Psychedelics as a Potential
Treatment Option in ADHD
Semester 6, 2020
Supervisor: Michiel Vellema
Psychedelic drugs have recently gained popularity among both recreational and scientific
communities, and some preliminary research suggests they show promising results when used
clinically. Microdosing, which features the use of sub-threshold doses to achieve therapeutic
effects rather than a “trip”, may also lead to significant improvements in some psychological
disorders. One such disorder, which this paper considers in detail, is ADHD - a rather prevalent
and persistent dysfunction in attention, impulsivity and excessive motor activity. The aim of the
paper is to review the, unfortunately still scant, evidence considering microdosing psychedelics
for the treatment of ADHD. Indeed, preliminary evidence points to psychedelic microdosing’s
beneficial effects on ADHD patients, and even mentions some who have voluntarily and
successfully switched their stimulant medication with psychedelic microdoses. The paper also
found theoretical matches between dysfunctional neural mechanisms and behavioral
manifestations in ADHD and the subjective and neural effects of psychedelics. Microdosing
these substances may even be safer and possibly more effective than both macrodosing them,
and current ADHD medication. The paper concludes that rigorous research on psychedelics’
effects on brain and behavior, as well as their application to the treatment of ADHD is warranted,
but also necessary to draw any firm conclusions about microdosing’s relevance.
ADHD, psychedelics, classical psychedelics, LSD, DMT, psilocybin, macrodosing,
microdosing, fronto-striatal regions, limbic system, basal ganglia, cognition, emotion
Chapter I. Attention Deficit Hyperactivity Disorder (ADHD) 5
1.1 Neural mechanisms of ADHD 6
1.1.1 Structural brain impairments in ADHD 6
1.1.2 Functional brain impairments in ADHD 8
1.1.3 Neurotransmitter systems involved in ADHD 11
1.2 Treatments for ADHD 12
Chapter II. Psychedelics as a Potential Alternative Treatment 15
2.1 Neural Mechanisms of Psychedelics in Relation to ADHD 16
2.1.1 Structural brain effects of psychedelic drugs 16
2.1.2 Functional brain effects of psychedelic drugs 17
2.1.3 Neurotransmitter systems involved in psychedelics 19
2.2 Research into macrodoses of psychedelics 21
2.3 Safety of psychedelic macrodoses 22
Chapter III. Microdosing Psychedelics as a Potentially Safer Route to Psychedelic
Treatment for ADHD 24
3.1 Research into microdoses of psychedelics 26
3.2 Anecdotal and preliminary experimental evidence of microdosing for ADHD 28
3.3 Safety of psychedelic microdoses 31
Attention Deficit Hyperactivity Disorder (ADHD) is one of the most prevalent disorders
worldwide, starting around age 5 and continuing well into adulthood (DSM-V, 2013; National
Institute of Mental health, 2017). It affects patients’ ability to function efficiently in everyday
life, to pay attention and be productive in academic and work settings, and maintain
goal-directed motivation (DSM-V, 2013). In addition, cognitive disturbances in terms of
attention and memory, as well as emotional and mood disruptions, and impulsivity are involved
(DSM-V, 2013). Current pharmacological medications for ADHD, although effective for
addressing the symptoms of the disorder, have a lot of unpleasant side effects (Meijer et al.,
2009) which are not always tolerable for all patients. Thus, alternative medications or treatment
options are warranted, and the current paper proposes one such option in the face of psychedelic
The aim of this paper is to compile a review of the possible utilization of psychedelics for
the treatment of ADHD. More specifically, the research question this paper will consider is
whether psychedelics are a viable treatment option for ADHD and whether microdosing these
substances should be considered in this disorder. The paper will focus on one sub-class of
psychedelics, called classical psychedelics, which includes lysergic acid diethylamide (LSD),
n,n-dimethyltryptamine (DMT), and psilocybin. It includes research done on all of these classical
psychedelics, as they work through almost identical mechanisms in the brain. Because research
on the use of psychedelics as a medicine for ADHD is limited, a more indirect route is taken to
answer the research question. The paper starts by reviewing ADHD, focusing mainly on its
relevant neural and chemical mechanisms, and briefly considers its current treatments, as well as
the need for development of new treatment options. Then, it discusses psychedelics as a possible
alternative treatment for ADHD, considering possible connections between them in terms of
their subjective effects, as well as their mechanisms of action in the brain. The paper argues for a
correspondence between the neural deficits experienced by ADHD patients and the brain
mechanisms of psychedelic drugs in general. It also considers some research conducted on
patients, as well as some of the potential concerns of psychedelic macrodoses. Following the
discussion on safety, the paper introduces the concept of psychedelic microdosing as a
potentially safer route of administering psychedelics that greatly limits the possible negative
outcomes of macrodoses. Finally, the paper discusses some preliminary evidence from
microdosing on both healthy participants and ADHD patients, which might suggest a role of
these substances in treating the disorder.
Chapter I. Attention Deficit Hyperactivity Disorder (ADHD)
Attention deficit hyperactivity disorder (ADHD) is defined in the Diagnostic and
statistical manual of mental disorders (DSM-V, 2013) as a neurodevelopmental disorder that
features “a persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with
functioning or development” (DSM-V, 2013, p.59). Inattentive symptoms may include having
difficulty focusing and maintaining attention on tasks, being easily distracted or forgetful, being
neglectful of details and having difficulty organizing work or belongings (American Psychiatric
Association, 2017). On the other hand, hyperactivity-impulsivity can manifest itself as frequent
fidgeting, running or climbing, feeling restless and having difficulty staying seated, excessive
talking, and frequent interruption of others (American Psychiatric Association, 2017). The DSM
also stresses that in order to be characterized as part of ADHD, the symptoms must directly
interfere with one’s social activities or daily functioning at school and/or in the workplace.
Symptoms of inattention or impulsivity should not be limited to only one setting, such as only at
home or only when surrounded by peers, to exclude any context-dependent causes. In addition,
the symptoms presented should not be merely the expression of developmentally normative
opposition or inability to carry out or process cognitive tasks. It is also important to note that
typically, ADHD is associated with some form of impairment of cognitive or academic
performance, learning and memorization, and executive functioning,as well as some delays in
cognitive and motor development (DSM-V, 2013). However, these should not stem from another
learning or mood disorder.
ADHD is a prevalent disorder, and according to the DSM-V, 5% of children and 2.5% of
adults suffer from ADHD worldwide (DSM-V, 2013). It is important to note however, that
despite these estimates, many researchers express their frustration at the DSM criteria for ADHD
diagnosis, and blame it as a reason for the underestimation of the prevalence for adult ADHD.
Indeed, the disorder typically begins in childhood, with an age of onset between 4 and 7 years of
age (National Institute of Mental health, 2017), and some symptoms must be present before the
age of 12 for a formal diagnosis of ADHD (DSM-V, 2013). However, despite ADHD being most
prevalent amongst children and adolescents, with the symptoms gradually lessening with age,
this does not necessarily mean that they disappear altogether and that adults with ADHD are not
impaired. In fact, about a third of all children with ADHD maintain the disorder into adulthood
(National Institute of Mental health, 2017). In adults, motor and hyperactivity symptoms are
usually not present, however cognitive impairments such as difficulties with planning, attention
and impulsivity endure (DSM-V, 2013).
1.1 Neural mechanisms of ADHD
1.1.1 Structural brain impairments in ADHD
ADHD is a neurodevelopmental disorder, and its behavioral manifestations are caused by
underlying structural deficits in dispersed brain areas, mainly in frontal regions and the basal
ganglia (Rubia et al., 2014). The frontal cortex is mainly involved in higher-order functions such
as attention and working memory, learning and motivation, as well as planning and
decision-making (Buchsbaum, 2004), which seem to be impaired in ADHD. The basal ganglia,
on the other hand, is mostly involved in behavioral and motor control, as well as in planning and
controlling movement and learning (Aghoghovwia, 2020), which might contribute to the
hyperkinetic and impulsive behaviors seen in ADHD patients. A review of MRI studies in
children with ADHD found converging evidence from the literature that children suffering from
the disorder have significantly smaller brain volume globally, including reductions in the size of
the frontal and prefrontal cortex, and the basal ganglia (especially the caudate nucleus and the
putamen) (Krain and Castellanos, 2006). Brain volume seems to be correlated with severity of
ADHD symptoms, as smaller sizes increase symptoms of inattention or hyperactivity
(Castellanos et al., 2002). The prefrontal cortex (PFC) in particular is considered the center for
executive control of behavior, cognition and emotion, and is also involved in more complex tasks
like reasoning and adhering to social norms (El-baba and Schury, 2020). The caudate and the
putamen, are also more specifically involved in learning and goal-directed behavior, with the
caudate being responsible for more flexible and adaptable behavior, while the putamen plays a
role in simpler habits and stimulus-response associations (Grahn et al., 2008). Impairments in
these regions may contribute to the learning and self-control difficulties encountered by ADHD
patients. Diffusion tensor imaging (DTI) studies also show structural connectivity abnormalities
in fronto-striatal and fronto-parietal white matter tracts in both adults and children (Rubia et al.,
2014). Albeit limited, evidence from DTI studies points to an overall reduction in the volume of
white matter in ADHD patients, which can be seen in a wide network of brain areas, including
frontal and basal ganglia regions (like the striatum and caudate), the PFC and parietal areas
(Konrad and Eickhoff, 2010). Some researchers also suggest that since white matter
abnormalities are mostly seen in neural circuits which usually develop late, this dysfunction in
structural connectivity may reflect a maturational delay in ADHD patients (Rubia et al., 2014),
however this idea still needs to be researched more.
In addition, longitudinal studies point to the fact that ADHD features a delay of about 2
to 5 years in structural brain development, especially in the cortical thickness and surface area of
frontal and parietal regions, among others (Rubia et al., 2014). This is presumably connected to
the delay in neuronal branching, followed by a delay in pruning and myelination in ADHD
(Rubia et al., 2014). The parietal cortex is involved in sensory processing, as well as in allocating
attention to certain sensory stimuli, and spatially localizing them (Culham and Kanwisher, 2001).
Impairment of these functions is likely to lead to inattentive or impulsive symptoms, as seen in
ADHD patients. Structural deficits in prefrontal cortex and parietal regions seem to persist in
adulthood (Cubillo and Rubia, 2010), although basal ganglia abnormalities generally normalize
with age (Rubia et al., 2014). Overall, there appears to be a delay in the maturation and
development of the brain in ADHD patients, with some cognitive functions taking longer to
develop compared to healthy controls. These “lags” seem most pronounced in frontal regions
(Cubillo and Rubia, 2010), which are associated with exerting conscious control over other brain
functions, including response inhibition, foresight into the future, and self-regulation
(Buchsbaum, 2004; Berger et al., 2013). Frontal lobe functions usually develop later in
adolescence in healthy people, however in ADHD patients, this “natural lag” is delayed even
further, and these important control functions take even longer to fully mature (Berger et al.,
2013). It has been suggested that structural delays and disruptions in brain circuits in ADHD may
be linked to genetic factors involved in the disorder (Konrad and Eickhoff, 2010).
1.1.2 Functional brain impairments in ADHD
ADHD also features deficits in relevant neural functions, such as executive functioning,
inhibition of response, and motivation to avoid delay (Krain and Castellanos, 2006). More
specifically, ADHD is thought to primarily manifest itself in deficits in the so-called “cool”
executive functions, which include response inhibition, maintenance and redirection of attention,
and working memory (Rubia et al., 2014). In contrast to “cool” functions, ADHD also features
dysfunctions in “hot” executive functions, including reward processing and motivation (Rubia et
al., 2014). This classification of the deficits suggests that both top-down and bottom-up functions
are involved in the disorder (Sergeant et al., 2003), which correspond to the “cool” and “hot”
categories of Rubia et al. (2014).
Research suggests that deficits in “cool” functions could be linked to dysfunctions in
dispersed areas in the brain, including the frontal and parietal cortex, and the basal ganglia
(Sergeant et al., 2003; Rubia et al., 2014). Attention tasks in adults with ADHD reveal that they
seem to engage the left inferior and dorsal prefrontal cortices (PFCs) less strongly than healthy
controls (Cubillo and Rubia, 2010). Meta-studies confirm the reduced activity in parietal and
prefrontal regions in attentional tasks, and also show lower activity in the posterior basal ganglia
(Rubia et al., 2014). As for working memory tasks, ADHD adults had less activity in the inferior
prefrontal and also in parietal regions (Cubillo and Rubia, 2010). Studies on impulsivity via
timing tasks point to a decreased activation in the left timing network, which spans the left
inferior frontal cortex and left parietal lobe, among others (Rubia et al., 2014). This study also
found that ADHD causes increased activation in the posterior cingulate cortex (PCC), which is
part of the brain’s default mode network (DMN). Other researchers also argue for the addition of
impairments in the DMN as a specific deficit in ADHD patients (Castellanos and Proal, 2012).
The DMN represents a widely distributed set of interconnected brain regions, including the
ventral and dorsal medial PFC, the PCC and the precuneus, which seem to be involved in “doing
nothing” and are most active when at rest (Raichle, 2015). Their activity also seems to decrease
when performing a task, and thus the DMN is thought to be involved in self-referential thinking
and to represent the baseline activity of the brain (Raichle, 2015). In addition, the different brain
areas that comprise the DMN play an important role in connecting different cortical regions and
thus allow for fast and efficient communication between neurons (Carhart-Harris et al., 2012).
Heightened activity in these brain areas is usually associated with negative outcomes, such as
depression, anxiety and pessimism (Carhart-Harris et al., 2012), as well as lack of concentration
and fewer cognitive resources for carrying out tasks (Lebedev et al., 2015). Increased activity in
the DMN in ADHD patients might contribute to excessive mind wandering, and thus, deficits in
attention (Bozhilova et al., 2018).
“Hot” executive functions, like motivational and reward processing, are thought to
represent more “bottom-up” processes and involve different brain regions than “cool” functions -
namely, they rely on limbic and paralimbic structures. The limbic system is mainly involved in
emotion response and regulation, social cognitions, and memories, especially those associated
with emotions (Rajmohan and Mohandas, 2007). It comprises many distinct brain areas, but
those more specifically proposed to be involved in ADHD are the amygdala and its connections
to the orbitofrontal cortex (OFC), contributing to the impaired social cognitions and behavior
seen in patients (Rajmohan and Mohandas, 2007). In addition, hippocampal changes in terms of
an increased volume, are also present in ADHD patients, and may reflect deficits in memory and
learning (Rajmohan and Mohandas, 2007). Meta-studies confirm that for these types of “hot”
functions, both adults and children with ADHD tend to show dysfunctions especially in the
striatum, amygdala, and the OFC (Rubia et al., 2014). Several other functional MRI studies have
found lower activation of the ventral striatum in ADHD patients and some ROI research points
to the role of the OFC and the limbic system, however these results are not confirmed by
whole-brain analyses (Rubia et al., 2014). Studies on another arguably “hot” function, emotion
processing, suggest hyperactivity of the amygdala and left PFC in ADHD patients, however the
results in the literature are inconsistent (Rubia et al., 2014).
Research has also demonstrated that there are differences in functional connectivity in
patients with ADHD, which suggests that rather than having dysfunction in isolated brain areas,
ADHD patients have impairments in more widespread networks (Rubia et al., 2014). During rest,
there appears to be reduced communication between hubs of the DMN, especially between the
anterior cingulate cortex (ACC) and the PCC (Rubia et al., 2014). ADHD patients also seem to
have reduced functional connectivity both within DMN regions and between the DMN and
fronto-parietal circuits (Bozhilova et al., 2018). As also mentioned above, dysfunctions in the
DMN may contribute to inability to concentrate one’s attention on particular stimuli due to
excessive mind wandering (Bozhilova et al., 2018). During response inhibition and working
memory tasks, there also appears to be reduced activity between regions in the inferior frontal
cortex and the basal ganglia, the PFC and ACC, and parietal regions (Rubia et al., 2014; Konrad
and Eickhoff, 2010). It is also possible that deficits in functional connectivity in ADHD patients
correspond to a maturational lag in brain development, and thus are similar to activity levels seen
in younger healthy people (Konrad and Eickhoff, 2010). This theory, however, has not been
EEG studies report differences in theta and beta brain waves between ADHD and healthy
controls. Theta waves are part of the slow-activity of the brain and are seen mostly when one is
feeling drowsy, is detached from the external world and is focused inward, while beta waves
correspond to a more heightened activation and are present when one is active, attentive, and
engaged with external stimuli (Brainworks; Abhang et al., 2016). A recent review of the ratio
between theta and beta waves in the EEG signal (the theta/beta ratio, or TBR) in ADHD patients
revealed that even though this may not be a reliable measure for diagnostic purposes, a large
proportion of ADHD patients do have problems in their TBR (Arns et al., 2013). The review
pointed out the numerous studies that have found an increased contribution of theta waves to the
EEG signal in children with ADHD, and another EEG study confirmed this and further
associated this change in activity with an accompanying decrease in beta activity (Clarke et al.,
2003). Thus, these differences in brain waves may offer an explanation of the ADHD brain as
continuously hypoaroused (Koehler et al., 2009; Clarke et al., 2003). One of the most popular
ADHD medications, methylphenidate, has been shown to specifically decrease the contribution
of theta waves to the EEG signal in ADHD patients (Kenemans, 2020). In fact, it has been
proposed that methylphenidate’s therapeutic efficacy is correlated with how much of a decrease
in theta waves there is after administering this medication. Some studies show that the higher the
theta activity in a certain subgroup of individuals with ADHD is prior to treatment, the better the
clinical response of these people to methylphenidate will be (Kenemans, 2020). This may seem
paradoxical at first, but suppressing theta waves from cortical areas (signals from which are
measured by EEG) which are already involved in inhibition and control of other brain areas, will
only increase the inhibition and ultimately result in decreased activity (Kenemans, 2020).
Moreover, this may be accompanied by an increased voluntary control over behavior, as
stimulants support the action of higher-order cortical areas for the control of brain and behavior.
1.1.3 Neurotransmitter systems involved in ADHD
Some research also points to the involvement of dopamine in ADHD and proposes that
dopamine dysfunctions play a role in the lack of motivation and reward anticipation seen in
ADHD (Tripp and Wickens, 2009). Indeed, dopamine has important functions in learning and
memory, especially as pertaining to motivated goal-directed behavior (Wise, 2004) and learning
with reinforcement (Tripp and Wickens, 2009). More specifically, dopamine acts to “mark”
neutral stimuli as important following a rewarded response to them, which in turn enhances
motivation for this behavior and is able to create a habit. Dopamine does not only play a role in
the learning of associations, but also for memorizing them (Wise, 2004). Thus, it is possible that
any dysfunction in this system would likely cause ADHD-like symptoms. Tripp and Wickens
(2008) even proposed the so-called dopamine transfer deficit (DTD) theory of ADHD, which
proposed that ADHD may arise from an altered sensitivity to reward. According to the theory, in
an early learning phase when there is a cue predicting reinforcement for a neutral stimulus,
dopamine cells fire in response to the stimulus and this dopamine response is transferred to the
cue that predicts this reinforcement. In this way, the person learns to associate the cue with the
later reward, so in a later learning phase, dopamine cells would fire in response to the cue only.
However, in patients with ADHD, this transfer of the dopamine signaling from the rewarding
stimulus to the cue predicting is impaired. This culminates in a delayed reinforcement, leading to
difficulty learning (Tripp and Wickens, 2008). In addition, dopamine also has motor functions,
including learning of motor skills, execution of movements and the formation of motor memories
(Molina-Luna et al., 2009). Given the motor symptoms of ADHD, although those are generally
decreased in adulthood, psychedelics might be beneficial in relieving excessive movements and
hyperkinetic symptoms in patients.
Another monoamine, norepinephrine, has also been implicated in the disorder, and
evidence from both animal and human studies point to the possible causal role of norepinephrine
in ADHD (Oades, 2005). Norepinephrine may be involved in motor hyperactivity, attention, and
other cognitive mechanisms (Oades, 2005), so it is conceivable how dysfunctions in this
neurotransmitter system can lead to ADHD symptoms. Other research has pointed out the
possible involvement of serotonin in ADHD as well (Oades, 2007). Although there is limited
research in serotonin dysfunctions in ADHD, serotonin does have functions in motor activity,
impulsivity and attention, for example by attributing an appropriate level of importance to
stimuli (Oades, 2007). Dysfunction in serotonin transporters has been suggested as an underlying
cause of some ADHD symptoms (Oades, 2008). It is also possible that serotonin and dopamine
systems interact in ADHD by directly affecting the receptors at the neurons, or indirectly via
intermediate neurons (Oades, 2008).
1.2 Treatments for ADHD
The first-line of treatment for ADHD is pharmacological, and usually consists of
stimulant medication, such as methylphenidate (Ritalin) or amphetamines (Adderall) (National
Institute of Drug Abuse, 2014). These medications are thought to exert their therapeutic effects
by blocking dopamine and norepinephrine reuptake and in turn, increasing activity in
fronto-striatal regions (Epstein et al., 2007). Both acute and chronic administration of stimulants
seems to be associated with neuroprotection and normalization effects of the activity of the
inferior frontal cortex and the striatum (Rubia et al., 2014). In addition, structural deficits, such
as cortical thickness and volume, are also increased through stimulants (Rubia et al., 2014),
which may act to further diminish symptoms. An imaging study using functional MRI compared
the effects of methylphenidate on a response inhibition task in ADHD, as compared to healthy
participants (Epstein et al., 2007). ADHD children on methylphenidate showed enhanced
behavioral responses, as well as a widespread increase in activation across the left inferior and
middle frontal gyrus, the inferior parietal lobule, the ACC, the cerebellum and the caudate
nucleus (Epstein et al., 2007). ADHD adults, on the other hand, did not have increased activation
in frontal regions, but still showed increased activity in the caudate nucleus. Interestingly, there
was a decrease in activity in ADHD adults compared to controls in the inferior parietal lobule
and the middle frontal gyrus (Epstein et al., 2007). Thus, it appears that methylphenidate is a
beneficial medication for children with ADHD, but may not be that effective in adults. This is
also supported by the apparent normalization of the TBR in ADHD with increasing age (Koehler
et al., 2009), which seems to be an important factor for the therapeutic efficacy of
methylphenidate (Kenemans, 2020). Pharmacotherapy, or a combination of pharmacological and
psychotherapeutic treatments seems to be the first-line treatment of ADHD in adults (Rostain
and Ramsay, 2006. The authors argue that psychostimulant medication can be likened to a
“bottom-up” mechanism of treatment, as it targets mainly to symptoms, whereas psychotherapy,
for example cognitive behavioral therapy (CBT) is more “top-down”, as it targets underlying
functional deficits and requires active participation from the patient (Rostain and Ramsay, 2006).
Combining these two approaches provides the patient with a supportive framework in which to
explore, identify and work on managing their issues (Rostain and Ramsay, 2006).
Stimulant medication also seems to be very effective for short-term treatments and reduce
core symptoms of ADHD in about 70% of patients, as well as behavioral responses (Rubia et al.,
2014). Nevertheless, meta-analyses of longitudinal studies have shown poor efficacy of chronic
stimulant administration, which is confirmed by neurochemical findings of increased dopamine
transporters in these patients (Rubia et al., 2014). This may lead to the brain adapting to the
stimulant medication and eliciting a structural modification of brain areas which were
continuously activated by these substances (Rubia et al., 2014) and thus, its beneficial effects
may decrease over time. For example, a Multimodal Treatment Study of Children with ADHD
showed that after 24 months, ADHD children treated with methylphenidate still showed
improvements, but they were smaller than 10 months ago. At 36 months, medication-related
differences were no longer evident (Meijer et al., 2009). However, these differences in
effectiveness may have arisen because after the 14th-month mark, the study became
observational and participants could choose and manage their own medications. This may have
caused a reduction in adherence to and thus, effectiveness of, the treatment. It is also important
to keep in mind that stimulants do not cure ADHD, but merely treat the symptoms associated
with it, which may lead to long-term use of and dependence on these medications (Meijer et al.,
2009). In addition, treatment with stimulant medication may have unwanted side effects in
children, such as loss of appetite, height and weight reductions, sleep problems and insomnia.
Less frequently, stimulants may increase blood pressure and heart rate, which in turn might
aggravate pre-existing cardiovascular issues. Moreover, suicidal ideation may also be a potential
side-effect of psychostimulant medication (Meijer et al., 2009). Adults seem to show similar
adverse effects, including headaches, decrease of appetite and insomnia (Meijer et al., 2009). In
up to 30% of ADHD patients, stimulant medication either does not have the desired effect, or the
side effects can not be tolerated (Banaschewski et al., 2004). Therefore, although current
pharmacological treatments are effective, alternative medications for ADHD are warranted.
Chapter II. Psychedelics as a Potential Alternative Treatment
Macrodoses of psychedelic drugs can refer to a wide range of doses, all of which are
above the threshold for a psychedelic “trip.” This is usually the intended effect of ingesting
psychedelics, and so macrodosing is the most popular way to administer these substances. These
macro, or supra-threshold, doses can produce various perceptual, emotional and cognitive
effects, and these vary with the exact dose taken, as well as other factors (Swanson, 2018).
Perceptual effects may include sensory intensification, open and/or closed-eye visual
hallucinations, auditory hallucinations, and altered somatosensory perception. Psychedelic use
may also induce intense emotional effects, which are usually positive and often characterized by
euphoria, uncontrollable laughter and a sense of empathy and connectedness. Generally,
psychedelics broaden one’s emotional spectrum and increase conscious access to and control of
emotional states. ADHD patients also suffer from some emotional dysfunction, mainly
connected to their emotional control and impulsivity. Thus, psychedelics might be able to help in
this domain and increase patients’ affective self-control. Changes in cognition include a
disruption of linear thought patterns and increases in creativity, unusual associations and
attribution of meaning to stimuli. These substances are also associated with cognitive flexibility,
openness and problem-solving, which seem to persist for some time after the experience is over
(Swanson, 2018). There appears to be a link also between the subjective cognitive effects of
psychedelics and the symptoms experienced in ADHD. Therefore, psychedelics seem promising
to help patients restore some of their cognitive functions. High doses of psychedelics may also
act to “transport” the user in an alternate dimension, accompanied by a feeling of not being in
one’s body (Nichols, 2016). This is connected to the so-called ego dissolution or ego death
experiences, which include a loosening of the boundaries between oneself and everything else.
These experiences are usually connected to positive clinical outcomes (Swanson, 2018). Lower
doses also affect the ego, and may act as to increase insight into one’s patterns of cognition,
behavior, and emotion (Swanson, 2018). Increasing insight into one’s own dysfunctional thought
and emotional patterns might help patients with ADHD deal better with their disorder, and may
aid them in leading a more functional life.
2.1 Neural Mechanisms of Psychedelics in Relation to ADHD
2.1.1 Structural brain effects of psychedelic drugs
Psychedelic drugs can affect gene expression by activating certain genetic sequences. In
this way, these substances are able to produce more long-lasting and structural changes in the
brain (Ly et al., 2018; Nichols and Sanders-Bush, 2002). This stands in contrast to stimulants’
weak effects in the long-term (see ex: Meijer et al., 2009). In addition, the structural deficits seen
in ADHD may arise because of genetic factors affected by the disorder (Konrad and Eickhoff,
2010), so the effects of psychedelics on promoting the expression on certain gene sequences may
be beneficial in counteracting these deficits. For example, long-term use of DMT has also shown
structural changes in the brains of psychedelic users expressed in terms of an increased cortical
thickness in the ACC, and a decreased cortical thickness in the PCC (Bouso et al., 2015). The
ACC is involved in attention and cognitive control, so greater cortical thickness there might
suggest an enhancement of cognitive function. The PCC, on the other hand, is part of the DMN
and is responsible for directing one’s attention inwards, so decreased cortical thickness in this
region would also suggest potential benefits. The ACC is reported to have reduced volume in
ADHD patients (Rubia et al., 2014), so psychedelics’ ability to increase ACC volume may
counteract some of the symptoms of the disorder.
Some research has found that psychedelics are able to increase the expression of
brain-derived neurotrophic factor (BDNF), which supports neurons’ growth and differentiation,
as well as dendritic growth (Ly et al., 2018). Altered BDNF activity may also be implicated in
the development of ADHD, as it leads to impairment in the dopaminergic system (Bergman et
al., 2011). Thus, BDNF restoration might be a possible mechanism for psychedelics to exert
therapeutic effects in ADHD patients. In addition, chronic administration of LSD was able to
increase the transcription of immediate-early genes that promote neural plasticity, including the
genes, the NOR1
transcription factor, and the gene coding for the arc
(Nichols and Sanders-Bush, 2002). Most of the genetic changes associated with psychedelics are
involved with neural plasticity and changing neuronal structure (Ly et al., 2018). For example,
gene and the arc
protein have an important function in brain development, synaptic
plasticity and long-term potentiation (Nichols and Sanders-Bush, 2002). A study by Ly et al.
(2018) demonstrated that like amphetamines, psychedelics are also able to promote structural
plasticity and increase the number of dendritic spines of neurons in the PFC. Unlike
amphetamines, however, psychedelics are capable of also increasing the density of dendritic
spines of PFC neurons. ADHD patients, who also suffer from reduced gray and white matter in
frontal and prefrontal regions, as well as a maturational delay in the PFC, may be positively
aided by treatment with psychedelic substances.
2.1.2 Functional brain effects of psychedelic drugs
Brain imaging studies reveal that administration of psychedelics acts to decrease activity
in certain brain areas, especially those high in 5-HT2A receptors. Several studies report more
complex actions of these drugs in that they are able to recruit various types of cells after
activating excitatory cells with 5-HT2A receptors, including inhibitory interneurons and glial cells
(Martin and Nichols, 2016). These cell populations are usually found in the medial PFC and the
somatosensory cortex (Martin and Nichols, 2016). Frontal and parietal regions are also involved
in ADHD dysfunctions (see ex: Sergeant et al., 2003; Rubia et al., 2014), so psychedelics’ action
in those brain areas might be of relevance for the disorder. Psychedelics may specifically act on
the cortio-striatal-thalamic-cortical (CSTC) feedback loops, which are especially involved in
learning, memory and the gating of sensory information (Vollenweider, 2001). The CSTC spans
frontal, striatal and other basal ganglia structures, which appear to be impaired in ADHD (see ex:
Sergeant et al., 2003; Rubia et al., 2014). The CSTC itself has also been suggested to be
implicated in ADHD, as it is involved in executive functions, and in regulating both cognitive
and emotional responses (Zhu et al., 2018). Since the CSTC consists of both frontal and basal
ganglia structures, it is involved in both “cool” and “hot” executive functions (Zhu et al., 2018;
Rubia et al., 2014). The fact that psychedelics specifically target the CSTC might suggest that
these substances may be able to provide relief from both categories of symptoms (“cool” and
“hot”) and thus, treat ADHD more holistically. Several studies also suggest that psychedelics are
able to affect limbic regions, such as the amygdala and the hippocampus, where they generally
act to diminish activation (Kyzar et al., 2017; Vollenweider and Kometer, 2010). More
specifically, decreases in amygdalar activity induced by psychedelic substances reduce fearful
reactions from negative stimuli (Mueller et al., 2017; Kyzar et al., 2017), and may be beneficial
in treating mood disorders (Vollenweider and Kometer, 2010; Kraehenmann et al., 2015).
ADHD patients also show dysfunctions in limbic regions, especially the amygdala, as pertaining
to the “hot” executive functions (see ex: Rajmohan and Mohandas, 2007; Rubia et al., 2014).
The disorder is thought to feature a hyperactivated amygdala (Rubia et al., 2014), which might
be normalized by psychedelic substances which are reported to decrease activity of these regions.
Other studies by Vollenweider have found that psilocybin increases activation of frontal regions,
including the ACC, the inferior and superior parietal cortices, and the striatum (Vollenweider,
2001). Functional MRI studies using psilocybin reveal decreased activation especially in the
PCC and the medial PFC and reduced coupling between those two areas (Carhart-Harris et al.,
2012; Lebedev et al., 2015). The study by Lebedev et al. (2015) also found decreased functional
connectivity between the PCC, the retrosplenial cortex (a part of the DMN) and the
parahippocampus during rest. This decrease in activation is thought to correlate to
ego-dissolution experiences and to allow an unconstrained and flexible cognition (Carhart-Harris
et al., 2012). These two areas are part of the DMN, which is usually hyperactive in ADHD
patients also (see ex: Castellanos and Proal, 2012, Bozhilova et al., 2018). Thus, psychedelics’
effect of decreasing DMN activity might prove beneficial in restoring the balance of brain
activity in this network in ADHD patients.
Psychedelics are also able to produce changes in brain waves, as measured by EEG, and
those studies also show evidence for the possible compatibility of psychedelics and ADHD.
Regardless of the specific psychedelic compound, all classical psychedelics are able to decrease
alpha and theta activity, while simultaneously increasing beta activity (Hoffmann, et al., 2001).
Thus, psychedelics are able to decrease the slow-wave activity in the brain and increase fast
oscillations, essentially activating the brain, much like stimulants do. Theta waves are
abnormally high in children with ADHD, while beta waves are relatively low, and thus
psychedelic drugs might be able to reduce this irregularity. Decreasing such slow-oscillations in
the brain is also a mechanism through which some stimulant medications exert their clinical
effects in ADHD patients, which could act as a further argument for the suitability of
psychedelics, at least for children.
2.1.3 Neurotransmitter systems involved in psychedelics
Psychedelic drugs have an agonistic action on the 5-HT2A receptor, which allows them to
easily bind to serotonin receptors and mimic serotonergic effects (Vollenweider, 2001). The
distribution of serotonin receptors in the brain sheds light on the subjective effects produced by
psychedelics. For example, 5-HT2A receptors are concentrated in cortical regions, specifically in
those responsible for higher-level cognition and perception, and especially in pyramidal neurons
of layer V in the PFC (Carhart-Harris et al., 2014). These pyramidal neurons are responsible for
the main output load of information from the cortex to other, lower, cortical or subcortical
regions, which may explain these drugs’ powerful effects on cognition and perception
(Carhart-Harris et al., 2014). Neurons that are activated by psychedelic drugs are thought to
comprise a small population mainly in the medial PFC and the claustrum (a part of the basal
ganglia) (Kyzar et al., 2017), which are involved in attention and memory. More specifically, the
claustrum contains a lot of projections to brain regions such as the cortex and the hippocampus,
and its high level of connectivity may act to organize and coordinate information from discrete
networks, especially from cortical to sub-cortical regions (Kyzar et al., 2017). Research has also
shown that chronic administration of psychedelics leads to a downregulation of the 5-HT2A
receptor - a mechanism thought to account for the rapid tolerance that one can develop towards
these substances (Nichols, 2016). This mechanism, however, can also underlie some of the
therapeutic effects of psychedelics, as selective serotonin reuptake inhibitors (SSRIs) also work
through downregulating these receptors, and some mental disorders, such as obsessive
compulsive disorder, feature a dysfunctional upregulation of these receptors (Nichols, 2016). In
addition to a decrease in serotonergic receptors, repeated exposure to psychedelics can lead to
persistent long-term increase in the expression of dopaminergic receptors (Bouso et al.,
2015).Therefore, chronic administration of psychedelics might constitute a therapeutic effect that
might be relevant for ADHD patients, which also have dysfunctions in dopamine systems.
Although all classical psychedelics are able to bind to the 5-HT2A receptor with relatively
high affinity, these substances can also attach to other serotonergic receptors (Vollenweider and
Kometer, 2010) and can also exhibit dopaminergic and adrenergic activity (Kyzar et al., 2017).
For example, activation of serotonin receptors can result in increased dopamine in the brain,
particularly in striatal areas (Vollenweider and Kometer, 2010). These changes in dopamine may
contribute to the euphoria and ego dissolution effects seen from psychedelics, which might
increase ADHD patients’ conscious access to their own dysfunctional cognitive and emotional
patterns and thus, ‘correct’ their behavior (Vollenweider and Kometer, 2010). Psychedelic drugs,
like LSD, have also been shown to have high affinity to bind to dopamine receptors in the brain
(Nichols and Sanders-Bush, 2002). This might suggest a possible role of psychedelics in the
treatment of ADHD, or at least for the improvement of some cognitive symptoms experienced by
patients. The DTD hypothesis, which states that ADHD patients have a reduced ability to learn
due to a delay in dopamine’s function to associate a stimulus with a reward, (Tripp and Wickens,
2008) may be a plausible explanation of ADHD symptoms, or at least point to an important role
of dopamine in this disorder. Thus, psychedelics’ dopaminergic action may prove to be
beneficial in relieving some ADHD symptoms. Thus, although primarily serotonergic,
psychedelic substances can also directly or indirectly affect other monoamines, which may
converge with neurotransmitter systems involved in ADHD, as it features dysfunctions mostly in
noradrenergic and dopaminergic receptors (Tripp and Wickens, 2009; Oades, 2005). Some
studies also suggest a role of serotonin in ADHD dysfunction (Oades, 2007; Oades, 2008), which
could provide a further route for the potential therapeutic effects of psychedelics in the disorder.
Many of the serotonin receptors that are activated by psychedelics are situated on
glutamatergic neurons, so a change in glutamatergic activity is also present (Carhart-Harris et al.,
2014). There appears to be an interaction between serotonin and glutamate in prefrontal areas, as
a result of classical psychedelics, and these substances are able to exert strong effects on both
networks (Vollenweider and Kometer, 2010). More specifically, activation of 5-HT2A receptors is
associated with an increase in activity of the layer V neurons, which is thought to result in an
increase in glutamatergic network activity and increases in synaptic activity in NMDA, AMPA
and metabotropic glutamate receptors (Vollenweider and Kometer, 2010). Glutamate is the main
excitatory neurotransmitter in the brain and is responsible for communication between different,
separate, brain areas (Riedel et al., 2003). Increasing the activity of it, for example by using
psychedelics, may result in greater network integration and global functional connectivity in the
brain. The reduced level of activity in the brain in ADHD patients, primarily in frontal areas and
their numerous connections to limbic and other regions, may possibly be aided by psychedelics
through this glutamatergic mechanism. Glutamate is also associated with learning and memory,
and more specifically with encoding information (NMDA receptors), memory consolidation and
recall (metabotropic receptors), and communication between neurons (AMPA receptors) (Riedel
et al., 2003). Glutamate may also be involved in long-term potentiation and long-term
depression, as well as in synaptic plasticity (Riedel et al., 2003). This mechanism of action might
also constitute a possible route of psychedelics’ therapeutic effects in treating ADHD, as patients
with the disorder have difficulty in learning and impaired memory processes. Reduced functional
connectivity in ADHD patients may also benefit from the glutaminergic action of psychedelics.
2.2 Research into macrodoses of psychedelics
Some empirical research of psychedelics exists that finds promising results for
macrodosing psychedelic substances for a wide range of psychiatric disorders and psychological
functions. Some of these studies also hint at a possible connection between psychedelics and
ADHD, suggesting that these substances might be potentially applied to this disorder as well. For
example, a study on psilocybin’s effect on OCD showed that it is effective and well-tolerated
(Moreno et al., 2006), and another confirmed its long-term benefits for personality disorders
(Griffiths et al., 2008). Other studies found LSD and psilocybin to be an effective treatment for
end-of-life anxiety in patients with terminal cancer (Gasser et al., 2014; Grob et al., 2010), as
well as an effective treatment for addiction (Johnson et al., 2014; Bogenschultz et al., 2015;
Krebs and Johansen, 2012; Vargas-Pérez, 2013; Sessa, 2015). Imaging studies using fMRI have
also been carried out, showing that psilocybin administration combined with psychotherapy
seems effective for treatment-resistant depression (Carhart-Harris et al., 2016). Anxiety and
depressive disorders, OCD, substance abuse and personality disorders, as well as a disrupted
mood regulation, are often comorbid with ADHD (DSM-V), so psychedelics’ apparent
effectiveness in treating such disorders might prove to be beneficial in ADHD patients,
especially those with comorbid psychiatric disorders. Unfortunately, there is no research to my
knowledge assessing the effectiveness of psychedelic macrodoses specifically for the treatment
2.3 Safety of psychedelic macrodoses
The general use of supra-threshold psychedelic doses might result in unwanted effects,
including triggering of psychotic states or increased feelings of anxiety or fear and an increased
heart rate during the trip itself (Tupper et al., 2015). After the experience, the user might have
perceptual distortions or visual flashbacks, but these usually subside with time and are not
serious (Tupper et al., 2015). A specific risk associated with psychedelic use, especially the use
of LSD, is the chance of development of hallucinogen persisting perception disorder (HPPD).
HPPD involves the spontaneous re-experience of flashbacks or visual distortions that are
characteristic of the psychedelic state without having any of the substance in one’s body
(Nichols, 2016), which cause significant distress to the patient. Despite these risks, the
prevalence of psychedelics-induced psychoses or HPPD is relatively low and they might be
triggered by the impurities in the drug, or an improper set and setting, more so than the actual
psychedelic substance itself (Tupper et al., 2015). In addition, the prevalence of HPPD is very
low in recreational users and even less in therapeutic settings, and psychedelics rarely lead to
psychotic symptoms (Nichols, 2016). It is not clear how HPPD might affect ADHD patients
specifically and whether it might worsen their attentional deficits. However, it is conceivable that
having persistent perceptual distortions might further decrease ADHD patients’ ability to
function in everyday life, complete tasks, and concentrate on their work.
Nevertheless, psychedelic drugs are one of the safest classes of psychoactive substances,
as they can not cause death or overdose (Nichols, 2016). Even at very high doses of LSD, people
have survived after appropriate medical treatment, and without any lasting negative effects
(Nichols, 2016). Despite having some effects on dopamine, classical psychedelics are not
considered addictive and their use is not physically rewarding (Nichols, 2016). For example,
animals can not be trained to self-administer psychedelic drugs (Nichols, 2016). Another study
reported no adverse effects of psychedelics on the brain and the body and confirmed the
non-addictive nature of these substances. It concluded that serious side effects resulting from
psychedelic use are rare (Johansen and Krebs, 2015). Indeed, research has shown that
psychedelics have negligible effects on the body, even at very high doses, and most adverse
effects are psychological in nature - for example, one can have a “bad trip” or feel anxious for
the duration of the “trip”. If adverse somatic effects do occur, they usually do so in only a small
subset of individuals, and do not persist in the long-term (Nichols, 2016).
It is also important to note that the psychedelic experience depends very much on the
proper set and setting of the user. The subjective effects of psychedelics may vary a lot from
person to person, and the experiences are usually tailored to the particular individual ingesting
the substance (Nichols, 2016). The exact experience depends on the user’s own psyche, their
expectations of and intentions towards the substance, and the specific place, time and potentially
other people that are present in the surroundings (Swanson, 2018). In certain cases, for example,
psychedelics have been known to induce intense feelings of anxiety or paranoia, but most studies
point out that negative effects will be greatly diminished if these external variables are taken in
consideration (Nichols, 2016; Swanson, 2018). It is important to use macrodoses of psychedelics
in structured settings where one can be guided by more experienced users or psychotherapists,
and have an appreciation and proper preparation for the experience. It is also important to be in
an environment that is comfortable and relaxing and where the user feels safe (Nichols, 2016). A
psychedelic-assisted psychotherapy for ADHD, where patients have sessions where they take
psychedelic macrodoses as a part of their psychotherapy, may be a good alternative for
mediating proper set and setting, but it is not a “quick” option, and would require expensive
training and development of proper protocol. Even if realized, this option would probably still be
difficult to implement and only be applicable for adults with ADHD, so a large portion of
patients would be excluded. It is also possible that the effects of psychedelic macrodoses are not
necessarily dose-dependent, as virtually all effects have the potential to occur on any
super-threshold dose (Nichols, 2016). This makes macrodoses not always predictable and
potentially dangerous when prescribed to patients if not assisted by a psychotherapist, for
example, and thus not very applicable for prescription similar to current ADHD medications.
Chapter III. Microdosing Psychedelics as a Potentially Safer Route to
Psychedelic Treatment for ADHD
The above mentioned safety concerns are reported for super-threshold doses of
psychedelics, and most adverse effects occur in very high dosages. Therefore, one would expect
that the practice of taking very small psychedelic doses to result in even less negative effects and
to be reasonably safe (Polito and Stevenson, 2019). Indeed, sub-threshold doses of psychedelics
might result in less side effects than macrodoses of these substances, or none at all. For example,
the negative psychological effects associated with “bad trips” and the mental illnesses that
sometimes are triggered by those are unlikely to occur on psychedelic microdoses (Kuypers et
al., 2019). Importantly, HPPD requires a “trip” experience and since psychedelic microdoses do
not elicit such a state, they are not able to induce these kinds of symptoms. This makes
microdosing psychedelics relatively safer and thus, possibly more suitable for therapeutic use.
Microdosing involves the ingestion of very low doses of psychedelic substances, which
do not produce the typical “trip” experience associated with psychedelic use. These doses are
considered below the threshold for a “trip” and thus, are referred to as sub-threshold doses. Since
microdosing does not feature the same “trip” experience as full doses of psychedelics do and
does not disrupt normal daily functioning, it might be better suited to be used as medicine.
Kuypers et al. (2019) define the term ‘microdosing’ more specifically as the chronic use of
sub-threshold doses that do not affect normal functioning with the goal of improving one’s
health, cognition or emotions. The exact dosage used depends on the specific substance, but is
usually between one tenth and one twentieth of a full recreational dose (Fadiman and Korb,
2018). For example, a microdose for psilocybin is less than a gram, while for LSD it is between
10 and 20 micrograms, and about 6 milligrams for DMT (Kuypers et al., 2019). The frequency of
administration of microdoses is important, as it is relatively easy to build tolerance and there
might also be residual effects of the microdose on the next two days (Polito and Stevenson,
2019). The most famous microdosing schedule is the one developed by James Fadiman and it
entails one or two days of dosing, followed by two days of non-dosing. Other approaches involve
dosing every weekday and not dosing on weekends, or dosing every other day (Kuypers et al.,
2019), however the Fadiman protocol is considered the best schedule.
Unlike macrodoses, a microdose should not be able to produce any kind of a noticeable
high and should only have minimal effects (Polito and Stevenson, 2019). These do not include so
much perceptual or sensory effects, like psychedelic macrodoses do, but more subtle effects on
cognition and emotion. Even though higher doses of psychedelics may sometimes result in a
reduction in performance on attention and working memory tasks (Swanson, 2018), this is not
the case for microdoses. In fact, some researchers claim that microdoses may enhance cognitive
performance (Swanson, 2018), concentration and creative thought, leading to increased
productivity and a reduction in the cognitive resources needed to perform cognitive tasks (Polito
and Stevenson, 2019; Fadiman and Korb, 2019; Anderson et al., 2019). This might in turn,
increase the resources available to deal with stressors and has been reported to reduce feelings of
stress and anxiety (Polito and Stevenson, 2019). These potential beneficial effects on emotion
and cognition might also be useful for ADHD patients, who also have similar deficits. In
addition, although microdoses of psychedelics do not usually produce most of the typical
subjective effects associated with psychedelic use, they still might work through similar neural
mechanisms. In fact, researchers point out that there is no reason for psychedelic microdoses to
affect different receptors in the brain than macrodoses (Fadiman and Korb, 2019). This also
suggests that microdosing these substances may also affect largely similar brain areas as
macrodosing them, as these are the regions rich in receptors for which psychedelics have an
affinity. Because psychedelics activate a relatively small and specific population of neurons in
the brain (Kyzar et al., 2017), small amounts of these substances may act on the same neurons
and thus, create similar patterns of neural activity as psychedelic macrodoses. Although
longitudinal research is lacking, it is possible that microdosing these substances may produce
long-lasting neural effects, especially with chronic use. Repeated exposure to sub-threshold
psychedelic doses may lead to structural changes in the brain similar to those reported from
psychedelic macrodoses (Bouso et al., 2015), as well as similar changes in the expression of
dopaminergic and serotonergic receptors (Bouso et al., 2015; Nichols et al., 2016). Thus, the
neural mechanisms of psychedelics described in Chapter 2 may also be applicable for
sub-threshold doses of the substances, at least to a certain degree. Nevertheless, the exact
workings of psychedelic microdoses in the brain are not yet clear, and more research is needed to
understand their specific neural mechanisms.
3.1 Research into microdoses of psychedelics
Recent research has suggested promising effects of psychedelic microdosing. One of the
first placebo-controlled studies by Hutten et al. (2020) administered 3 different doses of LSD (5,
10 and 20 micrograms) to 24 healthy recreational drug users. The researchers measured
participants’ cognitive function via a battery of attention, working memory and overall executive
function tests. Additionally, mood changes and perceived drug effects were also measured. They
found that the medium microdose (10µg) was able to increase subjective feelings of productivity
and showed minor cognitive improvements. The highest dose (20µg) was able to positively
affect participants’ mood and attention, however when more complex cognitive strategies were
warranted, this dose actually impaired performance. It is important to note that 20µg is
considered the threshold dose for a psychedelic “trip”, and it may not display the intended effects
of microdosing. The researchers also found individual differences in participants’ performance at
different doses, which might have arisen because the optimal dose likely varies with each person.
Perhaps participants would have experienced more beneficial effects if they had ingested a
personalized amount. Nevertheless, the apparent effects on cognition and attention seem
promising for further investigation, and might potentially be relevant for treatment of ADHD
patients, who show similar dysfunctions. Another placebo-controlled study (Bershad et al., 2019)
also found dose-related subjective effects across 6.5, 13 and 26 micrograms of LSD in a sample
of 20 healthy adults. They administered each dose once weekly and measured cognitive function
and working memory, mood and social exclusion, and creativity. At the medium dose (13µg),
the only statistically significant result was in the number of increased attempts at the creativity
task, however the highest microdose (26µg) was also able to produce additional effects on mood
by increasing feelings of vigor. There were no other significant effects on cognition, so the
researchers concluded that microdosing does little to enhance cognitive performance. It is
possible that Bershad et al. (2019) were not able to find significance in these measures because
they did not adhere to the Fadiman protocol for administering microdoses. Participants in their
study were dosed once a week, which may have been too little, as microdosing relies on the
cumulative effects of the substance and so it requires repeated exposure. Another double-blind
placebo-controlled study administered 5, 10 and 20µg of LSD to 48 adults and measured
participants’ time perception (Yanakieva et al., 2018). The study found significant distortions in
reproduction of timing intervals that exceeded 1 second. Because of this apparent specificity of
the results for particular time intervals, the authors suggested that these effects might be
mediated by a system that is responsible for more general cognitive functions, like attention and
working memory. If this is true, it might undermine a possible role of microdosing psychedelics
in treating ADHD, as patients also have impairments in attention and working memory
functions. Moreover, Rubia et al. (2014) report timing deficits in ADHD patients, which are
connected to dysfunctions in the left timing network in the brain. It is possible that these timing
dysfunctions might be exacerbated by psychedelics, which might weaken the argument for the
applicability of psychedelic drugs for ADHD.
Polito and Stevenson (2019) performed a systematic survey study on microdosers and
their beliefs about the effects of microdosing. They observed 98 microdosing participants who
ingested a dose once every 3 days for 6 weeks and provided daily ratings of their psychological
state. The results of this study showed reductions in self-reported stress and negative mood, a
decrease in distractibility and mind-wandering, as well as an increase in absorption of
information and general psychological functioning. In addition, the researchers found that
participants’ beliefs about the effects of microdosing were not associated with the observed
outcomes. Proper placebo studies are warranted, however, to confirm these results. This study
also found that the beneficial effects of microdosing had limited residual effects on the following
days and were not very well maintained in the long-term. However, Polito and Stevenson (2019)
relied on self-reported information and did not include a control group, so they might not have
been able to detect any sub-perceptual effects. Nevertheless, this study points to valuable
information about the administration of psychedelic microdoses - the fact that participants’
beliefs had no effect on the actual outcomes points that set and setting are not crucial for
psychedelic microdoses, which already eliminates a big factor that can potentially lead to
negative experiences. It also reveals important information about frequency of dosing and the
interplay between the limited longevity of the effects of psychedelic microdoses, and the rapid
tolerance that develops from these substances. Perhaps a different schedule than Fadiman’s is
optimal for some people, and this is an important factor to keep in mind when considering
psychedelic microdoses as medicine. Other qualitative studies have also shown benefit of
microdoses of LSD for self-reported enhancement of mood, concentration, energy and cognition
(Johnstad, 2018; Anderson et al., 2019). There are also reported increases in creativity of
psilocybin truffle microdoses via enhancing divergent and convergent thinking processes
(Prochazkova et al., 2018). The latter study found no effects on fluid intelligence, suggesting that
psychedelics might affect creativity independently of more general cognitive processes, however,
this was in the absence of a control group. Albeit qualitative, these studies also point to possible
cognitive benefits of psychedelic microdosing, and a possibility to improve productivity and
attention, as well as mood. Taken together, accumulating evidence from recent studies point to
potential therapeutic applications of microdoses in ADHD patients.
3.2 Anecdotal and preliminary experimental evidence of microdosing for ADHD
Unfortunately, there isn’t any experimental research testing microdosing psychedelics in
patients with ADHD. Non-scientific articles and case reports describe promising, and in some
cases even life-changing, benefits of microdosing psychedelics for ADHD. One such case report
describes how microdosing has helped ameliorate one adult’s ADHD symptoms and quit his
stimulant medication (Smith, 2017). Mike reports that after an initial LSD trip, which he firmly
believes cured him of his disorder, he began microdosing every other day. Since then, he feels
that he is more calm and focused, has an overall better attitude, and is better able to control his
ADHD. Further, Mike reports that unlike stimulants, microdosing does not result in the same
“crash” and exhaustion, tolerance, or “come-down”. According to him, microdosing has helped
him learn to control his own brain and use it in the way he wants to, which has helped him stop
his stimulant medication all together. Another case study, that of Marcel, features a similar story
- after a long time of taking stimulant medication, Marcel was forced to stop taking them because
of the unpleasant side effects he was experiencing (Smith, 2017). He reports that microdosing
has helped him develop his self-efficacy and self-control, and without magically curing him, he
believes they have helped him learn how to live a better life. Yet another case study talks about a
man who has been taking methylphenidate for more than a decade to treat his ADHD until he
started feeling he was losing his identity and turning into a “zombie” (De Boer, 2018). He
believes that after a certain point, stimulants no longer produced the beneficial effect. Then, in a
remarkably similar fashion to the former case studies, he decided to take a full dose of
psilocybin, which he also believe cured his ADHD and allowed him to take control over his
brain for the first time. Ever since, he has been microdosing with mushrooms and finds that it
helps him deal with his ADHD and makes him a more positive person. Psychedelics also aided
him in coming off stimulants without experiencing the usual withdrawal effects. Another ADHD
sufferer who successfully used microdosing to combat his disorder pointed out that although he
does think that psychedelics are an effective option, they are highly dependent on one’s
conscious efforts to correct one’s behavior (De Boer, 2018). As promising as these case reports
sound, it is important to keep in mind that these are not empirically tested, so the accuracy and
validity of the information provided by the users has not been confirmed by more sound
Preliminary anecdotal evidence suggests that there is, indeed, a connection between
ADHD and psychedelics. In an open microdose self-report study, Fadiman and Korb (2019)
followed microdosers for a month and found that some participants had an interest in
microdosing because they wanted to relieve their ADHD symptoms or to boost productivity,
attention or creativity. Most of them reported benefits in these domains, and some even
substituted their prescription stimulant medication for microdosing and found that psychedelics
did not produce the side-effects associated with stimulants. More specifically, psychedelics did
not lead to the same energy “crash” as stimulants do. The authors argued that although
psychedelics work through different neurotransmitters than those primarily involved in ADHD,
they still act as stimulants, which might account for the positive effects on cognition. The same
study also found improvements in mood in both healthy and depressed participants, as well as
reports of increased energy, productivity and effectiveness at work among microdosers. An
online survey on forum users reported a higher prevalence of ADHD among those participants
that microdosed compared to the general US population (Rosenbaum et al., 2020), suggesting a
potential role of psychedelics as a treatment option for ADHD. Another study using an online
questionnaire targeted microdosers’ ratings of the effectiveness of microdosing for treatment of
mental disorders, as compared to that of more conventional treatment options (Hutten et al.,
2019). The study found that microdosing was rated as significantly more effective than orthodox
treatments, and post-hoc analyses revealed that this effect was specific to ADHD and anxiety
disorders. The authors suggested that a possible reason for this is that microdosing does not
produce the unwanted side effects, such as a “crash” as most conventional medications do, and
also does not require daily ingestion, which potentially further reduces side-effects, as well as
costs. A review of the use of cognitive-enhancing drugs reports the use of psychedelic
microdoses to enhance productivity, cognitive performance, and concentration (D'Angelo et al.,
2017). The review also mentions the use of these drugs by ADHD patients in conjunction with
their prescription medication in order to reduce the stimulant dose, and thus the adverse effects,
without reducing the benefits. It is also interesting to mention that the Marine Corps
Intelligence, Surveillance, and Reconnaissance Enterprise (MCISRE) has expressed interest in
microdosing as a potential performance enhancing drug (PED), and has suggested that the
cognitive benefits from microdosing, combined with the much lesser degree of negative side
effects compared to other PEDs, might constitute an advantage for these types of substances
(Albayrak, 2019). More specifically, Albayrak (2019) mentions psychedelics’ superiority over
other stimulants and ADHD medication for enhancing cognition. In addition, Albert Hoffman,
the creator of LSD, proposed that low doses of this classical psychedelics might act as an
alternative to Ritalin (Fadiman and Korb, 2019). James Fadiman himself, who is dubbed the
“father” of microdosing research, is also reported to have said that psychedelic microdoses might
be an “extremely healthy” substitute for Adderall in a Rolling Stone interview (Leonard, 2015).
Taking all this preliminary research in consideration, it is safe to say that microdosing
psychedelics seems a promising way to treat symptoms of ADHD, and might even be superior
than current ADHD medication. Nevertheless, this is only anecdotal research, and more rigorous
experimental evidence is necessary for these suggestions to be confirmed.
3.3 Safety of psychedelic microdoses
Some studies cite adverse side effects of microdoses of psychedelic drugs in some users.
An observational microdosing study found slight increases in neuroticism and experience of
negative emotions in microdosers, which they explained as part of a general increase in
emotionality and an enhanced ability to recognize and process negative emotions (Polito and
Stevenson, 2019). Another interview study reported that some microdosers experienced negative
effects when microdosing, such as problems sleeping if taking the dose too late, accidentally
taking a low supra-threshold dose and not being prepared for the “trip” that ensues, or feelings of
anxiety and overstimulation (Johnstad, 2018). Some of the participants in this study also reported
feeling uneasy over the fact that there is still little research into the effects of microdosing,
especially in the long-term. Some of these negative experiences, however, might be greatly
diminished if the participants followed a more structural approach that is prepared by a physician
or researcher, and not by themselves. Identification and administration of a personalized, optimal
microdose might also be important for the achievement of the desired therapeutic outcomes. An
online questionnaire study in self-microdosing participants found that about one fifth of the
participants reported unwanted side effects, which generally occurred only while under the
influence and only about 3% of subjects reported these negative effects to last for several more
days (Hutten et al., 2019). When experiencing both physical and psychological side effects, some
participants decided to stop microdosing, however this was not the case when only one of these
types of side effects was seen. Moreover, the authors could not cite a cause for these side effects
and suggested that they might be the product of higher than usual doses, or an impure substance
(Hutten et al., 2019).
Another more practical concern is that these substances are still illegal in a lot of parts of
the world, and most users can only get them from the black market. This also means that they
can not be sure whether they are actually getting the substance they want without a testing kit.
And even then, the purity of the substance and the percentage of active ingredients still remain
unknown, which might contribute to some unexpected negative effects.
Animal studies paint a concerning picture, however. A study done in rats that
administered 0.16 mg/kg of LSD every other day for at least three months reported persistent
negative effects on behavior, including aggression, hyperactivity and anhedonia, which lasted for
weeks after microdosing stopped (Marona-Lewicka et al., 2011). The authors concluded that
chronic administration of this psychedelic might lead to schizophrenia-like symptoms, so
perhaps any ADHD patients who also have vulnerability towards developing psychotic disorders
should steer away from psychedelic medicine. It is debatable, however, whether this dose
constitutes a microdose for the rats and is comparable to a microdose in humans, and also
whether an animal model of psychedelics is comparable to effects seen in people (Kuypers et al.,
2019). Similar negative results have not been reported for psilocybin (Kupyers et al., 2019), so
perhaps this psychedelic drug will be more suitable for therapeutic purposes than LSD. Another
potential safety concern of chronic use of psychedelics is a possibility of cardiac valvulopathy
due to the repeated activation of the 5-HT2B receptor in the heart (Kuypers et al., 2019). Some
existing medicines derived from the ergot fungus have shown this side effect and have even been
withdrawn from the market because of this (Kuypers et al., 2019). Nevertheless, no adverse
effects on cardiac activity have been reported so far in the literature about microdosing
psilocybin or other non-ergotamines (Kuypers et al., 2019), which again points to the greater
suitability of psilocybin compared to LSD. It is important for such studies to be countered in
order for psychedelic research to continue, so a closer look into these potential negative effects is
crucial for the future of psychedelic medicine. Unfortunately, research is still in its infancy, and
proper safety measures need to be taken when administering psychedelic microdoses for clinical
or therapeutic purposes. Monitoring and advice by medical professionals and psychotherapists is
highly recommended to ensure a fruitful experience, where the therapeutic effects are enhanced
and the side effects are minimized.
The current paper aimed to review and try to find a connection between the behavioral
and neural effects of microdosing psychedelic substances and the dysfunctions experienced by
ADHD patients. As the disorder is quite prevalent in the population, and current medication still
results in a lot of unpleasant side effects in a lot of patients, it is important to find new treatment
options for ADHD, and one such potential alternative comes in the face of psychedelic drugs.
ADHD manifests itself primarily in cognitive and emotional deficits (DSM-V, 2013), while
psychedelic drugs have powerful effects on emotion and cognition and are able to enhance
cognitive performance and increase conscious access to and control over one’s emotions,
decisions and thought processes (Swanson, 2018), which seems beneficial for counteracting
ADHD’s symptoms. Moreover, psychedelic drugs seem to affect widely distributed networks in
the brain, including mainly frontal, parietal and basal ganglia regions, as well as limbic areas -
brain areas that are known to be affected by ADHD (see ex: Sergeant et al., 2003; Rubia et al.,
2014), suggesting a potential match in the effects of these substances and dysfunctions of the
disorder. Moreover, psychedelics seem to generally increase brain activation, which is usually
decreased in ADHD patients (Koehler et al., 2009; Clarke et al., 2003), but simultaneously
decrease the activity of the DMN, which is usually increased in ADHD (Castellanos and Proal,
2012, Bozhilova et al., 2018), suggesting yet another match between the mechanisms of action of
the disorder and psychedelics. While dopamine and norepinephrine are mainly involved in the
development of ADHD (Tripp and Wickens, 2009; Oades, 2005), serotonin is part of the primary
route through which psychedelics exert their effects (see ex: Vollenweider, 2001). Nevertheless,
connections between neurotransmitter systems are also evident, as both are able to affect all
monoamines directly or indirectly (see ex: Oades, 2007; Kyzar et al., 2007). In addition, some
preliminary anecdotal evidence suggests not only that healthy volunteers receive cognitive and
emotional benefits from microdosing (see ex: Hutten et al., 2020; Yanakieva et al., 2018;
Prochazkova et al., 2018; Bershad et al., 2018), but that it also helps ADHD patients deal with
their disorder and decreases their symptoms (see ex: Hutten et al., 2019; Fadiman and Korb,
2019; Smith, 2017; De Boer, 2018). Some ADHD patients even report substituting their
prescription medication for microdoses of ADHD and still experience therapeutic effects without
the many side effects elicited by stimulants (Fadiman and Korb, 2019).
In addition, psychedelics in general are relatively safe, and their potential for abuse or
adverse effects is greatly diminished by decreasing dosages (Polito and Stevenson, 2019). Thus,
microdosing psychedelics seems to not produce any serious significant side effects, nor does it
lead to addiction, and if used in a structured, medical setting, their unwanted effects might be
practically non-existent (Nichols, 2016; Swanson, 2018). Compared to more orthodox stimulant
medication, psychedelics also seem to have more long-lasting effects (see ex: Meijer et al.,
2009), and almost none subjective effects, so they appear to be suitable for chronic use without
disrupting normal daily functioning. However, more rigorous research is needed to better
understand psychedelic microdosin’s effects on brain and behavior before making any firm
conclusions about their safety or efficacy. Psychedelic drugs also don’t seem to produce the
same unpleasant “crash” after use, unlike stimulants do (Fadiman and Korb, 2019), which has
led to some ADHD patients using microdosing to self-medicate for their disorder, with positive
results (Fadiman and Korb, 2019). Therefore, microdosing psychedelic substances seems to be a
promising new therapeutic avenue that may also bring about desired therapeutic outcomes in
Nevertheless, there are limitations concerning the methodology of the current studies of
microdosing psychedelics, which might undermine their validity and reliability. Most of the
studies using psychedelics, and also most of those mentioned in this paper, use relatively small
samples, which decreases their power to detect any significant effects. Individual differences are
also a problem, especially with small samples, as a lot of research suggests that the psychedelic
experience is largely individual and depends on subjective factors. In this line of thought, it is
also likely that what is considered the “optimal” beneficial microdose is also highly individual,
and it might take time before one finds what works best for them. Not only the dose, but the
frequency and pattern of ingestion might also make a difference, but studies are not consistent in
their microdosing schedules. These all might lead to a high degree of variance in studies,
reducing the ability of studies to find meaningful effects. In addition, most of the studies that use
surveys or questionnaires rely on self-selected samples of drug users, who probably have more
experience with recreational drugs and thus, their opinion might be biased. This might also
decrease the ecological validity of studies, as the samples might represent a specific subset of the
population that is qualitatively different than the more general population. Another concern
about the generalizability of the results might be that the neuropsychological tests that are done
in a laboratory setting might not translate well to real-life situations which demand cognitive
functioning, especially for patients with ADHD. In addition, there is a general lack of research in
this field, and most studies that do exist are not proper double-blind controlled experiments, but
rather rely on qualitative and anecdotal evidence from users.
In addition, all speculations presented in this paper need to be verified by experimental
research. Rigorous empirical evidence for the effectiveness of these drugs is missing, and the
conclusions made are yet to be confirmed by controlled clinical trials on ADHD patients. Future
studies in this field should consider conducting randomized placebo-controlled studies to
objectively assess the safety and effectiveness of psychedelic microdoses, and compare them to
current pharmacological treatment for ADHD. In addition, it may be of interest to look into how
to combine microdosing with psychotherapy, such as cognitive behavioral therapy, to ensure the
proper set and setting that is so important for the psychedelic experience. Another important
consideration for future studies is to better research the possible side effects of psychedelics in
the long-term, as well as conduct quantitative longitudinal studies to objectively assess the
longevity of their desired effects. Despite the lack of conclusive evidence, the current state of the
literature convincingly suggests that there indeed is clinical value in psychedelic substances for
treating ADHD, and it is worthwhile to pay closer attention to the potential therapeutic
application of microdosing for this disorder.
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