Cannabis and Cannabinoid Research

Volume 9, Number 2, 2024 Open camera or QR reader and

ª Mary Ann Liebert, Inc. scan code to access this article
DOI: 10.1089/can.2023.0209 and other resources online.

REVIEW

Tolerability of High-Dose Oral D9-THC:

Implications for Human Laboratory Study Design
Jan Rozanc,1,2 Linda E. Klumpers,1,3 Marilyn A. Huestis,4 and Michael Tagen1,*

Abstract
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Background: D9-tetrahydrocannabinol (THC), the primary intoxicating compound in cannabis, has been tested
extensively in controlled administration human studies. Some studies require a high THC dose that may induce
adverse events (AEs), such as those testing novel treatments for cannabinoid overdose. Although there are eth-
ical concerns related to administering high THC doses, there is no systematic analysis on studies utilizing these
doses. In this review, we examine studies that administered oral THC doses ‡ 30 mg (‘‘high-dose THC’’), focusing
on reported tolerability, subjective effects, and pharmacokinetics (PK), with the objective to inform the design of
future studies.
Methods: A comprehensive PubMed search was performed to identify studies meeting pre-specified criteria.
Results: Our search identified 27 publications from 17 high-dose oral THC laboratory studies, with single doses
up to 90 mg and multiple doses up to 210 mg per day. The maximum plasma THC concentration (Cmax) appeared
to increase in a dose-proportional manner over this dose range. All high-dose THC studies enrolled participants
with previous cannabis experience, although current use ranged from nonusers to regular cannabis users. High-
dose THC was generally well tolerated with transient mild to moderate AE, including nausea and vomiting, anx-
iety, paranoia, and sedation. There were occasional participant withdrawals due to AEs, but there were no serious
AE. Participants with frequent cannabis use tolerated high-dose THC best.
Conclusion: Although based on limited data, THC was generally adequately tolerated with single oral doses of at
least 50 mg in a controlled laboratory setting in healthy participants with past cannabis experience.
Keywords: D9-tetrahydrocannabinol; tolerability; pharmacokinetics; adverse events

Introduction vomiting, anxiety, and transient psychosis-like effects

In 2020, an estimated 209 million people worldwide
aged 15–64 ( > 4% of the global population) reported
using cannabis in the past 12 months.1 The psychoac-
tive effects of cannabis are primarily attributed to D9-
tetrahydrocannabinol (THC), the main psychoactive
constituent of cannabis, which exerts its actions
through cannabinoid CB1 and CB2, and other recep-
tors.2 Although THC’s therapeutic properties are
being investigated, it is also associated with a variety
of potential adverse events (AEs), including tachy-
cardia, dizziness, motor incoordination, nausea and
such as paranoia.3,4
Many clinical studies of THC performed under con-
trolled laboratory conditions are not for a therapeutic
purpose, but to better understand THC’s pharmacol-
ogy. These studies often include characterization of
THC’s pharmacokinetics (PK) and pharmacodynamics
(PD) through visual analog scales (VAS) of subjective
effects. These studies also allow careful physician mon-
itoring to establish tolerability through the assessment
of AEs. Although human laboratory THC studies in-
cluded various routes of administration, oral dosing

1
Verdient Science LLC, Denver, Colorado, USA.
2
Institute of Biomedical Sciences, Faculty of Medicine, University of Maribor, Maribor, Slovenia.
3
Larner College of Medicine, University of Vermont, Burlington, Vermont, USA.
4
Institute of Emerging Health Professions, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

*Address correspondence to: Michael Tagen, PhD, Verdient Science LLC, 1942 Broadway Street, STE 314C, Boulder, CO 80302, USA, E-mail: mike@verdientscience.com

437
 438
is easier and has a longer duration of effect compared
with intravenous bolus or inhaled dosing.5
These properties make oral administration favorable
for clinical studies in some cases (e.g., there is more
time for study assessments), but with the disadvantage
that dose titration, which can reduce AEs, is not feasi-
ble. Most human laboratory studies with oral THC ad-
ministration utilized doses between 5 and 20 mg, which
corresponds to the common therapeutic and recrea-
tional dose range. These doses are established to be
generally well tolerated among cannabis-experienced
subjects.6 However, the objectives of some studies re-
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quire that higher doses be tested.
One example of where higher THC doses in a
human laboratory study may be needed is to assess
treatments for acute cannabinoid intoxication (ACI).
Between 2006 and 2014, emergency department visits
in the United States linked to cannabis saw an average
yearly increase from 12.3 to 34.7 visits per 100,000 pop-
ulation, but no evidence-based treatments yet exist for
ACI.7 Symptoms associated with ACI include nausea
and vomiting, anxiety, paranoia, and tachycardia.4
Although several CB1 antagonists, including surina-
bant, drinabant (now called INDV-5004), and rimona-
bant, were effective in inhibiting THC intoxication
effects in human challenge studies,8–10 none are yet ap-
proved specifically for THC intoxication treatment.
Several CB1 antagonists are currently under develop-
ment for treatment of ACI, such as ANEB-001 and
INDV-5004. Human laboratory THC studies can par-
tially replicate the effects of ACI and aid in the devel-
opment of new therapies. However, higher THC
doses are needed to mimic ACI, since cannabis-
experienced individuals typically tolerate oral THC
doses of 20 mg or less without notable AEs.
Even though high THC doses are sometimes needed
in human laboratory studies, there is currently little
guidance on the optimal way to design such as a
study. For example, there is no commonly agreed
upper limit on THC doses in healthy volunteers.
Although high-dose THC better recreates the symp-
toms of a patient seeking emergency department treat-
ment for cannabinoid intoxication, too high of a dose is
ethically problematic since it could cause distressing
AEs in study participants. The upper limit of acceptable
THC doses may also vary depending on factors related
to the study population (e.g., level of tolerance11 and
sex12,13), PK (e.g., THC formulation and whether it is
administered with food), and factors related to study
design (e.g., utilizing a dose escalation).
ROZANC ET AL.
Considering that no prior analysis has been per-
formed, we comprehensively assessed studies that tested
high oral THC doses, defining ‘‘high-dose’’ as ‡ 30 mg,
which is above the THC dose range commonly used for
recreational and medicinal purposes. We reviewed the
reported tolerability, general subjective effects, and PK
of THC and its active metabolite, 11-hydroxy-THC
(11-OH-THC). This analysis aims to inform the design
of future human laboratory studies.
Methods
Study identification
A comprehensive review of the literature was per-
formed up to August 21, 2023, using PubMed. The
search parameters included keywords ‘‘THC,’’ ‘‘tetrahy-
drocannabinol,’’ and ‘‘delta (9)-tetrahydrocannabinol.’’
Studies were included if they met the following criteria:
(1) conducted in humans (a total of 954 studies were
identified), (2) utilized an oral route of administration
(of which 143 are included in the human studies
count), and (3) included at least 1 cohort where THC
was administered alone with dose of at least 30 mg
(39 of these are counted among the oral administration
studies).
We excluded 12 publications from 9 studies14–23
where details of the AEs were not adequately reported,
for example, AEs not being reported by dose level
(27 studies of adequate reporting). We further grouped
multiple publications from a single study together and
identified 17 individual studies for the further analysis.
Figure 1 shows the process for inclusion of studies in
this analysis.
Pharmacokinetics
PK analyses were performed using R software (version
4.2.2; R Core Team, Vienna, Austria). THC and 11-
OH-THC concentrations quantified in whole blood
samples were converted to plasma concentrations
based on whole blood:plasma ratios of 0.66 for THC
and 0.64 for 11-OH-THC. For example, a whole
blood concentration of THC was converted to a plasma
concentration by dividing by 0.66. These ratios were
previously determined using validated analytical meth-
ods24 to quantify cannabinoid concentrations in fresh
whole blood and plasma samples analyzed within
24 h of collection after controlled THC administra-
tion.25 Dose proportionality was assessed by perform-
ing linear regression on the double-log transformed
plasma Cmax versus dose data and assessing whether
the 90% confidence interval of the slope contained 1.
 TOLERABILITY OF HIGH-DOSE ORAL THC
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FIG. 1. Flowchart for study inclusion.
Results
Study characteristics
A total of 27 publications describing the results of 17
clinical studies met the inclusion criteria (Table 1),
with a total of 266 participants (range: 6–53 participants
per study). Fourteen studies tested single oral THC
doses ranging from 30 to 90 mg per study and three
studies tested multiple doses with a maximum total
dose of 210 mg THC per day. Most of the studies
were randomized, double-blind, and placebo controlled.
We grouped participants into three different popula-
tions according to their recent cannabis use: non-
cannabis users (at least 1 month break since last use),
occasional cannabis users ( ‡ 2 times per month but
< 3 times per week), and frequent cannabis users ( ‡ 3
times per week). If a study did not clearly fit into one
group (e.g., ‘‘at least weekly’’), we placed it in the
group we thought best (Table 1).
The overall research goals of these publications were
varied. Five publications focused on toxicology, four
described drug discrimination, four reported func-
tional effects (e.g., cognitive performance, driving
439
ability, and sensory and perceptual motor skills), two
reported physiological effects (e.g., appetite and metab-
olism, and ammonia dynamics), six examined effects on
cannabis dependence and withdrawal symptoms, three
described the differential effects of cannabis and etha-
nol, one described subjective and physiological effects
of different administration methods, one described
abuse liability, one described brain scans, and one de-
scribed interactions between opioids and cannabinoids.
Pharmacokinetics
Of the studies evaluated, six reported on THC PK,12,26–30
five also included the PK of the active metabolite 11-OH-
THC,12,26–28,30 and four included THC-COOH metabo-
lite data.12,26–28
The means of the maximum plasma THC concen-
trations (Cmax) after single oral doses ranging from
10 to 90 mg are shown in Figure 2a. Although some
studies reported whole blood concentrations, we con-
verted them to plasma concentrations based on a
whole blood:plasma ratio of 0.66 for THC in fresh sam-
ples analyzed within 24 h of collection after con-
trolled THC administration.25 The plasma THC Cmax
appeared to increase in a greater than dose-proportional
manner.
This was assessed by performing linear regression on
the double-log transformed Cmax versus dose data and
observing that the slope was 1.44 with a 90% confidence
interval of 1.07–1.80, which did not contain 1. There are
several caveats to this analysis that we list in the discus-
sion. There was significant variability between the
means of some studies at the same doses. For example,
a 50 mg oral THC dose produced plasma Cmax ranging
from 5.3 to 22.5 ng/mL, a 4.2-fold difference.
The mean plasma Cmax concentrations for the active
metabolite 11-OH-THC are shown in Figure 2b. Whole
blood concentrations were converted to plasma con-
centrations as described earlier for THC based on a
whole blood:plasma ratio of 0.64 for 11-OH-THC.25
Similarly to THC, the mean Cmax for 11-OH-THC gen-
erally increased with dose and there was significant var-
iability in Cmax between studies at equivalent dose
levels. The slope from the dose proportionality test
was 0.87 with a 95% confidence interval of 0.60–1.15.
This indicates that the pattern for 11-OH-THC does
not deviate significantly from dose proportionality. It
is notable that the mean 11-OH-THC Cmax from one
dose group that appeared to be an outlier used a canna-
bis decoction,28 which is unique among the formula-
tions shown here.
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Table 1. Characteristics of Human Laboratory Tetrahydrocannabinol Studies Utilizing an Oral Dose of at Least 30 mg

Formulation and dose

References Use Population Dose Study design condition PK data VAS high

Spindle et al. (2020)12 NON 17 Adults (8 F), no cannabis
Schlienz et al. (2020)67 use ‡ 2 months
Vandrey et al. (2017)27 NON 18 Adults (6 per dose), no
Schlienz et al. cannabis use ‡ 3 months
(2018b)68
Melges et al. (1970)34 NON 8 M adults, no cannabis use
‡ 1 month
Ménétrey et al. (2005)28 OCC 8 M adults, no cannabis use
‡ 1 week
Tinklenberg et al. OCC 12 Adults, cannabis use
(1976)35 < 2 · /week
Roth et al. (1977)69
Kopell et al. (1978)70
Lewis et al. (1973)41 OCC 10 Frequent ( ‡ 2 · /week)
FREQ and 10 occasional ( £ 2 · /
month) cannabis users
(5 F per group)
Peters et al. (1976)42 OCC 10 Frequent ( ‡ 2 · /week)
0, 10, 25 or 50 mg THC
10, 25 or 50 mg THC, no
placebo
0, 20, 40, or 60 mg THC
0, 16.5, 20, or 45.7 mg THC
0 or 52.5 mg/75 kg THC
0, 15, 30, or 45 mg/75 kg THC
0, 15, 30, or 45 mg/75 kg THC
Single-dose crossover
Single-dose crossover
Single-dose crossover
Single-dose crossover
Single-dose crossover
Single-dose crossover
Single-dose crossover
One cannabis brownie after Yes VAS drug effect67
low-fat breakfast
One cannabis brownie after Yes VAS drug effect27
low-fat breakfast
20 mg/mL THC extract in Not reported Not reported
95% ethanol diluted in
water; fasted 8 h before
dosing
20 mg dronabinol capsules Yes VAS intoxication
or 200 mL decoction
containing medium or
high dose THC
One dose cannabis extract Not reported Not reported
after low-fat breakfast
Ethanolic THC extract, 4 h Not reported Not reported
fast before dosing
Ethanolic THC extract, 4 h Not reported Not reported

440
FREQ and 10 occasional fast before dosing
cannabis users ( £ 2 · /
month)
Newmeyer et al. (2016)26 OCC 9 Occasional ( ‡ 2 · /month 0 or *50.6 mg THC Single-dose within-subject One cannabis brownie after Yes Yes44
Newmeyer et al. FREQ and < 3 · /week) and 11 crossover low-fat breakfast
(2017b)44 frequent cannabis users
Newmeyer et al. ( ‡ 5 · /week)
(2017c)45
Abulseoud et al.
(2017)46
Farokhnia et al.
(2020)47
Vandrey et al. (2013)36 FREQ 11–13 Daily cannabis 0, 30 mg/day (10 mg tid), Multiple-dose within-subject Dronabinol at 9:00, 14:00, Yes Not reported
Lee et al. (2013)71 smokers ( ‡ 25 60 mg/day, (20 mg tid), or crossover and 19:00 each day for 5
Milman et al. (2014)72 days/month for prior 3 120 mg/day (40 mg tid) days
Lee et al. (2015)73 months) THC
Lile et al. (2013)30 FREQ 7 Adults (3 F), mean 4.8 0, 15, 30, 45, 60, 75, or 90 mg Intra-subject dose escalation Single ascending 15–90 mg Yes Yes
uses/week THC doses after low-fat snack
37
Lile et al. (2011) FREQ 6 Adults (3 F), mean 5.3 0, 5, 15, or 30 mg THC Drug discrimination THC discrimination learned Not reported Yes
uses/week followed by single-dose with 30 mg followed by
crossover test of 0, 0, 5, 15, and
30 mg; fast 4 h before
dose

(continued)
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Table 1. Continued

Formulation and dose

References Use Population Dose Study design condition PK data VAS high

Lile et al. (2012a)38 FREQ 8 Adults (2 F), mean 6 0, 5, 15, or 30 mg THC Drug discrimination THC discrimination learned Not reported Yes
uses/week followed by single-dose with 30 mg followed by
crossover test of 0, 0, 5, 15, and
30 mg; fast 4 h before
dose
Lile et al. (2012b)39 FREQ 8 Adults (3 F), mean 4.5 0, 5, 15, or 30 mg THC Drug discrimination THC discrimination learned Not reported Yes
uses/week followed by single-dose with 30 mg followed by
crossover test of 0, 0, 5, 15, and
30 mg; fast 4 h before
dose
Lile et al. (2014)40 FREQ 10 Adults (4 F), mean 5 0, 5, 15, or 30 mg THC Drug discrimination THC discrimination learned Not reported Yes
uses/week followed by single-dose with 30 mg followed by
crossover test of 0, 0, 5, 15, and
30 mg. Fast 4 h before
dose

441
Schoedel et al. (2011)29 FREQ Adults ‡ 1 use/week, 0, 20, 30, or 40 mg THC Qualification phase followed Qualification phase: 30 mg Yes Yes
qualification phase by single-dose crossover dronabinol or placebo;
(N = 58) and test phase test phase: 1 dose of
(N = 30) placebo, 20 and 40 mg
dronabinol
Budney et al. (2007)43 FREQ 6 M and 2 F adults, ‡ 25 use 0, 30 mg (10 mg/tid), or Multiple-dose within-subject Dronabinol 5 h apart (e.g., 9 Not reported Not reported
days/month 90 mg (30 mg/tid) THC crossover am, 2 pm, and 7 pm for 5
days)
Jones et al. (1976) FREQ 53 M adults, daily users 10 mg escalation every 4 h Multiple-dose crossover with THC or crude cannabis Not reported Yes
for 1–5 days, followed by escalation extract every 4 h (8 am, 12
30 mg THC every 4 h for pm, 4 pm, 8 pm, midnight,
11–21 days, with and 4 am)
additional 30 mg dose at
bedtime for 21 subjects

F, female; FREQ, frequent cannabis users ( ‡ 3 times per week); M, male; NON, non-cannabis users (at least 1 month break since last use); OCC, occasional cannabis users ( ‡ 2 times per month but
< 3 times per week); PK, pharmacokinetic, THC, D9-tetrahydrocannabinol; VAS, visual analog scale.
 442 ROZANC ET AL.
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FIG. 2. Means of (a) plasma THC and (b) plasma 11-OH-THC Cmax by study and dose. The dashed line
represents the line of best fit. Note that y-axis scale is different between panels. 11-OH-THC, 11-hydroxy-
THC; THC, D9-tetrahydrocannabinol.

Subjective effects
Subjective effects are useful for tolerability interpreta-
tion since AEs are typically not expected in studies
where the overall THC effect is low. Ten of 17 high-
dose studies reported general subjective effects
(Fig. 3). Although the study by Jones et al. reported
VAS high, we excluded it from this analysis due to un-
clear reporting by dose level. We included subjective ef-
fects measured by VAS high, VAS drug effect, or VAS
intoxication. Generally, a dose-dependent increase in
maximum subjective effects was observed.
Nonusers and occasional users reported the highest max-
imum effects relative to frequent users at the similar dose
range. This is likely to represent tolerance to THC effects,
although an intrinsically decreased sensitivity to THC ef-
fects in frequent users cannot be entirely ruled out. Notable,
the maximum VAS scores in the study by Lile et al. did not
increase much with dose.30 This may be due to high toler-
ance in these participants (4.7 times per week on average),
or it may also be due to a dropout effect, as this study uti-
lized a dose escalation design instead of a crossover or par-
allel group design utilized in the other studies (Fig. 3).

FIG. 3. Means of maximum VAS values (high, intoxication, or drug effect) by study and dose. VAS drug
effect was reported by Vandrey et al. and Schlienz et al., VAS intoxication was reported by Ménétrey et al.,
whereas other studies reported VAS high. VAS, visual analog scale.
 TOLERABILITY OF HIGH-DOSE ORAL THC
Tolerability
Frequent cannabis use resulting in tolerance to THC ef-
fects is one of the major factors in determining high
THC dose tolerability.31–33 Therefore, we assessed tol-
erability by cannabis use level as defined earlier in
Study Characteristics section.
Non-cannabis users. Two studies with current non-
cannabis users tested cannabis brownies containing 0,
10, 25, or 50 mg THC.12,27 Participants had a history
of cannabis exposure but reported no cannabis use
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for at least 1–3 months before the study and provided
a negative urine test for recent cannabis use at screen-
ing and before each session. AEs included vomiting and
anxiety. Of 17 participants in the study, Spindle et al.
reported one participant vomited 2.2 h after ingesting
the 25 mg dose and another vomited twice after con-
suming the 50 mg dose (2.25 and 3 h after ingestion).12
Of 18 participants in another study, Vandrey at al.
reported 1 participant experienced anxiety *2 h after
ingestion of the 25 mg dose, and 2 participants vomited
*3 h after administration of the 50 mg dose.27 Vomit-
ing was transient and both participants reported feeling
relieved afterward.
Melges et al. investigated the effects of 20, 40, and
60 mg THC or placebo in eight participants with min-
imal cannabis experience and abstinence for at least 1
month.34 At higher doses, three participants experi-
enced panic reactions due to an overwhelming fear
that their loss of control and identity might be irrevers-
ible. In one specific case, a participant who received a
dose of 60 mg THC described their panic as feeling as
though they were ‘‘helplessly drifting forever.’’ More-
over, five participants reported temporary episodes of
heightened suspicion, which arose when they felt that
they no longer had control over their own thoughts
and actions. Consequently, these participants expressed
a sensation of being controlled by external forces or
individuals.
Occasional cannabis users. Ménétrey et al. studied
eight occasional cannabis smokers who were given pla-
cebo, 20 mg dronabinol, and two doses of THC (16.5
and 45.7 mg THC) in decoctions.28 Two participants
experienced psychiatric AEs, leading to their with-
drawal from the study. The first participant experi-
enced severe anxiety with paranoid feelings after
16.5 mg THC in a decoction, whereas the second par-
ticipant experienced anxiety with altered perception
of reality after taking 20 mg dronabinol.
443
All AEs resolved spontaneously within 1 day. Symp-
toms included grandiosity, agitation, hostility, unco-
operativeness, disorientation, hallucinatory behavior,
and unusual thought content. Gastrointestinal AEs
such as nausea and vomiting were also observed, par-
ticularly with 45.7 mg THC in a decoction. These ef-
fects were more pronounced when the active
cannabinoids reached their highest concentrations. It
was also notable that the mean 11-OH-THC Cmax
was twofold higher compared with those of similar
doses from other studies.
In contrast, Tinklenberg et al. found relatively mild
clinical effects of THC and no reported AEs in a
study involving 12 occasional cannabis users given
cannabis extract with 0.7 mg/75 kg (*49 mg) THC or
placebo.35
Frequent cannabis users. Schoedel et al. included a
qualification step requiring participants to discriminate
and show positive subjective effects after 30 mg oral
THC.29 Of 58 participants in the qualification step,
39 met the criteria and 30 were randomized to the
main study. No serious AEs were experienced with dro-
nabinol doses up to 40 mg. Most AEs were mild and re-
lated to study drug. One participant experienced
moderate AEs including somnolence after 20 mg dro-
nabinol, and moderate paranoia after treatment with
40 mg dronabinol. Euphoric mood was the most com-
mon AE across all treatments. Another participant was
discontinued prematurely due to mild tachycardia and
moderate paranoia after 40 mg dronabinol treatment.
In a cannabis withdrawal study with 11–13 frequent
cannabis users who received up to 120 mg/day (40 mg
tid) dronabinol, the treatment was well tolerated and
resulted in few AEs. Some reported AEs on a side effect
questionnaire included dry mouth, rapid heart rate,
and flushing in the face or body (Vandrey et al.).36
In a study by Lile et al., five of seven participants
completed a single-dose escalation from 15 to 90 mg
THC doses.30 However, one participant at the 30 mg
dose and another at the 60 mg dose experienced
dose-limiting nausea and vomiting, leading to discon-
tinuation. No other AEs were reported beyond the typ-
ical cannabis effects, which were captured by the PD
assessments.
In a series of drug discrimination studies, healthy
adults who used cannabis weekly (between 2 and 7
days per week) were administered oral THC (0, 5, 15,
and 30 mg). Participants first learned to discriminate
30 mg oral THC from placebo and were then asked
 444
to discriminate oral THC (0, 5, 15, and 30 mg) from
nabilone (0, 1, and 3 mg; N = 6),37 baclofen (25 and
50 mg; N = 8),38 tiagabine (6 and 12 mg; N = 8),39 and
diazepam (5 and 10 mg; N = 10).40 No safety and toler-
ability data were explicitly reported in these studies;
however, personal communication with the author in-
dicated that participants generally tolerated all THC
doses well. It should be noted that in the 2012b
study, there was one withdrawal due to tolerability
issues.
In a study by Lewis et al., 10 participants were occa-
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sional users ( £ 2 uses per month), and 10 participants
were frequent users ( ‡ 2 uses per week).41 All partici-
pants received 3 doses of THC (15, 30, or
45 mg/75 kg) and placebo in a randomized crossover
manner. No specific AEs were reported by the authors
beyond feeling high. It was assumed that all THC doses
were adequately tolerated since participants completed
all sessions.
In another study by Peters et al., 10 frequent ( ‡ 2
uses per week) and 10 occasional cannabis users
(twice per month) received 15, 30, or 45 mg/75 kg
THC or placebo.42 Participants reported instances of
vomiting, nausea, coldness, dizziness, tiredness, and
sweating. Owing to the severity of these autonomic ner-
vous system effects, the experimenters terminated fur-
ther participation by some participants.
In a study by Budney et al., eight frequent cannabis
users (at least 25 days per month) received 30 mg/day
(10 mg/tid) or 90 mg/day (30 mg/tid) THC dose.43 Of
the 21 Adverse Event Checklist items, only 1 item re-
lated to nervousness showed a significant effect. None
of the participants withdrew due to an AE, no AE re-
quired any treatment, and there was no serious AE.
Only one participant reported experiencing a severe
strange dream and feeling paralyzed during the 30 mg
condition; however, this effect did not reoccur during
the 90 mg condition, and the participant had reported
similar experiences in the past.
In a study involving 9 occasional and 11 frequent
cannabis users receiving *50.6 mg THC, no tolerabil-
ity data were reported.26,44–47 Of the 28 participants en-
rolled, 20 completed the study and were analyzed. Four
subjects withdrew for ‘‘medical reasons,’’ but no details
of whether these were related to an AE was provided.
Jones et al. designed a study to induce THC depen-
dence in 53 frequent users (most used cannabis
daily).48 Participants were initially given a placebo for
3–7 days, followed by a dose of 10 mg THC every 4 h,
which was increased to 30 mg THC every 4 h for a pe-
ROZANC ET AL.
riod of 1–5 days. Twenty-one subjects received an ad-
ditional dose of 30 mg THC before bedtime, reaching
a maximum dose of 210 mg THC per day. The fixed
dose of 180–210 mg per day was then continued for a
period of 11–21 days.
During morning interviews, subjects reported un-
usual symptoms or complaints, which were categorized
into pre-drug, early drug, late drug, and post-drug
phases. The percentage of subjects complaining of de-
creased appetite, restlessness, irritability, sweating,
feverish feeling, nausea, muscle spasms, tremulousness,
and abdominal distress increased from pre-drug to
early drug in a range of 2–17%, but most of these com-
plaints were diminished as the drug was continued.
Discussion
This review assessed the PK, subjective effects, and tol-
erability of high oral doses ( ‡ 30 mg) of THC in human
laboratory studies with the goal of providing guidance
to future high-dose studies, particularly for develop-
ment of ACI treatments. This guidance is important
not just from an ethical point of view for minimizing
distressing AEs, but also from a practical standpoint:
AEs such as severe anxiety, paranoia, or vomiting can
hamper completion of study assessments, leading to
data gaps. To date, no expert consensus has been
reached on an upper limit for THC doses. We presume
that this is because relatively few research groups have
performed high-dose studies. The vast majority of clin-
ical studies of oral THC utilized doses close to 10 mg.
The current development of therapies for ACI may
increase the number of upcoming high-dose THC
studies.
There is an ethical framework for exposing healthy
volunteers to research risks and potentially distressing
AEs (Wendler and Miller; Miller and Joffe;
Ró_zyńska).49–51 These ethical questions extend beyond
THC studies to human laboratory studies of other
intoxicating drugs. For example, human laboratory
studies were performed for studying treatments of
methamphetamine, cocaine, opioid, and benzodiaze-
pine intoxication.52–55 The central ethical question
around high-dose THC studies is how high of a dose
can be justified against the potential AEs.
The aim of ACI treatment studies in healthy volun-
teers is to replicate the symptoms seen in an emergency
room setting as closely as possible, which is accompa-
nied by induction of distressing AEs. However, this is
to some extent necessary to document the safety and ef-
ficacy of the ACI treatment. THC alone does not
 TOLERABILITY OF HIGH-DOSE ORAL THC
strongly affect vital functions and does not stop the
heart or respiration. However, the psychiatric nature
of the reported AEs, such as anxiety, paranoia, and
panic reactions (Melges et al.,34 Ménétrey et al.28), em-
phasize the need for a cautious approach with partici-
pant inclusion and monitoring in studies with high
THC doses, especially in individuals with heighted sus-
ceptibility to such reactions.
These include populations with risk factors for de-
veloping anxiety or psychosis. Although initiating a
long-term episode of psychosis is theoretically possible
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in susceptible participants, it is not clear that this could
happen from a single dose,56 and the risk can likely be
mitigated by excluding participants with risk factors for
psychosis. Furthermore, no long-term clinical effects
have been identified from a single THC dose.
Through the evaluation of 17 clinical studies encom-
passing 266 participants, we observed that high-dose
oral THC up to 50 mg appears to be adequately toler-
ated, with most AEs being mild to moderate and tran-
sient. Most AEs resolved spontaneously and did not
require treatment. Even doses as high as 90 mg were
tolerated in one study, although this was in a popula-
tion that appeared to have rather extreme tolerance,
as their VAS high scores were well below those
reported in other studies. In general, the tolerability
profile of doses higher than 50 mg could not be ade-
quately evaluated since these doses were used in so
few studies.
Tolerance
Overall, high-dose THC studies suggest that tolerability
varies among non-cannabis users, occasional cannabis
users, and frequent cannabis users. AEs were generally
mild and transient, including vomiting, anxiety, and
heightened suspicion in non-cannabis users. Similarly,
occasional users experienced some psychiatric and gas-
trointestinal AEs, whereas frequent cannabis users dis-
played the highest tolerability to high THC doses, with
AEs being less severe and less frequent compared with
non-cannabis and occasional cannabis users.
These findings are consistent with the extensive liter-
ature on the development of tolerance to the effects of
THC.31–33 Importantly, there are some limitations to
this approach for the translatability between study pop-
ulations and the general population. One is that the cat-
egories defining cannabis use frequency are often broad
and unclear. For example, frequent users are some-
times defined as those consuming cannabis at least
once per week,29,31,38–40 even though tolerance is likely
445
to be different between someone using once per week
and once per day.
Furthermore, participants with frequent cannabis use
may differ not just in tolerance to THC, but also have an
intrinsic difference in how they respond to THC, owing
to factors such as differing genetics, brain chemistry,
hormones, or body composition.5,57–59 Thus, significant
inter-subject variability in THC effects should be
expected even after controlling for differences in toler-
ance. Even considering these limitations, the design of
future high-dose THC studies must carefully consider
the selection of participants based on their current
level of cannabis use.
Pharmacokinetics
Despite experiencing less intense subjective effects and
fewer AEs, participants with higher tolerance generally
had similar plasma exposure after oral dosing.26,44 PK
data revealed that plasma Cmax values for THC, but
not its active metabolite, increased greater than dose-
proportionally. We cannot be sure that this trend is
real since it was a pooled analysis where studies had
varying formulations, dosing conditions, subjects, and
PK sampling. Significant variability in the typical
Cmax at equivalent doses was observed between various
studies, potentially contributing to differences in toler-
ability. Oral THC absorption is highly influenced by
food, particularly by a high fat meal, which can slow
gastric emptying and reduce THC metabolism to the
11-OH-THC metabolite.60–62
THC taken with food may be better tolerated than
under fasted conditions, as one study observed a
greater number of AEs after 10 mg THC administered
under fasted conditions compared with the fed state.60
The differing food conditions in the studies we evalu-
ated may have contributed to the extensive PK variabil-
ity observed, and also affected tolerability. Similarly,
THC formulation may affect PK and tolerability. Dif-
ferent types of lipids, for example, can affect cannabi-
noid bioavailability and rate of absorption.63,64
Considering the aforementioned, plasma PK should al-
ways be assessed in high-dose THC studies if possible.
Study designs to reduce AEs
Various study designs have been employed to reach
higher doses in the THC studies in the current analysis.
One method is intra-subject dose escalation, in which
the THC dose is gradually increased over several visits,
as was performed by Lile et al.30 Participants who do
not tolerate a given dose can stop escalation, whereas
 446
participants who adequately tolerate it can continue to
a higher dose. Limitations of this design include its
time-consuming nature, potential participant dropout
with repeated visits, and the potential for AEs even at
low doses in particularly sensitive participants. A qual-
ification phase is another approach that was utilized by
Schoedel et al.29
During this phase, individual participant THC toler-
ance was assessed, ensuring their suitability for the
high-dose study. However, the qualification phase
may introduce selection bias and thus reduce general-
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izability, and even with this design, there is still a risk
of AEs at higher doses. An alternative approach in-
volves interviewing participants about their past canna-
bis use and experience to personalize their dose level, as
done by Gilman et al.16 This personalized dosing may
help limit unexpected AEs by considering individual
tolerance levels, rather than depending on broad cate-
gories (occasional user, frequent user, etc.).
However, individualized dosing depends on the ac-
curacy of self-reports and changes in tolerance over
time need to be considered, as well as differences in for-
mulations or route of administration. Although a full
discussion of inhaled and intravenous infusion dosing
is out of the scope of this review, these methods
allow dose titration, which can potentially reduce
AEs. Furthermore, the duration of an AE is likely to
be shorter with these routes of administration com-
pared with oral dosing. Finally, rescue medications
such as benzodiazepines for emergency treatment of
anxiety or agitation can be specified in the protocol.
Limitations
Several limitations must be considered for our analysis
in addition to the factors already discussed earlier. The
17 studies included in our review were typically small,
with an average of *10 participants per treatment
group. There was significant variation in the study
designs. Most of the studies were blinded and placebo-
controlled, with either a single-dose crossover or parallel
group design. However, one study utilized an escalating
dose design, another used a qualification phase to en-
sure that participants showed positive subjective ef-
fects. Thus, the results may have been influenced by
participants dropping out for inadequate response or
lack of tolerability.
Nine studies that tested high-dose THC were not
included in the analysis because they did not report suffi-
cient details of AEs, such as at which doses they occurred.
Even many of the included studies lacked useful details
ROZANC ET AL.
such as the timing and severity of AEs. Ideally, all studies
would have included THC and 11-OH-THC PK and PD
data on subjective effects. However, the majority of stud-
ies lacked one or both. Although most studies included
males and females, they did not report AEs by sex.
This is understandable considering the small sample
sizes, yet there are reports that tolerability may differ be-
tween males and females.12,57,65,66 These limitations
made it challenging to compare results across studies
and draw definitive conclusions.
Conclusion
From the studies evaluated, high-dose oral THC of at
least 50 mg is adequately tolerated in a controlled lab-
oratory setting in healthy participants with past canna-
bis experience. Any future studies should consider the
following points:
 Individual tolerance levels, past use experience,
THC formulation, and food play a pivotal role
in determining the intensity of subjective THC ef-
fects and AE potential.
 Any study utilizing high-dose oral THC should
carefully select the relevant study population, op-
timal dose for this population, employ strategies
to minimize the likelihood and impact of AEs,
and consider the ethical balance between potential
subject distress and study objectives.
 It is recommended to include assessments of PK
and general subjective effects, which help in the
interpretation of AEs.
 All publications should report in detail the level of
recent cannabis use and any THC-related AEs,
which were often missing from past reports.
Acknowledgment
The authors thank Milica Brankovic for editorial
assistance.
Authors’ Contributions
All authors contributed to the conceptualization, anal-
ysis, writing, and review of this article.
Author Disclosure Statement
M.T. and L.K. are owners of Verdient Science LLC. J.R.
is a consultant for Verdient Science LLC. M.A.H. has
no conflicts of interest.
Funding Information
This study was not supported by any funding.
 TOLERABILITY OF HIGH-DOSE ORAL THC
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Cite this article as: Rozanc J, Klumpers LE, Huestis MA, Tagen M
(2024) Tolerability of high-dose oral D9-THC: implications for human
laboratory study design, Cannabis and Cannabinoid Research 9:2,
437–448, DOI: 10.1089/can.2023.0209.
Abbreviations Used
11-OH-THC ¼ 11-hydroxy-THC
ACI ¼ acute cannabinoid intoxication
AE ¼ adverse event
F ¼ female
FREQ ¼ frequent cannabis users
M ¼ male
NON ¼ non-cannabis users
OCC ¼ occasional cannabis users
PD ¼ pharmacodynamics
PK ¼ pharmacokinetic
THC ¼ D9-tetrahydrocannabinol
VAS ¼ visual analog scale