1
A Meta-Analysis of the Pharmacological Effects of LSD and MDMA on PTSD and MDD
Ali Alhafidh
WRITING 109ST; University of California, Santa Barbara
Contents
A Meta-Analysis of the Pharmacological Effects
of LSD and MDMA on PTSD and MDD ............ 1
Abstract .................................................................. 1
I. Introduction ................................................... 1
II. Literature Review .......................................... 3
A. LSD General Effects on Empathy, Cognition,
and Emotion .................................................. 4
B. MDMA General Effects on Empathy,
Cognition, and Emotion ................................ 6
III. Conclusion ...................................................... 7
References .............................................................. 8
Abstract
This paper serves as a holistic research and review of
pharmacological and biological effects of psychoto-
mimetic drugs such as lysergic acid diethylamide
(LSD) and 3,4-methylenedioxymethamphetamine
(MDMA) on relieving stress related issues in patients
suffering from severe trauma or disorders such as
PTSD as well as mood disorders. Furthermore, phar-
macological effects related to changes in stress and
prevention as well as treatment will be considered. A
collection of prior research as well as new research
will comprise the basis of this study to better under-
stand the effectiveness of these drugs on improving
conditions caused by stress-related issues. The pur-
pose of this meta-analysis is to demonstrate that the
psychotherapeutic nature of LSD and MDMA is pos-
itive and effective.
I. Introduction
Exposure to traumatic events has been known to
pose a serious risk in inducing mental mood and
stress disorders such as major depressive disorder
(MDD) and posttraumatic stress disorder (PTSD)
which can altogether deteriorate the mental and
physical health of patients suffering from them. Pa-
tient exposure to stress factors and traumatic events
are key contributing factors to the initiation of MDD
and/or PTSD which display a function of comorbid-
ity (can appear together in most cases in that patients
exhibit symptoms of both). Although the etiology of
MDD is less specifically known, it is widely ac-
cepted that it is related to and shares specific features
to PTSD. The onset of PTSD is usually exposed fol-
lowing certain traumatic life events such as assault,
domestic violence, wartime violence, child abuse,
and a myriad of other traumatic situations. In the
United States, the lifetime prevalence of PTSD in the
general populace is around 6 to 10% with much
higher counts being recorded in countries with en-
demic warfare and conflict [19]. The comorbid nature
of PTSD and MDD has been elucidated in previous
studies—95% of those diagnosed with PTSD also
share symptoms and will be diagnosed with MDD at
some point in their life [3]. High treatment resistance
towards PTSD and MDD mainly results from recall
of traumatic experiences which is highly associated
with self-harm, induction of anxiety, depression, and
substance abuse. In order to alleviate depressive
symptoms, a decreased fear response (but not neces-
sarily decreased emotional response or intensity to-
wards the fearful experience) must be generated arti-
ficially (in this case psychotherapeutic drugs are the
topic of discussion) in order to facilitate patient-ther-
apist communication and empathic connection. In
this way, traumatic experiences can be revisited and
worked on and potentially resolved over time.
 2

These specific disorders are primarily and often
associated with serotonergic systems (the 5-HT re-
ceptor family) and modulation of these receptors and
their ligands (serotonin or 5-HT, 5-hydroxytrypta-
mine) through pharmacological substrates has been
known to induce positive behavioral effects through
various downstream effects further discussed in the
body of this paper. Exposure to chronic stress or trau-
matic events can cause deregulation and impairment
of serotonin neurotransmission. Pharmacological ap-
plication of drugs which modulate the 5-HT system
such as selective serotonin reuptake inhibitors
(SSRIs) have been seen to positively correlate with
treatment of both PTSD and MDD and therefore
speaks to the similarity of the mechanisms which
cause them. Because psychotomimetic drugs such as
LSD and MDMA are known to primarily affect the
serotonergic system it is believed that they can be a
safer alternative to medicines such as opioids and
other anti-depressant drugs which have numerous
side effects and addictive properties of their own
which can easily associate with the substance abuse
characteristics of patients suffering from PTSD and
MDD. In the U.S. market, only two conventional
pharmacological therapeutic drugs have been ap-
proved by the Food and Drug Administration (FDA)
for PTSD treatment, one of them being Zoloft ® (ser-
traline) which has marked chronic effects on seroto-
nin levels and like other antidepressants has a highly
addictive nature.
Although research on LSD has been greatly lim-
ited by federal regulations marking the drug as
Schedule I, its effects have been widely noted, expe-
rienced, and worked with in the lab for many years.
The research compiled in this paper serves to analyze
the various effects of LSD and MDMA on PTSD and
MDD and how they might serve as a better alterna-
tive to psychotherapy and opioids as treatments.
In order to understand how drugs such as LSD
and MDMA might alter or better the effects of stress-
related disorders, proper knowledge and citation of
prior pharmacological knowledge, such as but not
limited to, receptor-ligand interaction and down-
stream effects of those connections as well as side
effects and the biological nature and health of the pa-
tient (which will not be taken into account in this
study). By connecting various research topics from
prior literature to the topic at hand, hopefully a better

Figure 1 - Model of serotonergic (5-HT; green arrow), neurogenic (blue arrow), and behavioral effects of stress.
Acute stress (leading left of “STRESS”) increases dorsal raphe (DR) 5-HT firing. Chronic stress resulting from
PTSD and MDD leads to monoaminergic changes (solid box), decreased neurogenesis, and decreased general 5-HT
firing in the dorsal raphe nuclei (DR). Image reproduced from Mahar, I., et al. [21]
 3

understanding of how stress-related issues can be

treated is elucidated.
In the major portion of this paper (Literature Re-
view), similarities between a few key stress-related
disorders such as MDD and PTSD and their associa-
tion with stress will be covered in order to uncover
connections to treatment properties of drugs like
LSD and MDMA. Effects of various psychotomi-
metic drugs will be looked at and how they might
negatively or positively affect stress issues in a ther-
apeutic setting.

II. Literature Review

In order to better understand why drugs such as

LSD and MDMA can be used as therapeutics targets
for PTSD and MDD, the properties of the sero-
tonergic 5-HTx receptor family and the effects of
these drugs upon this family must be taken into ac-
count. Serotonin (5-HT) is derived from the amino
acid L-tryptophan in the neurons of dorsal raphe
(DR) nuclei which project to various neural connec-
tions throughout the central nervous system (CNS)
including the hippocampus [6]. Serotonin is required
Figure 2 – Representation of psychological effects of LSD based
on phases of LSD progression following onset of the effects and fi-
nally the enduring effects. Before psychedelic exposure, users with
prior deficiencies in 5-HT2A receptor stimulation induces negative
thinking, psychosis, and constrained thought patterns (usually de-
pressive). The onset and initial ‘blast’ of stimulation and the ‘acute
state’ effects result in a variety of psychotomimetic effects includ-
ing altered perception and cognition (could induce paranoia or anx-
iety, heightened imagination, and possibilities of ego dissociation
and free thinking. Figure reproduced from R.L. Carhart-Harris et
al. [5]
Figure 3 – This figure demonstrates the effects of adminis-
tered LSD (100µg and 200µg doses) vs. placebo on patients’
cognitive and emotional empathy. A Multifaceted Empathy
Test (MET) using photorealistic stimuli was used to measure
empathy based on patient visualizations and reactions. Per the
data, emotional empathy increased while cognitive empathy
decreased. The study showed significant difference from pla-
cebo. Figure reproduced from Dolder, et al. [8]
for depressant and anti-depressant effects and there-
fore the negative effect of stress upon the 5-HT sys-
tem causes reductions in neural excitability and neu-
rotransmission [21]. To support this, genetic modula-
tion resulting in a knockout of 5-HT vesicle trans-
porters in mice resulted in a depressive phenotype
[27].
Lowered 5-HT activity in humans has been asso-
ciated with aggression, impulsiveness, and suicidal
behavior [36]. Stress related to depression occurring
from PTSD and MDD Fig 1 is resultant in decreased 5-
HT firing which can lead to depressive and stress-
inducing effects. A mean 35% decrease in spontane-
ous firing of the DR neurons is associated with low-
ered 5-HT activity [21]. Effects are specifically related
to down regulation of presynaptic 5-HT1A auto-re-
ceptors (G-protein receptors which induce delayed
 4

Figure 4 – In this figure effects on mental states of patients (researchers used the Visual Analog Scale [VAS]) administered LSD
(100µg and 200µg doses) vs placebo doses of the same quantity are compared. These tests were taken about 3-4 hours post-admin-
istration at or around the “plateau phase” in order to mediate patient response and to receive proper data while patients were under the
effect of LSD. According to the VAS all patients actually administered LSD demonstrated increased ratings across the board, however
ratings for ‘Fear’ did not increase that much past control. Figure reproduced from Dolder, et al. [8]
downstream effects) which is neurologically associ- stress-affected 5-HT system without adversely af-
ated to patients with mood disorders and PTSD [16]. fecting a patient’s physical health. The biological and
Chronic stress results in structural changes in brain mental interactions of each drug will be analyzed in-
plasticity (largely reversible by proper psychother- dividually.
apy or pharmacotherapy) due to deregulatory effects
on the 5-HT system (such as that in the hippocampus) A. LSD General Effects on Empathy,
and also negatively impacts hippocampal neurogen- Cognition, and Emotion
esis [21]. These effects can be reversed by application
of SSRIs to reduce reuptake of serotonin as well as LSD acts a partial 5-HT1A and 5-HT2A receptor
various other antidepressants but their efficacy has agonist and the psychedelic effects are controlled by
been shown to be weak to moderate due to patient 5-HT2A receptor stimulatory effects [38]. Its selective
relapse and environmental and mental factors caus- binding to 5-HT2A receptors results in consistent fir-
ing an up-regulation in depression. Also, antidepres- ing of the receptor for many hours due to a strong
sants are largely addictive by nature and can exacer- binding affinity of the ligand to the receptor. It spe-
bate acute and chronic stress effects of PTSD or cifically inhibits firing of the 5-HT1A receptor class
MDD rather than help them [36]. The interactions of as well. This makes LSD a partial agonist because it
drugs such as LSD and MDMA with the 5-HT sys- can modulate its own effects (positive and inhibitory
tem can possibly help in the process of rehabilitation regulation). LSD binds to these receptor classes and
in patients suffering from PTSD and MDD by alter- induces long-lasting (8-10 hours or longer) effects
ing the excitability and inhibitory effects of a chronic such as hallucinogenic visuals, increased somatosen-
sory sensation, and a general elevation in mood and

empathy [23] not including situations of high dose
which can result in what users call a “bad trip” which
can consist of anxiety, paranoia, and ego dissociation
none of which is physically impactful.
LSD-assisted psychotherapy is comprised of a
variety of mechanisms by which treatment can occur.
These include, greater openness to accessing emo-
tions, relief during traumatic memory recall, sensa-
tions of catharsis when recalling trauma, and coordi-
nating greater emotional and intellectual perception
and insight during the trip [14]. According to Gasser
P., et al., LSD-assisted therapy consists of a cognitive
experience (lucid thoughts and alterations of associ-
ations and relationships between concepts and ideas
and seeing problems in a new light), a psychody-
namic experience (conscious retrieval of new, pro-
found ideas about inner conflicts, life, and reality),
and a psychedelic peak experience (loss of sense of
self usually due to positive ego transcendence, sense
of awe and astonishment towards the world, etc…).
These various aspects of an LSD trip could contrib-
ute to sustaining therapeutic communication between
patient and therapist. This could also facilitate appli-
cation of new ‘frames of mind’ through psychedelia.
Induction of ‘tension-free’ states in which LSD ad-
ministered patients are able to move past an initial
stage of tension and anxiety into a state of comfort
and well-being while being totally receptive to past
trauma demonstrates an important mechanism to
LSD’s psychotherapeutic qualities. Sustained de-
creases in anxiety and elevated emotions are essen-
tial to establish a patient-therapist dynamic [12].
Increases in emotional empathy Fig 3 following
LSD usage are associated with heightened emotional
responses to fearful or depressing stimuli. A general
decrease in cognitive empathy which involved pa-
tients inferring others’ mental states was shown
across both doses as well [8]. A psycholytic (height-
ened altered state of cognition and processing of
thoughts without much, if any, psychedelic experi-
ence) application (lower doses 20-100 µg but more
frequently) is more commonly associated with psy-
chotherapeutic processes which is recommended in
preliminary stages of treating PTSD and MDD due
to a more controlled, accessible dosing for patients
without prior psychedelic experience. Higher doses
(>100 µg) can be recommended as well for patients
experiencing intense trauma resultant in PTSD or
MDD due to data conferred by P. C. Dolder, et al.
5
Figure 5 – This graph demonstrates the STAI scores for pa-
tients following administration of LSD. Baseline measurements
show high levels of state and trait anxiety which effectively
lower following LSD application and remain lowered a year
following the experiments. Patients were tested qualitatively
and quantitatively using emotionally arousing therapy sessions
and photo-visual media. Figure reproduced by Gasser et al [13]
According to researchers’ usage of Visual Analog
Scale (VAS) tests Fig 4, a dose of 200 µg resulted in
greater feelings of trust, unity, wanting to be with
others, feeling close to others, and a marked reduc-
tion in fear as well [8]. Usage of a lower 100 µg dose
demonstrated similar effects however, effects such as
openness and feelings of wanting to be with others
(unity) were far less pronounced than with a higher
200 µg dose. Patient anecdotal information in terms
of drug effect was largely observed to be “good” and
tolerable even across a relatively lengthy time of ef-
fect (8-12 hours). This correlates positively with
analysis that supports LSD as a psychotherapeutic
drug which generates generally positive effects on
mental state with reproducible results.
Further quantitative measures were found in
LSD’s ability to reduce anxiety over long periods of
time. Tests conducted by Gasser P. et al. utilized a
quantitative measuring system called the Spielberger
State and Trait Anxiety Inventory (STAI) [35]. Meas-
urements were taken at baseline, one week following
experimental sessions, and during two month and
one year follow-up sessions. A separation between
state and trait anxiety is essential. State anxiety is de-
fined as a negative emotional arousal following some
form of threat or danger [20]. Trait anxiety is defined
as a reflection of individual differences in the pro-
pensity to respond with state anxiety towards antici-
 6

pation of some threat or danger. Nine patients re-
ceived doses of LSD at 200 µg and were evaluated
for their STAI trait scores Fig 5. Patients showed high
levels of state and trait anxiety during baseline but
exhibited highly decreased scores by the end of the
study and a sustained decrease in STAI scores even
after one year during follow-up studies [12]. First, this
indicates that LSD is capable of a reduction in state
anxiety which reflects reduced immediate reaction
towards traumatic or anxiety-inducing experiences.
Second, lowered trait anxiety reflects that patients
experienced reduced tendencies to react with anxiety
and high emotional tension when dealing with past
traumatic experience even when those situations are
not readily present. Moreover, state and trait anxiety
demonstrated greatly similar reductions signifying
LSDs shared effects on both forms of anxiety in pa-
tients and possibly shared properties between the two
forms of anxiety themselves.
sive symptoms, increased sentiment of unity and in-
terpersonal closeness without intense psychedelic ef-
fects comprise the basis of MDMA as a well-suited
PTSD/MDD therapy agent [7].
There are several possible mechanisms of func-
tion for MDMA in psychotherapy. For a drug like
MDMA to be effective in therapy, drug exposure
must be followed up with therapeutic emotional en-
gagement between the therapist and patient and/or
‘fear activation’ of prior trauma must be carefully
presented without causing overwhelming emotions
to arise [11]. Prior research has defined the degree of
proper emotional engagement with the patient as a
‘window of tolerance’. Because patients diagnosed

B. MDMA General Effects on Empa-

thy, Cognition, and Emotion

MDMA (ecstasy) is a particularly effective em-

pathogen-entactogen (drugs that produces a sense of
emotional communion, unity, and general stimula-
tion of a person’s empathic nature) stimulant which
acts as a psychoactive drug with limited psychedelic
experience. Instead of exhibiting psychedelic prop-
erties native to hallucinogens like LSD, MDMA
greatly influences empathic capabilities, feeling, sen-
sation, and general emotion. MDMA acts in similar
ways to LSD and other monoamine neurotransmitter
agonists, but also elicits release of dopamine and nor-
adrenaline to a higher degree. Stimulation of the 5-
HT1A and 5-HT1B receptors results in reduced feel-
ings of depression and anxiety due to direct effects
on the amygdala via serotonin. Oxytocin release is
also increased upon activation of the 5-HT1A receptor
[1]. Oxytocin is involved with affiliation, trust, and
increased specific attention to one’s emotions [9].
MDMA also increases activity of the 5-HT2A recep-
tor which provides perceptional alteration in vision
Figure 6 – Established CAPS mean scores for placebo and
and cognition through elevation of serotonergic out- MDMA administered patients from Time 1 to Time 4. Time 1
put, albeit much less pronounced than other psyche- establishes a baseline for both groups at a high CAPS score
delic drugs [4]. The unique combination of various (severe symptoms). For placebo patients, a minor decrease in
positive psychological features including emotional CAPS score was identified. The figure shows an evident de-
and sentimental arousal, relaxation, reduced depres- crease in CAPS score in MDMA administered patients even
after two months (Time 4). Figure reproduced from Mithoefer,
M.C., et al. [24]

with PTSD and MDD suffer from emotional numb-
ing and extreme anxiety attacks, they naturally have
a small window in which they are between the
thresholds for under and over-arousal [26]. MDMA
may establish its therapeutic effects by broadening
this window of therapy and allowing patients to re-
main emotionally engaged without having anxiety
overpower them while revisiting past trauma. Also,
increased oxytocin post-MDMA intake has been
noted to increase sociability, excitability, and interest
in communication with other persons [10].
A proposed ‘neurocircuitry’ model for PTSD
suggests that there is a deficit in the extinction of fear
conditioning mediated by the amygdala and the ven-
tral/medial prefrontal cortex (vmPFC) [30]. A human
Positron Emission Tomography (PET) test con-
ducted by Mithoefer et al. about 75 min. following
MDMA administration to test subjects showed an in-
crease in cerebral blood flow to the ventromedial
frontal and occipital cortices and a decrease to the
left portion of the amygdala [24]. MDMA may instill
some of its therapeutic effects by affecting brain
plasticity through a reversal of negative abnormali-
ties caused by intense trauma; this would also aid in
allowing for more effective processing and commu-
nication during therapy sessions.
To specifically diagnose for levels of chronic
PTSD treatment-resistant symptoms, DSM-V-R cri-
teria utilizes a Clinician-Administered PTSD Scale
(CAPS score) which consists of questions held dur-
ing a therapist and patient interview and defines a
score of ≥50 as moderate to severe and scores <40 as
moderate to low. The MDMA study on twenty pa-
tients conducted by Mithoefer, et al. defined a >30%
reduction from baseline CAPS scores as a clinical re-
sponse to the drug Fig 6. In a double blind test con-
ducted as a preliminary stage of testing, the clinical
response was found to be 83.3% for MDMA admin-
istered patients (10 out of 12 patients responded with
greatly lowered CAPS severity scored) compared to
25% in the placebo group (2 out of 8 people showed
lower CAPS severity scores but not nearly as de-
creased as those given MDMA). In stage 2 of the
study, seven of the eight placebo subjects chose to
participate in a crossover test in which they were
given MDMA and CAPS severity scores were re-
tested for. Significant decreases in CAPS scores
were identified and were of similar magnitude to
7
stage 1 non-placebo patients initially administered
full doses of MDMA [24].
III. Conclusion
By analyzing prior and current data on LSD and
MDMA, it is undeniable that these drugs can serve
as therapeutic aids in helping treat PTSD and MDD.
Deficiencies in the 5-HT serotonergic system is
closely tied to these stress disorders, and the ability
of LSD and MDMA to modulate the 5-HT system
actively and safely (from a physical standpoint)
demonstrates their useful function in therapeutics.
However, LSD research and usage is heavily moni-
tored and regulated due to its drug scheduling in the
United States and other areas. Because of this, con-
trolled patient studies are difficult to conduct and
sparse. Regardless, quite a bit of information is
known about the neurophysiological effects of LSD
and countless experience reports have been docu-
mented. Given that LSD has very few lasting side ef-
fects even shortly after administration, LSD can be
an especially effective as a therapy agent even with
its characteristically psychedelic qualities and long
duration of effect. On the other hand, MDMA pre-
sents its therapeutic qualities on a shorter time scale
which is far easier for therapists to handle from a
time perspective during extended therapy sessions.
Also, MDMA does not provide an intense psyche-
delic experience which many users (especially for
their first time) might be averse to especially given
their high stress and high anxiety states. Because of
this, it can be argued that MDMA may not neces-
sarily be more effective at reducing depression, stress
and anxiety compared to LSD, but may be more ef-
ficient and reliable in doing so with a broader collec-
tion of patients. Essentially, LSD and MDMA should
be used specifically and thoughtfully depending on
each patient’s specific situation and needs in order to
maximize psychotherapeutics for patients suffering
from PTSD and MDD.

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