls with a closed gastric
fistula (141). Bilateral perfusion in the NAc of the indirect
ACh agonist, neostigmine, reduced food intake in food-deprived
animals (142). Conversely, lesion of the cholinergic interneuron
in the NAc with a specific toxin (AF64A) produced a significant
increase in food intake (142). Moreover, injection of the anorectic
drug combination phentermine/fenfluramine increased ACh
release in the NAc (143). All these results suggest that ACh in
the NAc probably signals satiety. Recently, researchers found
that increasing the activity of the cholinergic interneuron in the
NAc reduced palatable food consumption, lending support to the
hypothesis that NAc-ACh acts as a stop signal (144).
What happens if food becomes an aversive stimulus? Using
a conditioned taste aversion paradigm, it has been shown that
the aversive stimulus (in this case saccharin) would decrease DA
release (78) while increasing ACh output (145). Furthermore,
injection of neostigmine (indirect ACh agonist) is sufficient
to provoke a conditioned taste aversion (146). Therefore, an
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Wiss et al. Sugar Addiction
increase in DA simultaneous to an increase in ACh release in
the NAc signals satiety (stop) but if the change in release of these
neurotransmitters is divergent (decrease in DA and increase in
ACh) then the stimulus becomes aversive (140). Taken together,
animal feeding induces an initial and long-lasting increase in
DA release followed by an increase in ACh output signaling
satiation, making the animal feel satisfied (DA release) and stop
the behavior (ACh).
EFFECT OF DRUGS OF ABUSE AND
WITHDRAWAL ON ACETYLCHOLINE
RELEASE IN THE NAC
Drugs of addiction exert differential responses on the accumbens
cholinergic interneuron. One could separate these drugs by
their effect on feeding, for example, ACh release is decreased
or not changed in the NAc if the drug increases food intake
(opioids, alcohol, benzodiazepines) (147–150) while those that
act as anorectic (cocaine, amphetamine, nicotine) produce the
opposite effect, an increase in ACh release (142,151–153).
Moreover, cholinergic ablation in the NAc increased sensitivity
to cocaine (154). What is common for most drugs of addiction
is that during drug withdrawal ACh is increased in the NAc
(147,149–151,155). In addition, enhanced functioning of the
ACh interneuron in the NAc prevents addictive behaviors for
cocaine and morphine (156). The augmented release of ACh
in the NAc occurs simultaneously to a decrease in DA release
(150,151,155,157), identical to the response observed during
a conditioned taste aversion.
WHAT IS THE DIFFERENCE BETWEEN
FOOD AND DRUGS OF ADDICTION?
First, feeding behavior, as with other “natural” behaviors, has
a satiety system provided by the mechanical limitations of the
stomach and peptides like CCK that signal satiety while drugs of
addiction apparently do not. Secondly, even in the presence of
a palatable meal, the pleasant effect seems to wane simultaneous
to a blunting of the DA response (74,75,79,82) even though
in some cases “sensory-specific satiety” can lead to continued
consumption behavior after a novel food is introduced (82).
Finally, the magnitude of the DA increase is lower during meal
than during drug administration. Drugs of abuse not only release
striatal DA but also block or reverse DA reuptake, creating a
more potent reinforcement through the euphoric state (158).
Some authors have made the argument that there is no concrete
evidence of withdrawal from food, especially when compared
to drugs like opioids (159) and that calling food addictive
risks trivializing more serious addictions (160). Other arguments
against FA have suggested “eating addiction” as behavioral rather
than substance-related (161). Evidence of withdrawal in animal
models will be reviewed below.
Given that adolescence is a critical period of
neurodevelopment, it appears as though exposure to sucrose
during this time (rodents from postnatal day 30–46) leads to an
escalated intake during the exposure period and a subsequent
decrease in c-Fos-immunoreactive cells in the NAc (measured
at postnatal day 70) which is involved in the processing of
hedonic properties of sweet foods (162). In this experiment,
adult rats consumed less sugar after heightened exposure in
the adolescent period, which is consistent with other findings
(163,164). These studies also demonstrate that sugar-exposed
adolescents exhibit higher preference for cocaine (164) but not
alcohol (163) in adulthood. Differences in the neurobiological
substrates underlying intake behavior of food and drugs abuse
are likely explained by changes in the motivational aspect of food
intake rather than by deficits in hedonic processing (162). These
findings point to deficits in the “liking” component of sweet
foods and drinks which offers insight into our understanding
of reward-related disorders. Interaction effects between genetic
predisposition to addiction and exposure to sugar during
adolescence on the “wanting” mechanism in adulthood warrants
further study.
CAN SUGAR BE ADDICTIVE?
Before we can make a case for sugar as an addictive substance,
we must first define addiction, which is now referred to
as substance use disorder (SUD). The American Psychiatric
Association defines addiction, in its web page for patients
and family, as “a complex condition, a brain disease that
is manifested by compulsive substance use despite harmful
consequence.” Operationally, experts utilize the Diagnostic and
Statistical Manual of Mental Disorders (DSM) as a tool to unify
diagnostic criteria in clinical and/or experimental design. The
current version of this manual known as the DSM-5 includes a
section for SUD and it incorporates eleven criteria for diagnosis.
A patient must fulfill at least two of these criteria. In turn, these
eleven criteria, by their characteristics, can be compiled into four
broader groups (165) (see Table 1).
These guidelines are designed to help with the diagnosis
of patients, however, scientists use them in animal models,
discarding those that are unique to human behavior (i.e., social
impairment). Our animal model for sugar addiction consists
of rodents with restricted access to 10% sugar or 25% glucose
solution during a 12-h period starting 4 h into their active cycle
TABLE 1 | Four broader categories for eleven criteria used for substance use
disorder (SUD).
A. Impaired Control 1. Use larger amount and for longer than intended.
2. Craving.
3. Much time spent using.
4. Repeated attempts to quit and/or control use.
B. Social Impairment 1. Social/interpersonal problems related to use.
2. Neglected major role to use.
3. Activities given up to use.
C. Continued use Despite
Risk
1. Hazardous use.
2. Physical/psychological problems related to use.
D. Pharmacologial Criteria 1. Tolerance.
2. Withdrawal.
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Wiss et al. Sugar Addiction
(as Bart Hoebel would remark “animals skipped breakfast”) for
21 days (details of the protocol can be found in Avena et al. (166).
We are able to examine the following criteria met by our model:
A. Impaired control:
1. Use larger amounts and for longer than intended: rats will
typically escalate their sugar ingestion progressively from
an initial 37 mL up to 112 mL by day 11 when they reach
an asymptote that persists for the next 10 days (79,167).
Escalation cannot be attributed to neophobia which is easier
to overcome. In addition, experimental and control animals
drink about 6 mL in the first hour during the first day and
doubles in experimental subjects (over 12 mL) on day 21, while
controls (ad lib sugar) drank the same 6 mL as the first day
(79,167). This increase could be considered a “binge” (168).
Certainly, the gastrointestinal system has intrinsic mechanical
restraints limiting the amount consumed during escalation of
a sugar solution, if bypassed (i.e., with a gastric fistula), rats
will binge over 40 mL in the first hour (141). So, intermittent
administration of sugar mimics those used for drug self-
administration (169) and creates a “binge” pattern of intake
that resembles the compulsive behavior seen in drug abuse
(170,171). Binge-like consumption patterns of sucrose has
been associated with decreased dendritic length of the NAc
shell which supports the formation of increased excitatory
inputs (172). Ghrelin’s ability to interact directly with DA
reward circuitry and ACh receptor gene expression in the VTA
has been implicated in the motivational aspects of feeding
under high-sugar conditions (173) which is consistent with
findings that ghrelin is necessary for reward from alcohol (174,
175) and drugs of abuse (176). Meanwhile, a shortcoming here
is that we cannot determine “intention” in our animal model
the way it can be assessed in humans. Therefore, “intended” is
an assumption.
2. Craving: defined by the Cambridge Dictionary as “a strong
feeling of wanting something” or “feeling of desire.” In
laboratory conditions, it is defined as the motivation
(“wanting”) to obtain an abused substance (177) and is
indirectly studied in animal models using instrumental
behavior. In one case, rats bar press to self-administer drugs of
abuse and when forced to abstain they will keep pressing the
bar although unrewarded (resistance to extinction). Second,
rats will readily press the bar in presence of a cue that
was previously associated to the drug (incubation) (178–
182). A third paradigm, used initially in alcohol addiction,
is the alcohol-deprivation effect (ADE). Alcohol drinking
rats will increase their consumption following an abstinence
period (181,183). Experiments carried out in rats trained
to respond for sucrose, instead of drugs of abuse, exhibited
resistance to extinction and incubation much like cocaine
(184). Moreover, the incubation response was attenuated by
naloxone administration arguing in favor of the endogenous
opioid involvement in sugar craving (185). Additionally,
rats trained to drink a non-caloric solution (saccharin) also
showed incubation, consequently, the phenomenon depends
on taste (hedonic) and not just the caloric content of the
solution (186). Lastly, rats trained for 28 days to drink a
sucrose solution and deprived for 14 days displayed a sugar-
deprivation effect analogous to ADE (187). These results are
an indirect measure of the motivation to use sugar (craving)
and fulfills one of the DSM-5 criteria for SUD. Craving has
been intimately related to high rates of relapse in drugs of
abuse (171) and now with sugar.
B. Social impairment (unable to assess with animal model).
C. Continued use despite risk:
1. Hazardous use: In the context of drug abuse, a conditioned
suppression paradigm is utilized as an indicator of a
compulsive behavior and gives indirect evidence of the power
of craving (168). Animals will seek a drug (i.e., cocaine)
despite an aversive conditioned stimulus (188). The results on
sucrose consumption, using this paradigm, is controversial.
On one hand, it was found that the conditioned stimulus
suppressed sugar intake indicating that the animal would not
take the risk (188). In this case, rats were trained to obtain
sucrose on a “seeking/taking” chain schedule that paralleled
cocaine use, and the conditioned stimulus suppressed sucrose
intake as well as increased seeking latency, however, in
this paradigm we do not know whether rats were sugar-
dependent or not. Meanwhile, others have found that mice
on a highly palatable food diet were insensitive to the
aversive conditioned stimulus (189–191) or would withstand
an unpleasant environment to gain access to the meal (192).
Further research is needed to determine if sugar dependent
rats will endure an aversive stimulus to seek the sugar
solution.
D. Pharmacological criteria:
1. Tolerance: is the gradual decrease in responsiveness to a drug
demanding an increase in doses consumed to obtain the
same initial effect (168,193). In our model, rats progressively
escalated their sugar intake as explained above and it probably
argues in favor of a tolerance effect (79,167).
2. Withdrawal: corresponds to a set of signs and symptoms
that a drug user presents once the drug is suspended or
the specific antagonist is injected. One of the most clearly
defined, in animals, are the signs of opiate withdrawal
either spontaneous or induced with a specific antagonist
(i.e., naltrexone, naloxone) including: wet-dog shakes, teeth-
chattering, piloerection, diarrhea, grooming, rearing, writhing
(149). Two other symptoms in opiate withdrawal are anxiety
and behavioral depression. The former is inferred in rats using
the plus-maze and measuring the amount of time spent in
the open or closed arms (194). Spontaneous and naloxone-
induced opiate withdrawal in rats decreased exploration into
the open arms confirming the anxiogenic-like effect following
the abandonment of the drug (195). The latter symptom
is explored using the forced-swim test and monitoring the
amount of time swimming (196). Morphine withdrawal causes
a prolonged enhancement of immobility in rats confirming
the behavioral depression induced when the drug was
suspended (197).
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Wiss et al. Sugar Addiction
Sugar acts as an analgesic most likely by releasing endogenous
opioids (198). Hence, it is sensible to look for signs of opiate
withdrawal in rats made dependent on sugar or palatable
food (199). Injection of naloxone in sugar-dependent rats
generated several of the opiate withdrawal symptoms and
anxiety-like response on the plus-maze (200,201). Similarly,
sugar deprivation (analogous to spontaneous drug withdrawal)
produced signs of opiate withdrawal including anxiety-like
behaviors (200,202). Only recently have withdrawal symptoms
been elucidated in humans meeting criteria for FA by way of
predictive reference resetting (allostasis) controlled by the rostral
anterior cingulate cortex and the dorsal lateral prefrontal cortex
(203).
Neurochemically, morphine withdrawal is accompanied by
a decrease in accumbens DA release with a simultaneous ACh
increase (147,149,157). An equal response was observed when
sugar experienced rats were injected naloxone or sugar deprived
(200–202), confirming the involvement of the endogenous opioid
system in the development of sugar dependency.
ADDITIONAL ASPECTS OF SUGAR
ADDICTION ARE COMPARABLE TO
DRUG ADDICTION
So far, this model of sugar addiction meets five of the criteria
established in the DSM-5. In addition to the clinical criteria, there
are other behavioral and neurochemical attributes observed in
animal experimentation that we will discuss below.
Behavioral sensitization is a phenomenon linked to several
facets of drug dependence and consists on a long-lasting
increase in locomotor activity following repeated administration
of psychostimulants or opioids (204–206). Animals sensitized
with one drug of abuse often show the same hyperactivity when a
different drug is injected. This has been called cross-sensitization
and occurs between different drugs of addiction (207). For
example, rats sensitized to 9-delta-tetracannabinol displayed a
sensitized behavior when morphine was injected (208). Equally,
rats sensitized to cocaine are cross-sensitized to ethanol and vice-
versa (209). Comparable to drugs of abuse, sugar dependent rats
show cross-sensitization to drugs of abuse and the other way
around. For instance, rats maintained on an intermittent sugar
schedule display cross-sensitization to amphetamine (210) and
rats sensitized to amphetamine increase their locomotion when
exposed to 10% sucrose solution (211). Furthermore, sucrose
intake has been shown to enhance behavioral sensitization
induced by cocaine and ethanol (212,213). Thus, intermittent
sugar promotes behaviors observed with drugs of abuse.
Human research on behavioral sensitization has been used
to explain the progressive nature of drug use and the role of
internal and external cueing in the motivation process. Highly
caloric food elicit the strongest DA response but it has been
suggested that only a subset of susceptible individuals become
conditioned for behavioral sensitization (214) likely due to
genetic variability in the dopaminergic system. There is still some
debate if individuals are more susceptible under conditions of
reward hyposensitivity (215) or hypersensitivity (216). There has
also been discussion that energy density, but not sugar specifically
plays the most important role in determining the reward value of
food (217).
The gateway hypothesis claims that legal drugs (alcohol
or nicotine) precedes consumption of cannabinoids, and
cannabinoids precede other illicit drugs (218). In animal models
of drug abuse this phenomenon appears to be linked to cross-
sensitization and instead of increasing locomotor activity it
increases the intake of another drug (“consummatory cross-
sensitization”) (168). For instance, exposure to cannabis in young
adult rats enhanced opiate intake when adults (219). In a separate
experiment, pre-exposure of ethanol enhanced cocaine self-
administration in adult mice (220,221). Sugar dependent rats
forced to abstain intensified their intake of 9% ethanol. In this
case, sugar seems to act as a gateway to alcohol use (222).
Other neurochemical similarities between drugs of abuse
and sugar dependent rats have been observed. As previously
described in this review, DA response to palatable food habituates
following repeated exposure (74,79), however, when sugar is
given intermittently this effect disappears and like drugs of abuse,
DA increases every time that the animal is exposed to sugar (79).
Changes in mu-opioid and DA (D1 and D2) properties have
also occurred in different experimental models of drug abuse.
For instance, repeated cocaine application was correlated with
upregulation of mu-opioid receptors (MORs) and increased
binding of DA-D1 receptors (223). Self-administration of cocaine
in monkeys increased DA-D1 density and decreased DA-D2
receptors (224). However, conflicting results have been detected
for the DA-D1 receptor while a consistent DA-D2 receptor
downregulation in cocaine addicted subjects occurred (225),
alike human studies (112,226–229). In our sugar intermittent
model, an increase in DA-D1 and MOR binding with an opposite
response in DA-D2 binding was detected (167). Posteriorly,
studies show a decrease in DA-D2 mRNA or binding in the NAc
of sugar and high-fructose corn syrup drinkers while the MOR
mRNA increased only in high-fructose corn syrup drinkers (230–
232). Therefore, palatable food and drugs of abuse share similar
neurotransmitter systems with changes in DA release, as well as
in receptor function.
In summary, rats in the intermittent sugar access schedule
fulfill five of the eleven criteria in the DSM-5 and induces other
brain changes that resemble drugs of abuse. Thus, confirming
that sugar can be addictive and plays a key role in the broader
construct of “food addiction,” at least in this animal model. A
brief overview on human data will be summarized below, as well
as some of the arguments against FA.
ADDICTION POTENTIAL OF HIGHLY
PALATABLE FOOD RELATED TO
MATERNAL INFLUENCE
Given ethical limitations, prospective studies examining the
impact of extreme dietary imbalances (high-sugar, or high-
fat) during human pregnancy cannot be undertaken. Rodent
models show that such dietary extremes (high-sugar and/or
high-fat) can impact fetal neurodevelopment, providing evidence
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Wiss et al. Sugar Addiction
of “addiction transfer” from mother to the newborn (233).
These animal studies highlight the importance of biological
processes (absence of social factors) in the development of
FA. Specifically, maternal exposure to drugs of abuse or to
highly palatable foods during both the pre- and postnatal period
alter behavior via the DA reward system (234,235) and MOR
(236) of the offspring. Intrauterine nutritional experiments in
animal models have demonstrated perturbations in hormone
(e.g., insulin, leptin, ghrelin) signaling that interact with the
development of the reward system in the VTA. Both under-
and overfeeding have the potential to increase obesity prevalence
in the offspring by way of the DA and opioid systems (237)
and such effects have been observed at the intergenerational
level (238,239). Changes in DNA methylation appear to modify
genetic expression of DA transporter and MOR (240). While
more research has been conducted using a high-fat compared
to high-sugar model, caloric sweeteners have been shown to
favor hedonic over homeostatic mechanisms (241). Hormonal
regulation of food reward may partially explain why sucrose is
preferred over artificial sweeteners.
HUMAN RESEARCH ON “FOOD
ADDICTION”
The major construct that has emerged from the theory of FA is the
Yale Food Addiction Scale (YFAS). Preliminary validation of the
YFAS occurred in 2008 in order to “identify those exhibiting signs
of addiction toward certain types of foods” (242). The scale is
designed to mirror established alcohol and drug addiction criteria
described above. Questions were adapted to assess consumption
of high-fat and high-sugar foods and were reviewed by a panel of
experts as well as patients with binge eating disorder for feedback
on wording. The authors concluded that the YFAS may be a
useful tool in identifying individuals with addictive tendencies
toward food and propose its use in exploring whether FA is a
valid and useful concept. In 2016, the YFAS 2.0 was developed to
maintain consistency with the current diagnostic understanding
of SUDs described in the DSM-5 which also includes severity
indicators (243).
Evidence is accumulating on the overlap of neural circuitry
and commonalities between drug abuse and FA in humans
(244). Population studies carried out using both YFAS and
recently YFAS 2.0 have detected a prevalence of food addicts
from as low as 5.4% to as high as 56% depending on the
population studied (weighted mean prevalence reported at 19.9%
in systematic review) (242,245–248). Interestingly, this figure
[19.9%] closely matches the prevalence of other legal drugs
like alcohol (249) and tobacco (250). When considering the
association between FA and BMI, close to 20% were obese and
little over 40% were underweight (248). One could speculate on
the reason of this disparate result. Addictive mechanisms serve
a homeostatic function so that if food is scarce one will seek it
and binge when found. Additionally, those in the underweight
category may be dieting or displaying restrained eating patterns
which can increase reward sensitivity for food. The failure of
human models of food addiction using YFAS to control for
dieting behaviors is a shortcoming of this construct (discussed
below).
Dysfunction of the reward system in the presence of highly
palatable food becomes a major driver in the prevalence of
obesity. While there is an interaction between FA and obesity,
they are not the same condition. We cannot discard FA because
not all obese people are food-addicted and not all food-addicted
are obese (251–253). Many factors are involved in the appearance
of obesity and food addiction is just one of them (254), but
when 15% of the US population consider themselves as “food
addicts” of an estimated 330 million people (census.gov accessed
July 2018), then close to 50 million people and (if estimates are
correct) close to 20% are obese (248), that gives us a figure of
10 million people that are both food-addicted and obese. This
is a substantial number of people with maladaptive functioning.
A recent systematic review and meta-analysis of human studies
“support that altered general reward-related decision making
is a salient neuropsychological factor across eating and weight
disorders in adulthood” (255). Taken together, the FA perspective
suggests that biochemical changes and genetic predisposition to
addiction can lead to excess food consumption independent of
social factors. An important theme that has emerged is that FA
is both an individual problem as well as a collective problem
that should be addressed on a societal level. Given the obesity
trends and more recently the opioid epidemic, it can be argued
that addiction is the number one public health problem in the
United States.
FOOD ADDICTION AND EATING
DISORDERS
Research into the interaction between food addiction and eating
disorders (EDs), specifically binge eating disorder (BED) and
bulimia nervosa (BN), has led to conclusions of separate but
related constructs. In one study of individuals with BN, 96%
met criteria for FA (244). It has been proposed that those
who meet criteria for BN should be separated into distinct
subtypes: hyporesponsive to reward (akin to anorexia nervosa)
and those with hypersensitive reward circuitry (akin to FA)
(256). Approximately half of BED patients meet criteria for FA
(257). Overlapping mechanisms include reward dysfunction and
impulsivity and unique features for BED include dietary restraint
and shape/weight concerns (258).
The biggest gap in our understanding of the interaction
between FA and EDs is the restrictive eating component. There
are many detractors of the FA hypothesis from the ED treatment
community who argue that dieting (also referred to as restrained
eating) is what causes elevated scores on the YFAS. It has
also been argued that the role played by ingested substances is
nonspecific meaning that they apply to EDs as well (259). Future
research should control for restrained eating, which has not been
adequately done. So, it is not surprising that high prevalence of
FA occurs in the underweight category (248,260) and normal
weight category in the case of BN (261). Recently investigators
have suggested that FA data can be incorporated into the case
conceptualization of EDs from a trans-diagnostic perspective
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Wiss et al. Sugar Addiction
(262,263). Conclusions suggest giving more consideration to the
impact of highly palatable foods for some people seeking ED
treatment. A few studies have linked FA and SUD (264,265) but
additional research should be conducted on individuals with SUD
in order to further understand how eating behaviors can progress
throughout the recovery process. Interaction effects between FA,
SUD, and ED have not yet been adequately described.
SUGAR AND OBESITY
Considerable controversy exists with respect to sugar intake and
obesity (266). There is general consensus indicating that sugar
(sucrose, fructose) is not a direct cause of obesity (267,268),
however, other studies have linked sugar-sweetened beverages
(SSB) to an increase in body weight in children and adults
(269,270). Several reasons are offered to explain this discrepancy,
but somehow SSB appears to be a special case. First, it is possible
that liquid calories are not compensated by a total decrease in
energy intake. Second, ingestion of SSB might be an indicator of
unhealthy lifestyle (266). None of these studies have linked SSB to
sugar addiction so we cannot adequately assess the direct impact
of compulsive SSB consumption on body weight.
Nutrition transition theory proposes that “with economic
development populations shift from minimally processed diets
rich in staple food of vegetable origin to diets high in meat,
vegetable oils, and processed foods” (271). As mentioned,
this transition in diet is coupled with the obesity epidemic
observed in developing countries (272,273). Research shows
that several developing countries in Asia are shifting their diets
to preferentially processed foods and carbonated soft-drinks as
the main “product vector” for sugar intake (271). Similarly, a
shift from minimally processed foods to ultra-processed (more
added sugar, more saturated fat, more sodium, less fiber) food has
been seen in Brazil (33). Both studies condemned ultra-processed
food as an important culprit in the obesity epidemics and ask
policy-makers to include legislation and “regulatory approaches”
to minimize the impact on health. This approach must be parallel
to education programs.
POLICY IMPLICATIONS
While ecological approaches targeting global nutrition policy
appear promising, agricultural systems remain directed by
multibillion-dollar multinational food corporations rather than
by governments. It is difficult to predict how emerging data
on FA can impact policy, particularly given that corporations
have fiduciary responsibilities to their shareholders which require
them to maximize profits and may compromise other social and
ecological goals (274). Some public health experts propose that
we will need to address food corporations similarly to how the
tobacco industry was addressed in recent years, with interdiction
and litigation (275). It remains unclear how an understanding of
FA will translate to behavior change, however, a recent survey
suggests that framing certain foods as addictive may increase
obesity-related policy support such as warning labels, similar to
tobacco (276). Other researchers believe that sugar addiction is
too narrow and therefore still premature, warning against policy
changes that are unlikely to have an impact since sugar is already
so ubiquitous in the food supply (253).
The FA theory directly implicates the food industry, while the
nutrition transition theory implicates other global industries also
potentially negatively impacting our environment. We propose
that the FA framework can lead to improved health outcomes but
are more likely to be more pronounced in socially advantaged
groups, given barriers created by socioeconomic status. Many
public health interventions focused on obesity aim to reduce
disparities between groups, which we believe can also have a
meaningful impact on long-term health outcomes. Given the
evidence reviewed herein, we make the case for sugar addiction
in the animal model. Overlooking these findings will represent
a missed opportunity for obesity-related policy and a potential
public health revolution. Potential treatment strategies for FA
have been reviewed elsewhere (277). A commentary on the
necessity as well as potential downsides of the food addiction
model was published previously (278).
CONCLUSION
The FA framework for understanding obesity is the notion
that highly processed “hyperpalatable” foods have hijacked the
reward centers in the brain thus impairing the decision-making
process, similar to drugs of abuse. The major assumption is
that biochemistry drives behavior. The sugar addiction theory
bridges current gaps between food science and neuroscience, and
between nutrition and psychology. This theory was originally
developed from animal studies, however there is no shortage of
compelling human data. While FA has been sensationalized in
the popular press with headlines such as “Oreos More Addictive
Than Cocaine?” we propose that processed FA in humans is much
more like caffeine or nicotine addiction than it is like cocaine or
heroin. There is a subtlety to food addiction where a significant
majority of the people who meet criteria may not be aware of
it, likely because it is not widely accepted as a social norm.
Meanwhile, there have been non-clinical recovery movements
of self-identified “food addicts” dating as far back as 1960 when
Overeaters Anonymous was formed.
A seminal paper by Glass and McAtee envisioned a future for
public health which integrates the natural and behavioral sciences
with respect to the study of health. Their multilevel framework
extends the “stream of causation” to include both social and
biological influences. The authors use the term “embodiment” to
describe the “sculpting of internal biological systems that occurs
as a result of prolonged exposure to particular environments”
(279). These authors propose that next-generation models focus
on how social environments affect the organism (human) which
will affect the organs, cells, sub-cellular, and molecular levels,
and how these will provide feedback at multiple levels. They
argue that while social factors act as mediating risk regulators,
explanations of obesity must incorporate the biological substrate:
“whatever has changed in the environment that has led to
exponential expansion in population body weight, must be
conspiring with epigenetic and psychophysiological factors.
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Wiss et al. Sugar Addiction
Eating behavior is an example of a phenomenon that results from
synergistic interactions among biological (hunger) and social
(eating cues) levels” (279).
To date the YFAS is the only validated measure to
evaluate addiction-like eating. While there are over 100 original
research studies using the YFAS and the tool has undergone
several iterations (now YFAS 2.0), brain imaging studies in
humans remain somewhat limited, and a gap remains between
psychological assessment and reward-related brain circuitry.
More importantly, FA research has not been able to account for
all of the social factors (e.g., income, education, access, culture)
that contribute to food consumption patterns. Additionally, FA
is not limited to obesity, as this construct has been extended to
non-obese populations which makes causal inference difficult to
assess. Much of the appetite-related research does not include the
term “food addiction” likely due to the cultural stigmas associated
with addiction.
Finally, there is strong evidence of the existence of sugar
addiction, both at preclinical and clinical level. Our model has
demonstrated that five out of eleven criteria for SUD are met,
specifically: use of larger amounts and for longer than intended,
craving, hazardous use, tolerance, and withdrawal. From an
evolutionary perspective, we must consider addiction as a normal
trait that permitted humans to survive primitive conditions
when food was scarce. As we evolved culturally, the neural
circuits involved in addictive behaviors became dysfunctional
and instead of helping us survive they are in fact compromising
our health. From a revolutionary perspective, understanding
the molecular, and neurological/psychological intricacies of
addiction (sugar, drugs of abuse) will permit the discovery
of new therapies (pharmacological and non-pharmacological)
and possible management of at least one crucial factor in the
occurrence of obesity.
AUTHOR CONTRIBUTIONS
All authors listed have made a substantial, direct and intellectual
contribution to the work, and approved it for publication.
FUNDING
This work is funded by Kildehoj-Santini (NMA).
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