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REVIEW
Safety and Toxicology of Cannabinoids
Jane Sachs
1
& Erin McGlade
1
& Deborah Yurgelun-Todd
1
Published online: 13 August 2015
#
The Author(s) 2015. This article is published with open access at Springerlink.com
Abstract There is extensive research on the safety, toxicolo-
gy, potency, and therapeutic potential of cannabis. However,
uncertainty remains facilitating continued debate on medical
and recreational cannabis policies at the state and federal
levels. This review will include a brief description of canna-
binoids and the endocannabinoid system; a summary of the
acute and long-term effects of cannabis; and a discussion of
the therapeutic potential of cannabis. The conclusions about
safety and efficacy will then be compared with the current
social and political climate to suggest future policy directions
and general guidelines.
Keywords Cannabis
.
Cannabis safety
.
Cannabis policy
.
Cannabis efficacy
.
Cannabis
Introduction
There are more than 60 systematic reviews and meta-analyses
discussing the safety, toxicology, potency, and therapeutic po-
tential of exogenous cannabinoids. However , the general con-
sensus of these reports is largely mixed and inconclusive. The
uncertainty surrounding safety and efficacy of exogenous can-
nabinoids is not a product of the lack of research, but rather a
product of the extreme variability in study methodo logy and
quality. This review provides a summary of the current research
on the safety and efficacy of exogenous cannabinoids, includ-
ing a brief description of the chemical constituents of cannabis
and how it interacts with the endocannabinoid system; a sum-
mary of what is known about the acute and long-term e ffects
of cannabis; and a discussion of the therapeutic potential.
Conclusions on safety and efficacy will then be compared
with the current social and political climate in order to high-
light the need for polic y c hanges and general guidelines.
Cannabinoids and the Endocannabinoid System
Marijuana, or cannabis, colloquiallyreferredtoasweed,pot,
grass,herb,bud,ganja,andsoon,isthemostcommonlyused
illicit drug both nationally and internationally. Roughly, 180.6
million people worldwide report lifetime cannabis use [1], and
24.6 million people in the USA report past-month use [2].
Cannabis is derived from the plant Cannabis sativa, Cannabis
indica,orCannabis ruderalis, which is includes 70 known
cannabinoids, including 7 cannabigerols, 5 cannabichromenes,
7 cannabidiols (CBD), 9-Δ-9-tetrahydrocannabidiols (THC-9),
2-Δ-8-tetrahydrocannabidiols (THC-8), 3 cannabicyclols, 5
cannabielsoins, 7 cannabinols, 2 cannab inodiols, and 9
cannabitriols [3]. In addition to whole-plant cannabinoids, there
are a variety of synthetic cannabinoids (e.g., dronabinol and
nabilone, both synthetic THCs) and cannabinoid extracts
(e.g., the oro-muco sal spray nabi ximols that contain both
THC and CBD) that are used both clinically and in research [4].
THC and CBD are the most commonly researched canna-
binoids in the literature and there is variability in the location,
mechanism, and consequences of their actions. THC has a
high affinity for cannabinoid type 1 receptors (CB
1
R) [5],
which are found in the highest densities in the neuron termi-
nals of the basal ganglia, cerebellum, hippocampus,
Neurotherapeutics (2015) 12:735–746
DOI 10.1007/s13311-015-0380-8
Electronic supplementary material The online version of this article
(doi:10.1007/s13311-015-0380-8) contains supplementary material,
which is available to authorized users.
* Jane Sachs
jane.sachs@utah.edu
1
Department of Psychiatry, University of Utah, 383 Colorow Drive,
Salt Lake City , UT 84108, USA
neocortex, and hypothalamus and limbic cortex [6–10]. These
brain regions are involved in motor activity, coordination,
short-term memory, executive function, and appetite and se-
dation, respectively, and it is possible that THC activity in
CB
1
R in these regions may explain many of the acute effects
of cannabis use [9], which will be addressed later. The
endocannabinoid system also contains cannabinoid type 2
receptors (CB
2
R), which are found primarily in immune cells
and tissues [6, 11]. There is evidence that activity of endog-
enous cannabinoids (e.g., anadamide) and exogenous canna-
binoids (e.g., THC) at CB
2
R may have opposing effects on
the immune system, with endogenous cannabinoids enhanc-
ing immune response and exogenous cannabinoids having
immunosuppressant effects [12]. In contrast to THC, CBD
has relatively low a ffinity for both CB
1
R and CB
2
R[5].
Despite the relatively low affinity of CBD at CB
1
Rand
CB
2
R, it demonstrates high potency as an antagonist.
Furthermore, there is evidence that CBD may mitigate some
of the effects of THC [13–15], potentially through indirect
agonism, either by augmenting CB
1
R constitutional activity
or endocannabinoid tone [5].
The already complex interactions of exogenous and endog-
enous cannabinoids in the cannabinergic system are further
obfuscated by different methods of administration, inconsistent
dosing measure s, and highly variable cannabinoid conten t of
cannabis plants. Cannabinoid content and consequent potency
has shown extreme variance depending on the light, tempera-
ture, humidity, and soil type during cultivation, as well as ge-
netic factors [16–19]. This is evidenced by changes in potency
over time as more cannabis is grown in doors and as strains are
engineered with diff erent THC and CBD ratios [17, 19, 20].
Furthermore, the method of administration (e.g., oral, smoked,
vaporized) and form of cannabinoid consumed (e.g., stems and
buds, hashish, hash oil, extract, synthetic) can impact the bio-
availability and consequently the response to use [4, 6, 18,
21–25 ]. This is particularly salient when comparing recreation-
al and medical forms of cannabis. Collectively, these factors
contribute to the difficulty in deciphering the relative safety
and efficacy of cannabinoids both medically and recreationally.
Safety: Acute and Long-term Effects
Despite the variability in research methodology and quality,
there are some generalizable findings regarding the acute and
long-term effects of exogenous cannabinoids.
Effects on Physical Health
Cardiovascular
Cannabinoids have shown both acute and long-term cardio-
vascular effects. Acute dose-dependent effects of cannabis
include tachycardia, increased cardiac labor, systemic vasodi-
lation, and increased blood pressure [15, 26–29]. More severe
effects such as increased angina, myocardial infarction, cardi-
ac death, and cardiomyopathy have been recorded in individ-
uals with pre-existing cardiovascular conditions [16, 20, 28,
30], and as such it is recommended that these individuals
avoid cannabis use [31]. Paradoxically, the long-term cardiac
effects of chronic cannabis use include bradycardia and hypo-
tension, which may reflect tolerance and down-regulation
over time [16, 32, 33].
Respiratory
Smoking is one of the main methods of cannabis administra-
tion. As such, the impact that smoking cannabis has on the
respiratory system has been a point of serious concern for
policy makers. A number of acute and chronic effects on the
respirato ry s ystem are associat ed with cannabis use.
Specifically, acute cannabis use has been shown to increase
inflammation of large airways, increase airway resistance, and
destroy lung tissue [15, 20, 29]. Further, there is evidence that
chronic cannabis use also results in increased risk of chronic
bronchitis [20, 29, 34], increased risk of emphysema [29],
chronic respiratory inflammation [20, 26, 29, 35], and im-
paired respiratory function [27, 28].
Cancer
Although there is a pathophysiologic al proc ess by which
chronic cannabis use could confer an increased risk of cancer
the epidemiological literature on the causal relationship is
mixed [34–36]. Hashibe et al. [36] found that smoking canna-
bis was not associated with an increased risk of smoking-
related cancers (e.g., lung, head, and neck), but might be as-
sociated with an increased risk of prostate cancer, cervical
cancer, and glioma. Conversely, Reece [29]reportedthat
smoking cannabis is associated with an increased risk of lung
cancer. Other findings suggest that while cannabis does in-
crease the risk of lung cancer, it is still lower than the risk of
lung cancer associated with tobacco [20].
Comparisons of cannabis and tobacco smoke have pro-
duced mixed findings. Repp and Raich [20] found that canna-
bis smoke contains ammonia, hydrogen cyanide, nitric oxide,
and aromatic amines at 3–5 times the rate of tobacco smoke.
However, Maertens et al. [37
] found that aside from the can-
na
binoids and nicotine, cannabis and tobacco smoke conden-
sates contained mixtures that were qualitatively similar. They
also found that cannabis smoke condensate and tobacco
smoke condensate influence the same molecular processes
but have subtle pathway differences that potentially account
for differential toxicities and the mixed results with respect to
lung cancer [37].
736 Sachs et al.
Immune System
Given the prevalence of CB
2
R in immune cells and tissues,
exogenous cannabinoids likely produce immunological im-
pacts both acutely and chronically [11]. However, the influ-
ence of exogenous cannabinoids on the immune system is
multifaceted and while comprehension is improving, contin-
ued research is required [16]. While there is some evidence of
immunosuppressive properties of cannabis [15, 26], there is
evidence of anti-inflammatory and neuroprotective effects of
CBD [13]. Specifically, CBD inhibits interleukin-10, while
also increasing interleukin-8, which could have potentially
therapeutic results in immune disorders [13]. The presence
of both positive and negative impacts of cannabis on the im-
mune system illustrate the potential biphasic impact on the
immune system, with benefits at high and low levels an d
detriments at moderate levels [13, 15, 26]. Similarly, Suarez-
Pinilla et al. [12] found that endocannabinoids enhanced im-
mune response, while exogenous cannabinoids had immuno-
suppressant effects.
Sleep
There is mixed evidence regarding the impact of cannabinoids
on sleep [38]. Sedation and somnolence are commonly de-
scribed acute adverse effects of heavy cannabis use [4,
39–41]. Furthermore, cannabis has been shown to increase
total sleep time in individuals with difficulty sleeping, includ-
ing in cancer patients with chronic pain [42], individuals with
post-traumatic stress disorder [43], and individuals with in-
somnia [41]. However, cannabis has been show to decrease
slow wave sleep [6, 38]. This suggests that a consequence of
the increased sleep time may be decreased sleep quality. There
is also some evidence that sleep difficulty is a withdrawal
symptom associated with cannabis use disorders [15, 44].
Effects on Cognition
It is clear that exogenous cannabinoids have an effect on cog-
nition; however, there is considerable variability between the
acute neuropsychological, chronic neuropsychological, and
neuroimaging findings.
Acute Effects
Cannabis use has well evidenced acute impacts on cognition
[13, 16, 20, 26, 34, 45–48]. Specifically, it has been reported
to impair free recall [16, 20, 45], acquisition [16], working
memory [15,
45],
and procedural memory [20, 45].
Impairments are also demonstrated on measures of attention
[15, 20, 48], impulsivity [15, 20], inhibition [49], sensory
perception [26], and executive function [20, 26, 50–52]. On
other measures of cognitive function the, evidence of deficits
is less clear. Some studies report impairments in gross and
simple motor tasks after acute cannabis use [13, 15, 16, 26,
34], whereas others find that evidence on impairments in psy-
chomotor function is inconclusive [45]. Likewise, evidence
for the impact of acute cannabis use on abstract reasoning
and decision making is mixed, with some reports of impair-
ment [20, 34], and other studies demonstrating no impact [15,
45]. Although there are clear acute cognitive effects of canna-
bis use, the majority are relatively short lived and diminish
over time with abstinence [20, 26, 48, 53, 54].
Chronic Effects
Most studies have found limited evidence of persistent neuro-
psychological deficits among cannabis users [20, 45, 47, 51,
53–55], particularly for those who initiated cannabis use as
adults [56]. However, the risk of long-term cognitive effects of
cannabis use appears to increase with earlier age of onset [26,
45, 47, 48, 56–58], frequency of use [15, 34, 45, 47, 49, 59],
an
d duration of use [15, 34, 45, 47, 49]. For instance, Repp
and Raich [20] found that adolescents who initiate cannabis
use before the age of 15 years demonstrate persistent pro-
nounced deficits in visual attention, verbal fluency , inhibition,
short-term recall, impulsivity, and executive functioning.
Similarly, Meier et al. [46] found that cessation of cannabis
did not fully restore cognitive deficits among adolescent-onset
cannabis users, and may result in a greater loss of IQ in ado-
lescence [46, 57]. Moreover, adolescent-onset users diag-
nosed with cannabis dependence prior to the age of 18 years
were more likely to become persistent users and showed im-
pairments in executive functioning and processing speed [46].
Other factors that may influence long-term neuropsychologi-
cal effects and make between-study comparisons difficult in-
clude length of abstinence and the THC to CBD ratio [26, 45,
47]. This is particularly interesting because studies of acute
administration suggest that CBD may be protective against the
negative cognitive impacts of THC [45].
Neuroimaging Studies
In addition to the neuropsychological assessments, a number
of studies have applied neuroimaging techniques to examine
the effects of exogenous cannabinoids on brain structure,
function, and connectivity. Recent morphological studies of
adults and adolescents have found structural abnormalities in
CB
1
R-rich areas, particularly in the medial temporal and fron-
tal cortices and cerebellum, and most notably among chronic
cannabis users [6, 28, 49, 60–64]. Specifically, structural neu-
roimaging findings suggest there are reductions in
parahippocampal, hippocampal, and thalamic volume associ-
ated with chronic cannabis use when compared with healthy
controls [47]. Studies of chronic adolescent cannabis users
also showed structural differences in the hippocampus and
Safety and Toxicology of Cannabinoids 737
amygdala [65]; gray matter volume reduction in the medial
temporal cortex, temporal pole, parahippocampal gyrus,
insula, and orbitofrontal cortex [6]; and reduced prefrontal
volumes and white matter integrity when compared with con-
trols [49, 60]. Studies of marijuana users who have also used
alcohol or tobacco have also shown changes in brain mor-
phometry. Heavy marijuana using adolescents with co-
occurring alcohol use were found to have increased cortical
thickness, particularly in frontal and parietal regions [66]. An
investigation by Wetherill et al. [67] comparing adult cannabis
users with and without co-occurring tobacco use reported that
both groups showed smaller thalamic gray matter volume than
nonusers; however, both cannabis groups and a cohort of to-
bacco smokers showed increased left putamen volumes.
Reduced left cerebellum gray matter in nico tine users but
not in cannabis users suggested that nicotine and cannabinoids
exert differential effects on regional brain tissue volume [67].
Moreover, evidence suggests that in adolescents functional
alterations may appear shortly after starting drug use [60].
Therefore, while cannabis use may result in morphological
alteration in adults and adolescents, early onset, longer dura-
tion, and heavier use are associated with more significant al-
terations in structural integrity [49].
Alterations in brain function have also been observed dur-
ing cannabis use. There is strong evidence that acute cannabis
administration increases cerebellar and prefrontal blood flow
[49, 62, 65]. However, resting state prefrontal blood flow is
lower in chronic cannabis users when compared with controls
[49, 60, 62]. This may represent the down-regulation of CB
1
R
receptors during the resting state among chronic users [60].
Additionally, acute administration of cannabis may increase
anterior cingulate cortex activity during cognitive tasks and
increase brain metabolism in multiple regions during impul-
sivity tasks [49, 62, 68, 69]. The greater task-related activation
among chronic cannabis users may reflect impaired efficiency
and recruitment of additional regions [49, 60, 62, 70].
Furthermore, there is also evidence that adults who initiated
regular cannabis use in adolescence may have impaired func-
tional connectivity [34]. Specifically , neuroimaging data indi-
cate reduced connectivity within prefrontal networks, which
may be partially responsible for deficits in executive function
among regular heavy cannabis uses who initiated use in ado-
lescence [34]. These abnormalities may be explained by the
influence of cannabis on the still-developing endocannabinoid
system, particularly the disruption of normal pruning during
adolescence when extensive re-organization of gray and white
matter is occurring [57, 60]. However, while changes in white
matter have been reported in adolescent cannabis users, the
mechanisms for the change and long-term effects have not
been fully characterized [65].
Finally, magnetic resonance spectroscopy (MRS) is a non-
invasive measurement technique that enables the in vivo quan-
tification of a range of neurometabolites, including γ-
aminobutyric acid (GABA) and glutamate. The effects of
chronic marijuana exposure have been examined through the
application of MRS imaging. For example Chang et al. [71]
reported reduced glutamate, choline, and myoinositol concen-
trations in the basal ganglia of chronic marijuana users.
Applying MRS imaging, Hermann et al. [72] identified lower
concentrations of N-acetyl aspartate in the dorsolateral pre-
frontal cortex of adult smokers. Prescot et al. applied recently
completed a small pilot study using proton MRS to the ante-
rior cingulate of marijuana smoking and non-smoking adoles-
cents and also found reduced N-acetyl aspartate, as well as
reduced glutamate and creatine in marijuana-using individuals
[73].
Effects on Mental Health
Disruptions of the cannabinergic system may have important
implications for a number of neurobehavioral processes [74].
There is evidence of an association between cannabis use and
both acute and chronic mental illness and psychiatric condi-
tions, including depression, anxiety, psychosis, bipolar disor-
der, schizophrenia, and an amotivational state [29, 34].
However, given the variation in the disease process, as well
as inconsistent cannabis dosing and composition, the full na-
ture of the associations remains to be clarified.
In studies of cannabis use and bipolar disorder, it appears
that cannabis use may exacerbate or trigger manic symptoms
among individuals previously diagnosed with bipolar disor-
der. Gibbs et al. [75] found a 3-fold increase in risk for onset of
manic symptoms after cannabis use [75]. However, there does
not seem to be evidence that cannabis use is a risk factor for
developing bipolar disorder [75]. Mixed findings are found
when examining the relationship between cannabis use and
depression and anxiety. There is some evidence that cannabis
us
e and cannabis withdrawal may result in acute depressed
mood [15, 29, 76]. Similarly, studies suggest that cannabis
may increase acute anxiety [4, 15, 77]. The picture of chronic
anxiety and depression and cannabis use is more complicated,
in part because frequent cannabis users have both a higher
prevalence of anxiety disorders, and individuals with anxiety
have high rates of cannabis use [77, 78]. The fact that individ-
uals who initiate cannabis use in adolescence may develop
depression and anxiety that persists after cessation may also
influence this relationship [20]. Furthermore, interpreting cau-
sality is complicated by the fact that a low concentration of
THC may have anxiolytic effects, whereas higher concentra-
tions produce anxiogenic effects [15, 77], and the evidence
that CBD may mitigate the effects of THC in animal models
of anxiety [5].
A significant portion of the literature dedicated to cannabis
use and mental health focuses on the relationship between
cannabis use and schizophrenia and psychosis. A number of
studies suggest that acute cannabis exposure may induce
738 Sachs et al.
temporary psychosis [4, 26]. Additionally, chronic cannabis
use may trigger psychosis and schizophrenia in individuals
with a predisposition or genetic susceptibility to mental illness
[12, 20, 26, 57, 65, 79, 80]. This appears to occur in a dose-
dependent manner, such that heavy cannabis use, longer du-
ration, greater potency, and early onset of use may be more
closely aligned with disease trajectory, often significantly ad-
vancing the first psychotic episode and development of
schizophrenia [15, 20, 57, 65, 80, 81]. Additionally, lifetime
cannabis use has been associated with higher schizotypy
scores [82], and cannabis may exacerbate pre-existing symp-
toms of psychosis and schizophrenia [6]. Furthermore, indi-
viduals with psychosis may be more vulnerable to brain vol-
ume loss, which has been suggested as a result of cannabis
exposure [6, 63, 83].
Although there is strong evidence that early cannabis use
among at-risk individuals may increase the likelihood of de-
veloping schizophrenia or psychosis at a later time point, ad-
ditional research is necessary to parse out the intricacies of the
interaction between THC and CBD on the cannabinergic sys-
tem. For example, several systematic reviews found that while
cannabis use may increase subclinical symptoms of psychosis,
the findings to date do not support an association between
cannabis use and first psychosis [84]. Additionally, there is
some evidence that cannabis with a high CBD and low THC
content may mitigate psychosis [5, 85, 86].
Public Health and Safety
In addition to the physical, psychological, and cognitive ef-
fects of cannabis, there are clear concerns about public health
and safety. A potentially serious public health effect of canna-
bis use is a high incidence of drugg ed driving and motor
vehicle accidents [16, 26]. Moreover, driving impairment oc-
curs in a dose-dependent fashion [26, 87], and individuals
driving under the influence of cannabis are anywhere from 2
to 7 times more likely to be involved in both fatal and nonfatal
motor vehicle collisions [20, 34].
Another risk associated with cannabis use is addiction and
cannabis dependence. Nine to ten percent of individuals who
initiate cannabis use will become addicted [6, 20, 34]. That
number increases to 16–
17 % among individuals who initiate
u
se as an adolescent and 25–50 % among individuals who use
cannabis daily [20]. The risk for addiction appears to wane as
the individual ages, such that it is rarely addictive if use begins
after the age of 25 years [65]. However, currently 6.5 % of
twelfth graders in the USA report daily cannabis use [34], and
there is evidence to suggest that as perception of harm de-
creases, prevalence of use increases [88]. This is particularly
important because early exposure to cannabinoids may alter
the reactivity of the dopamine reward centers in the brain,
thereby increasing vulnerability to abuse of and addiction to
other substances, and adding support to the g ateway
hypothesis [34, 89]. Furthermore, heavy cannabis use may
be linked to negative consequences downstream, including
lower income, greater need for socioeconomic assistance, un-
employment, and lower life satisfaction [34].
There is also evidence of negative impacts on maternal and
child health. Cannabis use during pregnancy is associated with
poor physical outcomes, including birth defects, low birth
weight, and an increased risk of childhood cancer, as well as
poor neurodevelopmental outcomes, including aggressive be-
havior and attention problems in girls [20, 29, 35]. For exam-
ple, children who were exposed to marijuana prenatally are
more likely to demonstrate decreased problem-solving skills,
as well as poor memory and attention [90, 91]. Similarly,
babies exposed to marijuana prenatally show traits indicative
of neurological development problems [92, 93].
Therapeutic Potential
Despite the acute and chronic side effects of cannabis use,
there is a growing body of evidence suggesting the therapeutic
potential of cannabis. This is likely facilitated, in part, by the
fact that certain c annabinoids, like CBD, have been well-
studied and are well tolerated and safe in humans, even at high
doses and chronically [94]. Exogenous cannabinoids, includ-
ing nab iximols, CBD extract, and even smok ed cannabis,
have bee n rec ommended medically for ca ncer, a norexia ,
AIDS, chronic pain, spasticity, glaucoma, arthritis, migraine,
and other illnesses for which cannabis provides relief [15, 34].
Additionally, the American Academy of Neurology published
a position statement concluding that medical cannabis is
‘probably effective’ for some symptoms of multiple sclerosis
(MS), including spasticity, central pain, spasms, and urinary
dysfunction; is ‘probably ineffective’ for levodopa-induced
dyskinesia of Parkinson’s disease (PD); and of ‘unknown ef-
ficacy’ in nonchorea symptoms of Huntington’s disease (HD),
Tourette’s syndrome, cervical dystonia, and epilepsy [6, 95].
Neurological Conditions
The literature on the therapeutic potential of exogenous can-
nabinoids in the treatment of MS has been the most promising.
There is evidence that cannabinoids may have neuroprotective
and anti-inflammatory effects in individuals with MS through
the regulation of cytokine levels [96]. However, it should be
noted that the degree of therapeutic potential varies according
to preparation. There is evidence that oral cannabis extract and
nabiximols, an oral mucosal spray containing a 1:1 ratio of
CBD:THC, reduce spasticity in patients with MS [4, 6, 20,
95]; however, smoked marijuana is of uncertain efficacy [95].
Similarly, the American Medical Association found that a re-
view of small, short-term randomized controlled trials demon-
strated that smoked cannabis reduces neuropathic pain,
Safety and Toxicology of Cannabinoids 739
improves appetite, and may relieve spasticity and pain in pa-
tients with MS [97]. There is also some evidence of reduced
muscle stiffness, relief from pain, and improved sleep quality
among patients with MS using oral cannabis extract [6]; how-
ever, these findings arise from subjective assessment of symp-
tom relief and may be secondary to improvements in spasticity
[6, 96]. While many studies suggest that cannabis may be a
useful therapy for MS-related symptoms, it is important to
note that not all studies assess adverse physical and cognitive
impacts. Wade et al. [98] found that patients with MS who
demonstrate symptom relief after use of nabiximols can con-
tinue use in the long term without tolerance, intoxication, se-
rious adverse effects, or decrease in subjective symptomatic
relief. Although the literature suggests only mild adverse
physical effects associated with medical cannabis use for treat-
ment of MS, recent studies of cannabis use in patients with
MS have reported cognitive diminishment and impairment of
cerebral compensatory mechanisms when compared directly
with patients with MS who have not used cannabis [99–101].
Investigators from these studies raised concerns regarding the
use of cannabis in a patient group with cognitive challenges
prior to cannabis use.
Evidence for efficacy in other neurological conditions relies
heavily on testimonials and anecdotes [20]. Animal models
demonstrate the antiepileptic potential of cannabis [6, 102],
and suggest that CBD may enhance the efficacy in preclinical
models of epilepsy [5]. Nevertheless, there have been few con-
trolled trials. One systematic review found that short-term daily
cannabis use is safe in individuals with epilepsy, but there is
currently insufficient evidence to form a conclusion about effi-
cacy [34, 102]. Similarly, preclinical models Alzheimer’sdis-
ease, PD, and HD are mechanistically promising [6, 95, 103].
CB
2
R expression correlates with levels of β-amyloid-42 and
plaque density [104]. Furthermore, cannabinoids may inhibit
tau hyperphosphorylation and prevent β-amyloid aggregation
[105, 106 ], suggesting therapeutic potential in models of
Alzheimer’s disease. Similarly, the presence of striatal canna-
binoid receptors on GABA terminals demonstrates a mecha-
nism in which cannabinoids could improve dyskinesia by im-
proving GABA transmission in the globus pallidus in patients
with PD [107]. Finally, animal models of HD using cannabi-
noids as treatment demonstrate preservation of striatal neurons
[108]. However, despite the success of these preclinical animal
models, evidence from human studies remains scant [6].
Psychiatric and Psychological Conditions
Research on the therapeutic benefits of exogenous cannabinoids
on psychological conditions is equally sparse. Early clinical tri-
als have demonstrated that high-dose oral CBD may have an
anxiolytic effect, possibly through 5-HT
1A
agonism [5, 41]. In
patients with schizophrenia elevated anadamide levels are neg-
atively correlated with psychotic symptomology, which
suggests a protective role [ 86]. In spite of this, the benefits of
CBD monotherapy are not consistently demonstrated in individ-
uals with bipolar disorder or schizophrenia [41, 109, 110]. There
is some evidence that cannabis may have a beneficial impact on
sleep quality among individuals with post-traumatic stress dis-
order [6, 43]. However, more research is needed to confirm and
further explore the therapeutic ef fects of cannabis or synthetic
cannabinoids on psychological conditions.
Other Medical Conditions
Some of the first conditions medicinal cannabis was approved
for include glaucoma, chronic pain, and nausea and vomiting
associated with cancer treatments and AIDS. There is good
evidence that exogenous cannabinoids can decrease intraocu-
lar pressure in individuals with glaucoma [20, 21]. However,
in order to have a clinically significant impact the dose and
frequency of use needs to be extremely high, which may in-
crease the likelihood of negative side effects [34]. Medicinal
cannabis has also been used to treat chronic neuropathic pain,
particularly when conventional methods do not work. Current
research suggests that cannabinoids, including oral cannabis,
THC, and nabiximols, provide effective analgesia [4, 6, 34,
111–113]. There is also some evidence that cannabinoids may
be safe and moderately effective in the treatment of pain as-
sociated with fibromyalgia and rheumatoid arthritis [34, 42,
114]. Treatment with medicinal cannabis has resulted in de-
creased need for antiemetic in individuals undergoing chemo-
therapy [34, 39, 113, 115, 116]. Additionally, while medicinal
cannabinoids (e.g., nabilone, dronabinol, and levonantradol)
are not significantly better at treating nausea or vomiting than
conventional medications, patients receiving chemotherapy
often prefer them [34, 39, 116, 117].
Although there is evidence for the therapeutic potential of
exogenous cannabinoids in the treatment of a number of con-
ditions there is still serious trepidation regarding the potential
negative side effects. A large systematic review of the adverse
events associated with the use of medical cannabis demon-
strated that short-term use of existing medical cannabinoids
increases the risk of nonserious adverse events including mild-
to-moderate sedation, dizziness, dry mouth, nausea, and poor
attention [117]. The rates of serious adverse events (e.g., re-
lapse of MS, vomiting, and urinary tract infections) were not
different from controls [117]. Further research is needed to
better understand the long-term effects of medical cannabis.
Policy Perspective
Policy Timeline and Research Limitations
Perception s and policy regarding cannabis have vacillated
widely over the years, reflecting the relative temporal valence
740 Sachs et al.
of scientific evidence compared with public opinion at a given
point in time. For example, California legalized medical can-
nabis in 1996, despite the federal ban [118]. Shortly thereafter,
the Institute of Medicine issued a report acknowledging the
potential therapeutic benefits of cannabis, but calling for more
research. More recently, the pace and quality of research has
been limited by stagnant policy. Cannabis was and still is
categorized as a Schedule I drug, which means it is identified
as potentially addictive without any medical benefit. As a
Schedule I drug, the process for conducting research is ex-
tremely complicated. Researchers must have a Drug
Enforcement Agency Schedule I license, approval from their
institution, and funding. Obtaining all 3 is extremely challeng-
ing and has been a limiting factor in the advancement of cur-
rent cannabis research. In lieu of the ability to conduct ran-
domized controlled trials, many researchers must instead fo-
cus their efforts on retrospective cohort studies, case reports,
and observational studies. There has been significant debate
over the merits of re-classifying cannabis as a Schedule II
drug, as it would greatly increase research accessibility and
consequently methodological quality [119]. Ironically, the
limited clinical research coupled with divisive public opinion
and perception hinders the reclassification. In addition to re-
classification, research regarding cannabis safety and efficacy
is affected by a lack of standardization. Current clinical re-
search findings are constrained by inconsistency in definitions
of what constitutes a standard dose and how to quantify and
standardize methods of administration [120]. Additionally, a
great deal of the research relies on subjective, patient report,
and patient-driven symptoms rating scales [95]. Ultimately,
the federal policies remain stagnant because the process is
circular; the c linical research methods and standardization
are limited by the current policy, but the current policy is
difficult to change because the lack of research standardization
produces mixed findings.
Public Perspective and Perceived Risk
Despite the stagnant federal policy, public perspective and
perceived risk has demonstrated a noticeable shift.
According to the 2012 National Survey on Drug Use a nd
Health, cannabis is the most commonly used illicit drug in
the USA with a national prevalence of cannabis use in the past
month at 7 % [121]. Similarly, the Monitoring the Future
Study has documented increased rates of use and decreased
perceived risk between 2002 and 2012 among high-school
students [88, 122]. This is further evidenced by the fact that
62 % of recent cannabis initiates were 18 years of age or
younger when they first used [121]. The epidemiological ev-
idence on use and perceived risk demonstrates a relatively
clear trend in public opinion that is reflected in state but not
federal policy. Despite a federal ban and limitations in the
quality of evidence surrounding the potential risks associated
with cannabis use, medical cannabis is currently legal in 23
states and the District of Columbia, and recreational cannabis
is legal in 4 states [6, 123].
Implementation Variation
Currently, there is state-by-state variation in the way medical
cannabis legislation is designed and implemented.
Specifically, there is inconsistency in the way in which states
regulate patient use and access, caregiver rights, the role of
dispensaries, and product safety and packaging requirements
[124]. First and foremost, states can choose to enact medical
cannabis legislation by 1 of 2 mechanisms, either through the
introduction of statutory provisions or through the creation of
an amendment to the state’s constitution. The majority of
states with medical cannabis laws have opted to enact statuto-
ry provisions, in part because the process is easier, though also
less stable. The next aspect of legislative design is determining
who qualifies for medical use and how they obtain permission.
Because physicians are subject to sanctions from the federal
government, they cannot prescribe cannabis but rather must
recommend use. The contexts for which a recommendation
can be given vary. Some states require diagnosis of a medical
condition in addition to a physician recommendation, whereas
others simply require a physician recommendation [124].
After obtaining a physician recommendation there are 2 ap-
proaches an individual can follow to procure medical canna-
bis: home cultivation or from an approved dispensary.
Currently, 15 out of 24 jurisdictions allow home cultivation;
however, the circumstances under which home cultivation is
permissible and the defined quantity allowed in circulation
varies by jurisdiction (Table 1)[123]. Similarly, 19 out of 24
states allow dispensaries or compassionate care centers to en-
gage in some combination of dispensing activities, including
acquisition, possession, cultivation, manufacturing, delivery,
transfer, selling, supplying, and dispensing of cannabis [123,
124
]. Finally, there is variation in legal protections afforded to
ph
ysicians, caregivers, and patients who may be involved in
recommending, acquiring, or using medical cannabis. There
are 2 types of protections: legal privilege that prevents the
state from bringing criminal chargers, and affirmative defense
that allows the individual to prevail against the criminal
charges. Currently, legal protections for patients and care-
givers differ from t hose for recommending physicians.
Namely, the pro tections p revent the state from bring ing
charges against the physicians, whereas patients and care-
givers may be tried but have affirmative defense that excuses
criminal culpability [124].
While policy should be supported by the scientific evi-
dence, the ability to generate quality evidence thus far has
been hindered by federal policy. This has resulted in a piece-
meal state-based system without the ability to fully assess or
implement safeguards [97]. As legalization of medical and
Safety and Toxicology of Cannabinoids 741
recreational cannabis at the state level becomes more preva-
lent, jurisdictions are making an effort to implement safe-
guards, including safety testing, packaging requirements, la-
beling requirements, media advertisement restrictions, and
distribution site features. However, of the 24 jurisdictions that
have legal medical or recreational cannabis law, only 15 have
product testing and regulation requirements, and only 8 have
mandatory testing [123]. Therefore, while public perspective
trends suggest continued state-based legislative change, the
lack of federal regulation and infrastructure poses serious safe-
ty concerns.
Discussion: Future Directions
The literature on medical and recreational cannabis suggests
clear discordance between current federal and state policies,
public opinion, and the scientific evidence. Moreover, this
discordance appears to hinder the implementation of both high
quality research and adequate safeguards.
The scientific evidence is often inconclusive and burdened
by methodological inconsistency. The classification of canna-
bis as a Schedule I drug limits the type and quality of research,
forcing assessments of safety and efficacy to rely on observa-
tional studies. Furthermore, definitions of standard dose vary,
as do means of administration, cannabinoid content, potency,
and reason for use (recreational and medical). Despite the
methodological challenges, the findings to date illustrate rela-
tively clear acute cardiovascular, respiratory, cognitive, psy-
chological, and public health effects associated with both rec-
reational and medical cannabis use. However, the documented
persistence of these acute effects is considerably more vari-
able. Long-term cardiovascular and respiratory consequences
of cannabis use are fairly well evidenced. However, the find-
ings regarding long-term cognitive, psychological, and im-
mune effects are less clear. Few studies have assessed the
long-term impact o f cannabis on the immune system, and
questions remain regarding the relative impacts of THC and
CBD on immunity. Likewise, among healthy adults there is
mixed evidence for long-term cognitive and psychological
impacts of heavy cannabis use after discontinuation and wash-
out [4, 20, 45–47, 55]. Some studies do report long-term def-
icits in learning and memory, but the findings are inconsistent
[4, 15, 34, 45, 47 , 55]. It appears that persistent cognitive
diminishment and psychological impacts are closely related
to early age of onset, increased duration, and frequency of
Table 1 Medical and recreational marijuana legislation by jurisdiction [123]
Jurisdiction State authorizes
medical marijuana
States authorizes
recreational marijuana
Affirmative
defenses
Home
cultivation
State regulates
dispensaries
Product safety
testing
Alaska Yes Yes Yes Yes No No
Arizona Yes No No Yes Yes Yes
California Yes No Yes Yes Yes No
Colorado Yes Yes Yes Yes Yes Yes
Connecticut Yes No Yes No Yes Yes
District of Columbia Yes Yes Yes No Yes Yes
Delaware Yes No Yes No Yes Yes
Hawaii Yes No Yes Yes No No
Illinois Yes No No No Yes Yes
Massachusetts Yes No Yes Yes Yes Yes
Maryland Yes No No No Yes No
Maine Yes No Yes Yes No Yes
Michigan Yes No Yes Yes Yes No
Minnesota Yes No No No No Yes
Montana Yes No Yes Yes Yes No
New Hampshire Yes No Yes No Yes No
New Jersey Yes No No No Yes Yes
New Mexico Yes No Yes Yes Yes Yes
Nevada Yes No Yes Yes Yes Yes
New York Yes No No No Yes Yes
Oregon Yes No Yes Yes Yes Yes
Rhode Island Yes No Yes Yes Yes No
Vermont Yes No No Yes Yes Yes
Washington Yes Yes Yes Yes No No
742 Sachs et al.
use. Age of onset and frequency of use also have an impact
substance abuse and dependency later on, with addiction rates
of 16–17 % among individuals who initiate use as an adoles-
cent and 25–50 % among individuals who use cannabis daily
[20]. Collectively, these findings begin to depict vulnerable
populations who may be negatively affected by the effects of
by cannabis use, including adolescents, individuals with cur-
rent or past substance use disorders, individuals with a per-
sonal or family history of mental illness, those that have com-
promised cardiovascular, respiratory, or immune systems, and
those who are pregnant [31]. However, among the average
adult user the health risks associated with cannabis use are
likely no more dangerous than many other indulgences, in-
cluding alcohol, nicotine, acetaminophen, fried foods, and
downhill skiing [125–128]. This viewpoint is echoed in regard
to medical cannabis as therapy. The side effects of conven-
tional medications are weighted against the potential benefits,
but this same logic is rarely applied to discussions of medical
cannabis. This dilemma is further exacerbated by the fact that
research on the the rapeutic potential of cannabis relies on
testimony and anecdote and is consequently heavily
subjective.
Given these findings one option for the future direction of
research on cannabis is to approach cannabis as a legitimate
therapeutic agent. This would include reclassification, as well
as more stringent and uniform supervision of its use and dis-
tribution in a safe, ethically, and scientifically justified manner
[125–128]. Such policies would allow for improved research
and consequently a better understanding of the safety and
efficacy of cannabis.
In addition to rescheduling cannabis, further thought may
be given to policy design. As state-based legalization becomes
more common policymakers should consider how their poli-
cies affect production, price, and use. There is some evidence
that legalization deflates production costs [129, 130], thereby
potentially decreasing the market price. However, it has also
been suggested that decreased cost may lead to increased use,
particularly among adolescents [129]. As a result, policy
makers ought to consider mechanisms to control cost. Taxes
may be a useful tool to influence price and potentially adoles-
cent use [130, 131]. Furthermore, revenue from those taxes
can be utilized to promote prevention programs. Another
mechanism to alter use includes limiting media promotion.
Currently, only 6 jurisdictions have implemented policies
restricting media advertising [123], so there is limited evi-
dence on efficacy, but evidence from similar policies in alco-
hol and tobacco prevention is promising.
Conclusion
In conclusion, despite the general uncertainty on the safety and
efficacy of medical and recreational cannabis use there are some
general themes that remain consistent. There are clear acute car-
diovascular , respiratory, cognitive, psychological, and public
health effects of cannabis use. Additionally, persistent cardiovas-
cular and respiratory consequences are fairly well documented in
chronic users. The evidence of other long-term impacts of can-
nabis are mixed, and likely influenced by age of first use, dura-
tion of use, frequency of use, potency , and co-morbid conditions.
Finally, there is evidence suggesting a therapeutic impact of can-
nabis on reducing spasticity associated with MS, chronic neuro-
pathic pain, and nausea and vomiting in individuals undergoing
chemotherapy. However, studies of patients with MS who used
cannabis raise a cautionary note regarding further cognitive di-
minishment, which may affect clinical outcomes. Therapeutic
potential in the treatment of other diseases is unclear and requires
more research. Collectively , these findings support the continued
therapeutic use of cannabis when conventional treatments are
ineffectiv e. However , when recommending medical cannabis,
physicians and patients would benefit from discussions of the
risks, benefits, and uncertainties associated with cannabis use.
Furthermore, medical cannabis should be avoided in vulnerable
populations, including individuals under the age of 25 years,
individuals with current or past substance use disorders, individ-
uals with a personal or family history of mental illness, those that
have compromised cardiovascular , respiratory, or immune sys-
tems, and those who are pregnant. Finally , efforts to reclassify
cannabis should continue and policy makers must consider im-
pacts on production, price, and use when crafting legislation.
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