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Associations between classic psychedelics and nicotine dependence in a nationally representative sample

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Abstract

Tobacco use is the single largest cause of preventable death worldwide, but none of the established treatments aimed at smoking cessation work for a majority of smokers. As such, there is an urgent need for interventions capable of reliably treating nicotine addiction. The use of classic psychedelics has been associated with lower odds of many forms of substance dependence. Here we tested whether lifetime use of classic psychedelics (tryptamine, lysergamide, and phenethylamine) is associated with lower odds of current nicotine dependence. We tested these associations in a sample of 214,505 adult participants in the National Survey on Drug Use and Health (2015–2019) using multivariable logistic regression models. Lifetime psilocybin use was associated with reduced odds of odds of current nicotine dependence (aOR 0.87–0.93). Lifetime use of peyote and mescaline also conferred reduced odds of multiple subdomains of a main nicotine dependence measure (Nicotine Dependence Syndrome Scale [NDSS]) (aOR 0.79–0.91). Conversely, lifetime use of LSD was associated with increased odds of nicotine dependence (aOR 1.17–1.24). Psilocybin, mescaline, and peyote use are associated with lowered odds of nicotine dependence. Experimental studies are needed to establish whether these associations are causal. These results make the case for further research into the efficacy of both tryptamine and phenethylamine psychedelics in promoting smoking cessation.
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Associations between classic
psychedelics and nicotine
dependence in a nationally
representative sample
Grant Jones1*, Joshua Lipson2 & Matthew K. Nock1
Tobacco use is the single largest cause of preventable death worldwide, but none of the established
treatments aimed at smoking cessation work for a majority of smokers. As such, there is an urgent
need for interventions capable of reliably treating nicotine addiction. The use of classic psychedelics
has been associated with lower odds of many forms of substance dependence. Here we tested
whether lifetime use of classic psychedelics (tryptamine, lysergamide, and phenethylamine) is
associated with lower odds of current nicotine dependence. We tested these associations in a sample
of 214,505 adult participants in the National Survey on Drug Use and Health (2015–2019) using
multivariable logistic regression models. Lifetime psilocybin use was associated with reduced odds
of odds of current nicotine dependence (aOR 0.87–0.93). Lifetime use of peyote and mescaline also
conferred reduced odds of multiple subdomains of a main nicotine dependence measure (Nicotine
Dependence Syndrome Scale [NDSS]) (aOR 0.79–0.91). Conversely, lifetime use of LSD was associated
with increased odds of nicotine dependence (aOR 1.17–1.24). Psilocybin, mescaline, and peyote
use are associated with lowered odds of nicotine dependence. Experimental studies are needed to
establish whether these associations are causal. These results make the case for further research into
the ecacy of both tryptamine and phenethylamine psychedelics in promoting smoking cessation.
Tobacco is the single largest cause of preventable death worldwide, killing 8.7 million people each year, a number
that continues to increase, despite the steady expansion of prevention measures across the globe1. In addition,
tens of millions of individuals suer from a range of avoidable respiratory, cardiovascular, and other illnesses as
a result of smoking tobacco, and over the past two years, studies have demonstrated that cigarette smokers are
more likely to be hospitalized or die from COVID-191. In the United States, 70% of current adult smokers say
that they want to quit, and in 2018, 55% reported attempting to quit at least once in the past year2,3. However, to
date, even the most eective pharmacological and behavioral smoking cessation treatments fail to promote long-
term abstinence in a large majority of people who use them4,5. e development of more eective, reliable, and
long-lasting smoking cessation treatments represents one of the most important health needs around the world1.
In recent years, researchers have begun to explore the use of classic psychedelics (Greek for “mind-manifest-
ing”), typically in the context of a psychotherapeutic framework, as a treatment for a host of dierent forms of
addiction and substance abuse, including addiction to smoking tobacco. Classic psychedelics are found in nature
or can be synthesized from natural compounds, and have been demonstrated to elicit mystical-type experiences
characterized by self-transcendent awe that can have lasting personal and spiritual signicance69. On a pharma-
cological level, they are dened by their agonist activity at the 5-HT2A receptor site10. Six of the main substances
included in this class are: the tryptamine psilocybin (the active component within “magic mushrooms”), the
phenethylamines peyote (a psychoactive cactus) and mescaline (the active compound within peyote), ayahuasca
(a psychoactive brew including Banisteriopsis caapi and Psychotria viridis), DMT (the active component within
ayahuasca), and lysergic acid diethylamide (LSD; synthesized from the ergot fungus).
Recent evidence has linked classic psychedelics to lowered odds of substance abuse and dependence. In a
sample of 44,678 respondents who reported lifetime use of illicit opioids in the National Survey on Drug Use
and Health (NSDUH), Pisano etal. (2017)found that psychedelic use was associated with 27% reduced risk
of past-year opioid dependence, and 40% reduced risk of past-year opioid abuse11. Smaller-scale attempts at
measuring the association between naturalistic use of classic psychedelics, on one hand, and misuse of other
OPEN
1Department of Psychology, Harvard University, 33 Kirkland St, Cambridge, MA 02138, USA. 2Teacher’s College,
Columbia University, New York, USA. *email: gmj005@g.harvard.edu
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addictive substances, including alcohol, cannabis, and stimulants, on the other, have yielded results suggesting
an association between psychedelic use and large-scale remission from abuse disorders12,13. In addition, recent
evidence has emerged to suggest that the naturalistic use of mescaline, specically, is associated with reductions
in the symptoms of alcohol and drug use disorders14.
Additionally, over the past decade, a line of research by Johnson and colleagues has suggested an association
between the use of classic psychedelics and smoking cessation in both experimental and naturalistic settings.
First, in an open-label pilot study that combined two or three doses of psilocybin with a program of cognitive
behavioral therapy (CBT) targeted at smoking cessation, Johnson etal. (2014)found that 12 of 15 (80%) partici-
pants met the criteria for smoking abstinence at 6-month follow-up15. In a follow-up study on psilocybin-assisted
smoking cessation therapy, Johnson etal. (2017a)identied a 67% rate of smoking abstinence at 12-month
follow-up, compared to a 31% rate of abstinence at 12months post-treatment for gold standard smoking cessa-
tion medications16. However, these researchers note their ndings are limited by the small size and homogeneity
of their sample.
Johnson etal.(2017b)complemented these experimental clinical data by examining the eects of psychedelics
on smoking behavior in a naturalistic context17. e authors recruited 358 individuals who reported having quit
or reduced smoking aer ingesting any psychedelic in a non-laboratory setting a year or more ago, and found
that at the time of survey, 38% of participants reported continuous smoking cessation, and an additional 28%
reported persistent reduction from pre-psychedelic smoking levels.
Despite the novel contribution Johnson etal. (2017b)makes to the literature, there are signicant limitations
to this study as well. e authors acknowledge the issue of selection bias, given that the survey was distributed
to websites visited by individuals interested in psychedelics (e.g., www. erowid. org, www. shroo mery. org). Addi-
tionally, the sample was considerably male-skewed, with only 15% of respondents identifying as female. eir
sample also was heavily skewed toward users of LSD and psilocybin, with only a small minority reporting use
of phenethylamine psychedelics.
e current study seeks to address the limitations of past studies by testing the associations between lifetime
use of classic psychedelics and current (past month) nicotine dependence using a large-scale nationally-repre-
sentative sample. Although such an approach cannot be used to infer a causal association between psychedelic
use and nicotine dependence, the large and representative nature of this sample allows us to glean critical insights
about the robustness of the associations between psychedelic use and nicotine dependence and to build on the
existing small-scale research on this matter.
Method
Sample. Data are from the National Survey on Drug Use and Health (NSDUH; 2015–2019) (unweighted
N = 214,505), a survey that assesses behavior, health, and substance use outcomes in U.S citizens ages 12years
and older. Currently incarcerated individuals, individuals experiencing homelessness, and active-duty military
service members are not included in the NSDUH. Given that data for this project are publicly available, this
study was determined to be exempt from review by the Harvard IRB. All study procedures were carried out in
accordance with the relevant guidelines and regulations.
Measures. Dependent variables. Our main dependent variables were two measures assessing past month
nicotine dependence within the NSDUH: composite scores on the Nicotine Dependence Syndrome Scale
(NDSS) and the Fagerstrom Test of Nicotine Dependence (FTND), recently renamed and known elsewhere as
the Fagerstrom Test of Cigarette Dependence (FTCD). e NSDUH NDSS composite measure is based on 17
questions that assess various aspects of nicotine dependence. Scores on each question ranged from 1 (not at all
true) to 5 (extremely true) (some items were reverse coded). e NDSS composite score represents the mean
of these 17 questions. Individuals were coded as past–month nicotine–dependent based on the NDSS if they
received a score of 2.75 or above on the composite NDSS measure. e NSDUH FTND measure, by contrast, is
based on a single criterion: whether one smokes within 30min of waking up. Individuals meeting this criterion
were coded as dependent based on the FTND.
In addition to estimating models based on these two composite scores, we also estimated models based on
subdomains of the NDSS. e NSDUH indicates that the 17 questions comprising the NDSS can be grouped
into ve subdomains: smoking drive (compulsion to smoke), nicotine tolerance, continuous smoking, behavioral
priority (prioritizing smoking over other reinforcing activities), and stereotypy (having xed smoking patterns).
us, we took the mean for all questions within each subdomain and rounded these values to the nearest integer
to create ordinal subdomain variables ranging from 1 (low dependence) to 5 (high dependence).
Independent variables/covariates. Our main independent variables were NSDUH items assessing lifetime use
(yes/no) of the following classic psychedelics: psilocybin, peyote, mescaline, and LSD. Additionally, to test the
specicity of any observed associations, we included as independent variables items assessing lifetime use of
various legal/medicinal and illegal substances: MDMA/ecstasy, heroin, PCP, inhalants, cocaine, pain relievers,
tranquilizers, stimulants, sedatives, and marijuana. Several sociodemographic variables were included as a priori
covariates: sex, age, race/ethnicity, marital status, income, educational attainment, and self-reported engagement
in risky behavior.
Analysis plan. We used multivariable logistic regression to assess the associations between each independ-
ent variable and the two main nicotine dependence measures (the NDSS and FTND composite variables). For
our rst and second models, we simultaneously entered all of our predictor variables, with the aim of gauging
their respective associations with the NDSS and the FTND composites, respectively.
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Additionally, given that our subdomain variables are scored ordinally, we ran ve ordinal logistic regression
models to test the associations between our predictor variables and each of the ve nicotine dependence sub-
domains of the NDSS. For each of these models, we simultaneously entered all of our predictor variables, and
examined their association with the given NDSS subdomain.
We used the ‘Survey’ package in R to incorporate the complex survey design and sampling weights of the
NSDUH into our models18. Additionally, we used the ‘lmtest’ package to conduct our signicance tests for the
ordinal logistic regression models in this study19, as the ‘Survey’ package does not generate p-values for this
class of models.
Results
Demographic dierences between those who do versus do not meet criteria for past-month nicotine dependence
are presented in Table1. Individuals with nicotine dependence were more likely to be divorced or never married,
less formally educated, younger, Non-Hispanic White, lower-income, and to report slightly more engagement
in risky-behavior.
Results from the logistic regression models testing the associations between lifetime use of all substances and
the NDSS and FTND composite measures are presented in Table2. As hypothesized, lifetime psilocybin use was
associated with lower odds of current (past month) nicotine dependence as measured by both the NDSS (aOR
0.90) and FTND (aOR 0.87). No other substances examined were associated with lower odds of these measures.
Several, including LSD, were associated with increased odds of nicotine dependence.
Results from the models testing the associations between lifetime substance use and the ve subdomains of the
NDSS are presented in Table3. Mescaline use was associated with lower odds of all ve subdomains of nicotine
dependence (aOR 0.79–0.86) and peyote use was associated with lowered odds of the nicotine tolerance (aOR
0.89) and continuous smoking (aOR 0.88) subdomains. Psilocybin use was associated with lower odds of the
behavioral priority subdomain (aOR 0.93). Aside from one instance of sedatives conferring decreased odds of the
stereotypy subdomain (aOR 0.93), all other substances were either not associated with nicotine dependence or
associated with increased odds of nicotine dependence. Additionally, each of the aforementioned demographic
covariates shared signicant, varying relationships to nicotine dependence across all of our models.
Discussion
e primary nding from this study is that the lifetime use of classic psychedelics (both tryptamine and pheneth-
ylamine) was associated with lower odds of current nicotine dependence as well as the sub-domains underlying
this construct. Psilocybin conferred lowered odds of both composite measures of past month nicotine depend-
ence in the NSDUH (the NDSS and the FTND), and peyote and mescaline conferred lowered odds of various
subdomains of the NDSS. Aside from a singular instance of sedatives conferring lowered odds of one nicotine
dependence subdomain, all other substances either shared no association with nicotine dependence or conferred
increased odds of nicotine dependent behavior.
Although these results cannot be used to infer a causal association, they document the robust association
between the lifetime use of psilocybin, peyote, and mescaline and the lowered odds of nicotine dependence.
Moreover, these results suggest the possibility that psychedelic use might also be protective against future nico-
tine dependence, beyond the single time point captured in the dataset we analyzed. ese results are timely, as
the National Institute of Health (NIH) recently funded a multi-site clinical trial testing psilocybin for treating
nicotine dependence20. at trial marks the rst time in 50years that the NIH is funding a trial involving psych-
edelics. is study further supports the need for trials that test the therapeutic ecacy of psilocybin, peyote, and
mescaline for treating nicotine dependence and potentially other substance use disorders as well.
ese ndings also are consistent with other population-based survey research on classic psychedelics sug-
gesting that naturalistic use of LSD in particular is associated with increased odds of adverse outcomes21,22, despite
evidence for LSD’s therapeutic ecacy under clinical administration23. Negative outcomes have been associated
with the use of some psychedelics, such as paranoia, stress, anxiety, and increased odds of psychosis24, and might
underlie the association between LSD use and increased odds of nicotine dependence. Additionally, it is possible
that LSD use in particular is confounded with other factors associated with nicotine dependence. Alternatively,
naturalistic use of LSD might be associated with dierent cultural framing and settings than naturalistic use of
psilocybin, accounting for a higher probability of adverse outcomes. Further investigation into the potentially
adverse eects of classic psychedelics, and the potential harm of LSD use in naturalistic contexts, is warranted.
Limitations. ese results should be interpreted in the context of several major limitations. First, these
results are based on cross-sectional data and cannot be used to draw causal inferences about the observed asso-
ciations. ird-variable factors and pre-existing dierences between those who have versus have not used psilo-
cybin, peyote, and mescaline very possibly contribute to the associations we observed. Longitudinal studies and
clinical trials are needed to better understand the temporal and causal associations between psilocybin, peyote,
and mescaline use and lowered odds of nicotine dependence. Additional investigations into potential third vari-
able factors can have the additional benet of identifying factors that may be protective against nicotine depend-
ence as well.
Second, the questions in the NSDUH are based on self-report, and thus, for substance use and nicotine
dependence questions, under-reporting may be a complicating factor in our analyses and conclusions. Future
studies that strictly monitor and observe substance use can address this limitation.
ird, this study cannot clearly establish that classic psychedelic use took place prior to the onset of nicotine
dependence, given the overlapping time horizons of these two measures. However, classic psychedelic use was
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assessed over an entire lifetime and nicotine dependence was assessed over the past month; hence, many indi-
viduals likely engaged in use of classic psychedelics prior to the onset of nicotine dependence.
Fourth, we cannot establish recency or frequency of classic psychedelic use in our study, given the binary
nature of our lifetime use variable. Nevertheless, causal interpretations of our ndings remain plausible despite
this limitation, as psilocybin has been shown to elicit lasting reductions in nicotine dependence aer just two
to three administrations16.
Fih, multicollinearity represents a possible limitation to our ndings. Multicollinearity refers to substantial
levels of correlation between independent variables; furthermore, multicollinearity increases the standard errors
within a given model and can thus result in unstable model estimates. Multicollinearity is primarily measured
Table 1. Demographic characteristics of those with and without nicotine dependence (ND). ND Nicotine
Dependence. 1 Chi-squared test with Rao & Scott’s second-order correction.
Characteristic Does not have ND (weighted %)
(N = 188,367) (%) Has ND (weighted %) (N = 26,138) (%) p-value1
Marital status < 0.001
Married 54 36
Widowed 6.0 5.5
Divorced or separated 13 24
Never been married 28 35
Education < 0.001
5th grade or lower 1.3 0.5
6th grade 1.2 0.4
7th grade 0.4 0.7
8th grade 1.0 1.9
9th grade 1.5 3.6
10th grade 1.7 5.0
11th or 12th grade 4.5 9.0
High school diploma/GED 23 37
Some college credit 21 24
As soci ate’s 9.4 8.2
Bachelor’s or higher 34 9.9
Age < 0.001
18–25 14 12
26–34 16 19
35–49 24 29
50+ 46 40
Sex < 0.001
Male 48 53
Female 52 47
Race < 0.001
Non-Hispanic White 63 74
Non-Hispanic Black 12 13
Non-Hispanic Native American/Alaska
Native 0.5 0.9
Non-Hispanic Native Hawaiian/Pacic
Islander 0.4 0.4
Non-Hispanic Asian 6.1 1.7
Non-Hispanic more than one race 1.6 2.7
Hispanic 17 8.0
Yearly household income < 0.001
< $20,000 15 29
$20,000–$49,999 29 36
$50,000–$74,999 16 14
$75,000 + 40 21
Self-reported engagement in risky behavior < 0.001
Never 56 48
Seldom 32 33
Sometimes 11 16
Always 1.2 2.8
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by Variance Ination Factors (VIFs) and a VIF above 10 indicates the presence of multicollinearity for a given
independent variable. We report the VIFs for the independent variables within our study in Supplemental Table1.
As indicated within this table, some of our independent variables have VIFs above 10, indicating that multicol-
linearity is present within our study. However, the impact of multicollinearity on our results is likely limited,
as our large sample size serves to minimize the impact that inated standard errors may otherwise have on the
integrity of our models25. Nevertheless, future studies can further address this limitation by using modeling
approaches such as ridge regression that are designed to handle multicollinearity.
Lastly, our approach to calculating p-values in this study features limitations as well. As previously indicated,
we used the ‘lmtest’ package to conduct Wald tests (quasi-t tests) and generate p-values for our ordinal regression
models19. However, one can plausibly conduct z-tests for the ordinal regression models within this study as well.
Table 2. Associations between lifetime substance use and two measures of nicotine dependence. Signicant
values conferring lowered odds of nicotine dependenceare in bold. 1 *p < 0.05; **p < 0.01; ***p < 0.001; aOR
adjusted odds ratio, CI condence interval.
Lifetime use
Nicotine dependence (NDSS) Nicotine dependence (FTND)
aOR (95% CI)1p-value aOR (95% CI) p-value
Psilocybin 0.90* (0.83, 0.98) 0.017 0.87* (0.78, 0.97) 0.021
Peyote 0.92 (0.77, 1.10) 0.310 0.99 (0.85, 1.16) 0.941
Mescaline 0.90 (0.75, 1.06) 0.178 0.88 (0.76, 1.02) 0.075
LSD 1.22*** (1.13, 1.32) 2.37e−04 1.17** (1.07, 1.28) 0.004
MDMA/ecstasy 1.13* (1.03, 1.24) 0.018 1.13* (1.03, 1.25) 0.017
PCP 1.17* (1.02, 1.34) 0.026 1.06 (0.93, 1.21) 0.316
Cocaine 1.56*** (1.47, 1.67) 6.41e−08 1.64*** (1.51, 1.78) 1.97e−07
Heroin 1.83*** (1.62, 2.07) 1.48e−06 1.89*** (1.69, 2.11) 4.20e−07
Inhalants 1.08 (0.99, 1.17) 0.064 1.00 (0.91, 1.10) 0.971
Pain relievers 1.28*** (1.19, 1.37) 2.74e−05 1.13*** (1.07, 1.19) 9.61e−04
Tranquilizers 1.20*** (1.13, 1.27) 6.83e−05 1.18*** (1.11, 1.26) 2.07e−04
Stimulants 0.99 (0.93, 1.06) 0.799 0.95 (0.88, 1.02) 0.148
Sedatives 1.10* (1.02, 1.19) 0.015 1.03 (0.95, 1.11) 0.397
Marijuana 3.03*** (2.80, 3.28) 1.44e−10 2.71*** (2.53, 2.90) 1.00e−10
Table 3. Associations between lifetime substance use and the ve NDSS subdomains. Signicant values
conferring lowered odds of nicotine dependenceare in bold. 1 *p < 0.05; **p < 0.01; ***p < 0.001, aOR adjusted
odds ratio, CI condence interval.
Lifetime use
Smoking drive Nicotine tolerance Continuous smoking Behavioral priority Stereotypy
aOR (95% CI)1p-value aOR (95% CI) p-value aOR (95% CI) p-value aOR (95% CI) p-value aOR (95% CI) p-value
Psilocybin 0.96 (0.90, 1.01) 0.170 0.96 (0.91, 1.02) 0.188 0.98 (0.92, 1.04) 0.475 0.93* (0.88, 0.99) 0.048 0.97 (0.91, 1.03) 0.335
Peyote 0.90 (0.81, 0.99) 0.061 0.89* (0.81, 0.98) 0.038 0.88* (0.80, 0.96) 0.022 0.91 (0.83, 1.00) 0.081 0.90 (0.82, 0.99) 0.058
Mescaline 0.82** (0.73,
0.92) 0.008 0.79** (0.72,
0.88) 0.002 0.84* (0.75, 0.93) 0.010 0.83** (0.74,
0.92) 0.008 0.86* (0.77, 0.95) 0.015
LSD 1.24*** (1.17,
1.32) 4.54e−05 1.21*** (1.14,
1.28) 1.61e−04 1.22*** (1.15,
1.29) 8.64e−05 1.21*** (1.14,
1.28) 1.09e−04 1.17*** (1.11,
1.24) 3.55e−04
MDMA/ecstasy 1.25*** (1.19,
1.32) 1.49e−05 1.32*** (1.25,
1.38) 1.57e−06 1.26*** (1.19,
1.33) 1.59e−05 1.23*** (1.17,
1.30) 1.90e−05 1.26*** (1.20,
1.31) 4.01e−06
PCP 1.01 (0.92, 1.12) 0.795 1.00 (0.91, 1.10) 0.954 1.01 (0.92, 1.11) 0.851 1.03 (0.94, 1.13) 0.521 1.03 (0.93, 1.13) 0.597
Cocaine 1.70*** (1.62,
1.79) 5.24e−09 1.68*** (1.60,
1.76) 3.50e−09 1.66*** (1.58,
1.74) 7.14e−09 1.67*** (1.60,
1.75) 3.61e−09 1.60*** (1.53,
1.68) 9.75e−09
Heroin 1.73*** (1.56,
1.93) 3.22e−06 1.70*** (1.54,
1.88) 2.72e−06 1.57*** (1.42,
1.73) 9.72e−06 1.51*** (1.36,
1.67) 2.38e−05 1.31*** (1.19,
1.44) 3.81e−04
Inhalants 1.03 (0.98, 1.10) 0.285 1.02 (0.96, 1.07) 0.599 1.00 (0.94, 1.06) 0.960 1.01 (0.96, 1.07) 0.643 0.96 (0.90, 1.02) 0.190
Pain Relievers 1.12*** (1.07,
1.16) 4.69e−04 1.11*** (1.07,
1.16) 7.16e−04 1.10** (1.06, 1.15) 0.002 1.09** (1.05, 1.14) 0.003 1.06* (1.02, 1.10) 0.024
Tranquilizers 1.17*** (1.12,
1.22) 5.98e−05 1.17*** (1.12,
1.21) 4.09e−05 1.14*** (1.09,
1.19) 2.58e−04 1.15*** (1.10,
1.21) 1.47e−04 1.10** (1.05, 1.15) 0.003
Stimulants 1.10*** (1.06,
1.14) 8.40e−04 1.11*** (1.07,
1.16) 5.11e−04 1.09** (1.05, 1.13) 0.002 1.10** (1.06, 1.14) 0.001 1.09** (1.05, 1.13) 0.002
Sedatives 1.00 (0.95, 1.05) 0.966 0.98 (0.94, 1.03) 0.427 0.98 (0.93, 1.02) 0.337 0.96 (0.92, 1.01) 0.163 0.93* (0.89, 0.97) 0.013
Marijuana 2.80*** (2.69,
2.91) 2.66e−12 2.80*** (2.69,
2.92) 2.45e−12 2.79*** (2.68,
2.90) 1.93e−12 2.78*** (2.66,
2.90) 3.53e−12 2.68*** (2.57,
2.79) 4.39e−12
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Z-tests are typically used when one is certain that their data are normally distributed, but can also be used for a
sample with an unknown distribution if the sample size is large, as is the case with our study26. For transparency,
we also report the p-values yielded from z-tests for our ordinal regression models in Supplemental Table2. As
one can see from this table, our pattern of results remain largely unchanged, regardless of the approach one takes
for signicance testing within this study.
Potential mechanisms. Several distinct pharmacological and psychological mechanisms may underlie
our observed ndings, if the associations reported above are indeed causal. e eects of psilocybin, peyote, and
mescaline on the serotonin system may mediate the link between these substances and lowered odds of nicotine
dependence. It is currently understood that these substances primarily act as serotonin (5-HT2A) receptor ago-
nists, binding to a site typically targeted by serotonin. It has been suggested that downstream changes in func-
tional connectivity, information processing, and neuroplasticity lead to psychedelic states of consciousness with
therapeutic potential2729. Aberrant serotonin neurotransmission is implicated in many elements of addiction,
including attentional and motivational biases and impulse control decits associated with compulsive substance
use3033. Accordingly, serotonergic pharmacological interventions have been proposed as a promising treatment
option for nicotine dependence as well34,35. Future research that deepens our knowledge of the serotonergic
eects of classic psychedelics may shed light on their potential role in treating nicotine addiction.
In addition, the spiritual experiences elicited by classic psychedelics, best characterized as experiences of
self-transcendent awe, represent a plausible core psychological mechanism mediating our associations. In the
open label trial of psilocybin for nicotine dependence conducted by Johnson etal.(2014), reductions in nicotine
dependence were signicantly correlated with measures of mystical experience on psilocybin session days, as well
as with retrospective ratings of the personal meaning and spiritual signicance of the psilocybin experience36.
Spirituality is oen linked with positive substance abuse recovery outcomes, more broadly3739. Additional inquir-
ies into the role of self-transcendent spiritual experiences in the alleviation of addiction can shed light on the
potential link between classic psychedelics and lowered odds of nicotine dependence.
ere are several other potential psychological mechanisms that may underlie our observed relationships as
well, many of which have been described by Bogenschutz and Pommy30. Classic psychedelics can cause lasting
improvements in mood and well-being6 that in turn may reduce the risk for addiction and relapse40,41. Psych-
edelics also may cause shis in personality traits that lead to downstream reductions in nicotine dependence as
well4244. e aforementioned changes elicited by psychedelic experiences (e.g. increases in mood and spirituality,
changes in personality) may also elicit increases in self-ecacy and motivation that further support reductions
in addictive behavior30,45. Importantly, these proposed mechanisms are preliminary, and additional research is
needed to help determine which factors mediate the link between use of classic psychedelics and lowered odds
of nicotine dependence.
Conclusion
is study provides preliminary evidence supporting the association between use of classic psychedelics of both
the tryptamine and phenethylamine classes, and lowered odds of nicotine dependence. Future clinical trials are
needed to test whether this link is causal. Additional inquiry may also identify mediators and third-variable
factors underlying our ndings, which may act as protective factors against nicotine dependence. is study
represents an important step toward understanding the link between use of classic psychedelics and smoking
behavior in a naturalistic, large-sample context, as well as incremental progress towards reducing rates of nicotine
addiction and stemming a signicant source of morbidity and mortality worldwide.
Data availability
e data supporting the ndings from this project are publicly available at the Substance Abuse & Mental Health
Data Archive (SAMHDA) at the following web address: https:// www. data les. samhsa. gov/.
Received: 14 November 2021; Accepted: 13 June 2022
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Author contributions
G.J. conceptualized the study, conducted the analyses, and contributed to manuscript draing. J.L. contributed
to manuscript draing and editing. Matthew Nock provided supervision, mentorship, and manuscript revisions.
Competing interests
e authors declare no competing interests.
Additional information
Supplementary Information e online version contains supplementary material available at https:// doi. org/
10. 1038/ s41598- 022- 14809-3.
Correspondence and requests for materials should be addressed to G.J.
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Background Suicide is one of the leading causes of death worldwide and rates within the United States have risen over the past two decades. Hence, there is a critical need for novel tools to treat suicidal ideation and related mental health conditions. 3,4-Methylenedioxymethamphetamine (MDMA)/ecstasy and classic psychedelics may be two such tools. Aims The aim of this study was to assess non-causal associations between MDMA/ecstasy and classic psychedelic use and psychological distress and suicide risk. Methods In this study, we examined the aforementioned associations among 484,732 adult participants in the National Survey on Drug Use and Health (2008–2019). Results Lifetime MDMA/ecstasy use was associated with reduced odds of past year suicidal thinking (10% reduced odds; odds ratio (OR) = 0.90; 95% confidence interval, CI = (0.84–0.97); p < 0.01) and past year suicidal planning (OR = 0.88; 95% CI = (0.78–0.99); p < 0.05). Furthermore, lifetime psilocybin use was associated with reduced odds of past month psychological distress (OR = 0.78; 95% CI = (0.73–0.84); p < 0.001) and past year suicidal thinking (OR = 0.90; 95% CI = (0.83–0.96); p < 0.01). Finally, lysergic acid diethylamide (LSD) was associated with increased odds of past year suicidal thinking (OR = 1.07; 95% CI = (1.00–1.15); p < 0.05). Conclusion MDMA/ecstasy and psilocybin use are associated with reduced odds of suicidal thinking and related outcomes—though experimental studies are needed to determine whether these associations are causal. These findings call for more research into the efficacy of MDMA/ecstasy and classic psychedelics for treating psychological distress and suicidal thoughts and behaviors, and for updated drug legislation that allows for further investigation into these substances.
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Mescaline is a naturally occurring psychoactive alkaloid that has been used as a sacrament by Indigenous populations in spiritual ritual and healing ceremonies for millennia. Despite promising early preliminary research and favorable anecdotal reports, there is limited research investigating mescaline’s psychotherapeutic potential. We administered an anonymous online questionnaire to adults (N = 452) reporting use of mescaline in naturalistic settings about mental health benefits attributed to mescaline. We assessed respondents’ self-reported improvements in depression, anxiety, post-traumatic stress disorder (PTSD), and alcohol and drug use disorders (AUD and DUD). Of the respondents reporting histories of these clinical conditions, most (68–86%) reported subjective improvement following their most memorable mescaline experience. Respondents who reported an improvement in their psychiatric conditions reported significantly higher ratings of acute psychological factors including mystical-type, psychological insight, and ego dissolution effects compared to those who did not report improvements (Cohen’s d range 0.7 – 1.5). Many respondents (35–50%) rated the mescaline experience as the single or top five most spiritually significant or meaningful experience(s) of their lives. Acute experiences of psychological insight during their mescaline experience were associated with increased odds of reporting improvement in depression, anxiety, AUD and DUD. Additional research is needed to corroborate these preliminary findings and to rigorously examine the efficacy of mescaline for psychiatric treatment in controlled, longitudinal clinical trials.